-
Review Article Open Access
Ash and Djouma. J Addict Res Ther 2011, S4 DOI:
10.4172/2155-6105.S4-003
ISSN:2155-6105 JART, an open access journal Behavioral
Pharmacology J Addict Res Ther
Galanin Receptors as Pharmacological Targets in the Treatment of
AddictionBelinda L. Ash and Elvan Djouma*
School of Public Health and Human Biosciences, Department of
Human Biosciences, La Trobe University, Bundoora, Victoria,
Australia
Keywords: Addiction; Alcohol; Anxiety; Depression;
Galanin;GALR1; GALR2; GALR3; Nicotine; Opiates
Abbreviations: 5-HT: Serotonin; Ach: Acetylcholine;ADH:
Antidiuretic Hormone; AMG: Amygdala; Arc: Arcuate Hypothalamic
Nucleus; BST: Bed Nucleus Of The Stria Terminalis; Cb: Cerebellum;
CeA: Central Amygdaloid Nucleus; CNS: Central Nervous System; CPu:
Caudate Putamen (striatum); DA: Dopamine; DRN: Dorsal Raphe
Nucleus; GABA: Gamma-AminoButyric Acid; GAL-KO: Galanin Knockout;
GAL-OE: Galanin Over-Expressing; GALR1: Galanin-1 Receptor; GALR2:
Galanin-2 Receptor; GALR3: Galanin-3 Receptor; HIP: Hippocampus;
HYP: Hypothalamus; IPSP: Inhibitory Post-Synaptic Potential; LC:
Locus Coeruleus; LH: Lateral Hypothalamus; MDS: Mesolimbic Dopamine
System; NA: Noradrenaline; NAc: Nucleus Accumbens; PAG:
Periaqueductal Gray; PFC: Pre-Frontal Cortex; PNS: Peripheral
Nervous System; PVN: Paraventricular Hypothalamic Nucleus; SN:
Substantia Nigra; TH: Thalamus; VTA: Ventral Tegmental Area; DMN:
Hypothalamic Dorsomedial Nucleus
IntroductionAlcohol has historically been consumed in ceremonies
and
celebrations, as an addition to meals to enhance enjoyment of
food [1], and has been used for its analgesic and sedative
properties [2]. For recreational purposes, alcohol is the most
widely used drug of choice in Australia, with an average of 7.2
litres consumed annually per person [3]. While the majority of
drinkers are not considered to be dependent on alcohol, the
prevalence of alcohol abuse is increasing at an alarming rate.
Approximately 10% of Australians self-report that they drink at
levels considered to be of risk to their health [4] and a similar
percentage consume alcohol on a daily basis [3]. In addition, the
abuse of other illicit substances in Australia is on the rise with
the number of cannabis- and amphetamine-related hospital admissions
increasing each year [5]. The social and economic burden of drug
abuse in Australia was estimated to be around $55.2 billion in
2004/05 [6] with alcohol accounting for a large $15.3 billion
portion of this figure [6]. What this figure does not represent is
the incalculable and devastating human cost in terms of lost lives
and drug-associated illness.
The prevalence and associated costs of drug use in Australia
is certainly not isolated but is comparable to that of the rest
of the world. The World Health Organisation reported that 5.4% of
the world’s annual burden of disease in 2010 was attributable to
the use of illicit drugs and alcohol [7]. Alcohol-use disorders are
more common worldwide than drug-use disorders, and in accordance,
there is a greater demand for medical treatment of alcohol-related
conditions [7]. Despite a wide range of prescription medications
being available to treat alcoholism and drug abuse, the problem of
alcoholism still persists due to such profound effects on the brain
and the wide range of symptoms that must be concurrently treated.
Chronic use of a drug promotes progressive and persistent neural
adaptation in the brain [8-11], which leads to changes in
behaviours that positively reinforce drug seeking, ultimately
leading to addiction.
Addiction is characterised by its stubborn persistence and
compulsive nature that drives the user to constantly secure and use
a drug, despite adverse consequences [12]. Common characteristics
of addiction include drug craving and a very high tendency to
relapse in response to stress or environmental drug-related cues
[8,11,13-16] for weeks or even years after withdrawal from the drug
[8,12,17].The issues of relapse and drug-craving represent a major
obstacleto treating addictions and developing new therapeutic
medicinesto successfully treat drug-dependence is challenging. To
date, theavailable treatments for drug-addiction remain somewhat
inadequatefor most individuals [18].
Over three decades of research has looked at how addictive
AbstractDrug and alcohol abuse present an ongoing problem from
both a financial and psychosocial perspective. As the
worldwide prevalence of drug-abuse grows, research into the use
of novel pharmacotherapies continues. Recently, the neuropeptide
galanin has been implicated in the rewarding effects of addictive
substances and drug-seeking behaviour. Galanin acts by binding to
three receptor subtypes, which are localised within many brain
regions that play a primary role in addiction. Consequently, this
paper sought to review the most recent literature with particular
interest in the role of galanin and its receptors in alcoholism,
drug-abuse and associated mood disorders. Further, we compile the
experimental findings that suggest a potential role for galanin and
its three receptor subtypes in the treatment of addiction and
drug-seeking behaviour. Of particular focus in this review is the
large amount of experimental evidence that supports an association
between the galanin-3 receptor, alcoholism and mood disorders.
Ultimately, further investigation of galanin receptors as potential
drug targets may contribute to the creation of new
pharmacotherapies for drug dependence.
*Corresponding author: Elvan Djouma, School of Public Health and
Human Biosciences, Department of Human Biosciences, La Trobe
University, Bundoora, Victoria, 3086, Australia, Tel: +61 3 9479
5005; Fax: +61 3 9479 5784; E-mail: [email protected]
Received November 14, 2011; Accepted December 16, 2011;
Published December 20, 2011
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Copyright: © 2011 Ash BL, et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source
are credited.
Journal of
Addiction Research & TherapyJournal
of A
ddictio
n Research &T herapy
ISSN: 2155-6105
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 2 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
drugs interact with the brain and lead to changes in the
circuitry involved in reward [for reviews see 13,15]. As our
understanding of the mechanisms behind drug abuse increase, new
pharmacotherapies targeted toward disrupting these mechanisms are
being developed. In recent years, the neuropeptide galanin and its
receptors have been identified as promising drug targets for the
treatment of addiction [19]. A large amount of pre-clinical
evidence highlights a potential therapeutic role for galanin in the
treatment of alcoholism. In terms of new pharmacological approaches
to the treatment of alcoholism, interventions should be targeted
at: (1) preventing or reducing consumption, (2) reducing the
symptoms experienced as a result of drug withdrawal, (3) preventing
relapse or (4) a combination of the above.
This review aims to evaluate the role of the neuropeptide
galanin and its receptors in the treatment of addiction and
drug-seeking behaviour with a focus on alcoholism. Thus, a greater
understanding of the actions of galanin in the brain may contribute
to the development of novel and effective pharmacotherapies for
addiction.
GalaninIntroduction to galanin
Galanin is a neuropeptide of 30 amino-acids in humans and 29
amino-acids in other species [20] which was first isolated from the
porcine intestine in 1980 [21,22]. Galanin has since been found in
many species including humans [23], primates [24], rodents [25,26]
and fish [27], suggesting that the protein has been well conserved
throughout the evolution of species. There have been many important
physiological functions identified for galanin, but of particular
relevance to this review are the higher functions of the brain that
contribute to addictive behaviour. Galaninergic mechanisms are
recognised as playing an important role in cognition, learning,
memory [21], anxiety and depression [28], as well as reward and
drug-seeking behaviour [29,30]. Brain regions that contribute to
these functions highly express the galanin peptide and have a high
density
of galanin binding sites, which provides an explanation as to
how galanin modifies these functions and behaviours.
Galanin is expressed in a wide range of tissues including the
brain, spinal cord and gut [20]. Centrally, the galanin peptide is
highly concentrated within particular brain regions, especially the
forebrain, hypothalamus (HYP), amygdala (AMG) and locus coeruleus
(LC) [25,31]; areas which contribute to learning, feeding and
emotion. Galanin is synthesised at very high levels in the dorsal
raphe nucleus (DRN) and the LC [32,33], as well as many
hypothalamic nuclei [34], again supporting a role for galanin in
feeding and emotion. In addition, the density of galanin binding
sites in these brain areas is high, which further validates galanin
receptors as a target for pharmacological modification of these
functions.
Distribution of galanin binding sites
Early studies by Kohler and colleagues using post-mortem human
brain and monkey brain revealed that 125I-galanin binding sites
were widely spread in a similar pattern throughout the brain in
both species [35,36]. High densities of receptors were widely
spread throughout the human forebrain, neocortex, anterior
hypothalamus, lateral hypothalamus (LH), bed nucleus of stria
terminalis (BST), preoptic area, perifornical area [35,36],
periventricular nucleus and medial hypothalamus [37], with a medium
density of galanin receptors found in the central and medial
amygdala nuclei [35] and regions of the hippocampus (HIP) [36].
Similarly, a high density of galanin binding sites were found in
hippocampal regions and the neocortex of the monkey brain [36].
Galanin binding sites, characterised by125I-galanin in the mouse
brain, were found to be highest in the nucleus accumbens (NAc),
caudate putamen (CPu), AMG, BST, ventral tegmental area (VTA), HYP,
LC, and DRN and widely throughout other brain regions at a lower
density [38]. The distribution of galanin receptors in the human
brain closely resembles that of the monkey brain [35,36] and even
the brains of rodents [25,39], which is important, due to the very
limited number of galanin mapping studies
Figure 1: Brain Galanin PathwaysGalaninergic projections (green
lines) and neurotransmitter co-localisation with galanin (***) in
the rat brain. Dopaminergic projections (red lines) to structures
of the me-solimbic dopamine system. [Brain template taken from 57].
5-HT, serotonin; ACh, acetylcholine; ADH, antidiuretic hormone;
AMG, amygdala; Arc, arcuate hypothalamic nucleus; Cb, cerebellum;
CPu, caudate putamen (striatum); DA, dopamine; GABA,
gamma-aminobutyric acid; Glu, glutamate; HIP, hippocampus; HYP,
hypothalamus; LC, locus coeruleus; NAc, nucleus accumbens; NA,
noradrenaline; PFC, pre-frontal cortex; PVN, paraventricular
hypothalamic nucleus; TH, thalamus; VTA, ventral tegmental
area.
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 3 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
that have used human brain tissue. Although brains of primates
and rodents are much smaller, the galanin receptor distribution
pattern closely resembles much of the distribution pattern found in
the more complex and larger human brain.
The aforementioned brain areas have been shown to have a role in
processes related to drug addiction such as feeding, reward,
reinforcement, emotion, stress, anxiety, learning and memory
consolidation [40-56]. Regions of the HYP that have previously been
shown to have a role in promoting feeding behaviour include the
preoptic area [50], perifornical area [41], LH [52,55] and PVN
(paraventricular hypothalamic nucleus) [41,48,55], while the
ventromedial HYP functions to decrease feeding behaviour as a
signal of satiety [40]. Both the BST and CeA (central amygdaloid
nucleus) have been shown to have a role in the reinforcement of
drug dependence [54,56]; with the medial nucleus of the AMG [42],
central nucleus of the AMG and BST of the AMG having an involvement
in stress and emotional responses [43,46,53]. Neurons projecting
from the BST to the VTA contribute to functions of reward [46,51]
and motivation [46]. The LH plays a role in mediating learning and
reward-seeking behaviours [44,45] and also stimulates food intake
[52]. The HIP is predominantly involved with the transformation and
consolidation of memories [47,49].
Due to the high density of galanin binding sites in areas of the
brain involved in learning, memory, reward and emotion along with
the high density of receptors in hypothalamic regions that control
feeding [55], it is to be expected that galanin would play a role
in feeding behaviour, with an extension to the consumption of
alcohol. In addition, the co-localisation of galanin with classical
neurotransmitters [32] in brain regions that mediate these
functions further supports a role for galanin in drug-abuse.
Galaninergic projections and neurotransmitter co-expression
within the brain
Figure 1 provides a schematic representation of galaninergic
pathways that interconnect regions of the brain discussed below in
relation to a role in addictive behaviours and drug dependence. In
addition, galanin is co-localised in many cases with commonly known
neurotransmitters, which are indicated in Figure 1.
The hypothalamus: Within the HYP, galaninergic projections exist
from the Arc (arcuate nucleus) to the PVN [58], two regions that
play a role in appetite and feeding behaviour. In the Arc, galanin
is co-expressed with two neurotransmitters well known to mediate
the physiological effects of alcohol, GABA (gamma-aminobutyric
acid) [32,59] and glutamate [60]. It is widely accepted that one of
alcohol’s many actions is to reduce excitatory transmission at the
glutamate receptor subtype NMDA (N-methyl-d-aspartate) [reviewed by
61], an effect which galanin may potentiate through an inhibitory
effect on glutamate release in the Arc [60]. A small proportion of
neurons in the Arc co-express galanin with DA (dopamine) [32,62],
where it is suggested that galanin may stimulate DA release [63].
DA is also co-expressed with galanin in the PVN [64] and galanin
injection (300 pmol) into the PVN of Sprague-Dawley rats has
previously been shown to increase the release of DA, ultimately
leading to an increase in feeding behaviour [65]. Galanin is also
positively related to NA (noradrenaline) in the PVN, as shown by
increased local levels of NA following galanin infusion (0.5
µg/min) into the PVN of Wistar rats [48]. Increased levels of NA in
the PVN are known to stimulate feeding behaviour, with or without
food available [66-68]. NA release in the
PVN is increased by galanin [48], which may ultimately stimulate
the consumption of alcohol due to its similarity with food in terms
of the energy content. In addition, galanin in the HYP has been
reported to increase DA release into the NAc [69], which
contributes to the pleasurable and rewarding effects that follow
drug consumption. The co-localisation of ADH (anti-diuretic
hormone) with galanin in hypothalamic neurons [37,70] is suggestive
of a role in water balance.
The co-existence of galanin with opioids in many hypothalamic
neurons [71] is of importance in establishing a link between
galanin, feeding behaviour and ethanol consumption. The mu-opioid
receptor antagonist, beta-funaltrexamine (20 nmol), when centrally
co-injected with galanin (0.03 nmol) is known to decrease
galanin-initiated feeding behaviour in chicks, which suggests that
galanin may act indirectly via the mu-opioid receptor to stimulate
food intake [72]. Likewise, it has been confirmed that ethanol
intake can be stimulated through microinfusion of the opioid
agonist, DAMGO (D-Ala2, NMe-Phe4, Glyol5-enkephalin; 0.25 µg), into
the NAc of Sprague-Dawley rats [73].
The locus coeruleus: Galanin is synthesised in very high levels
within the LC [74,75] and is highly co-expressed with NA in around
80% of neurons [25,32]. The activation of LC neurons is responsible
for providing a major source of noradrenergic innervation to many
forebrain structures, including some limbic regions [76].
Galaninergic neurons of the LC project mostly to the HYP [77] and
subregions such as the PVN [58], medial and lateral thalamus [78],
HIP [33,77] and to a lesser degree from the LC to the cerebral
cortex [77] and the VTA [76]. Galanin acts to hyperpolarise neurons
in the LC [79,80], most likely through binding to GALR1 or GALR3
[80], therefore inhibiting the release of NA to regions of the
forebrain [81]. This effect has been demonstrated using brain
slices in vitro [79,80] and also through an electrophysiological
study that reported the GALR1 to mediate an inhibitory effect on
the polarisation of LC neurons in vitro [82]. In addition to
modulating NA release to regions of the forebrain, galanin also
acts locally within the LC to inhibit the release of NA within the
LC [74,81,83].
The dorsal raphe nucleus: Galanin is synthesised in the DRN [32]
and co-expressed with 5-HT (serotonin) in around 40-60% of DRN
neurons [84,85]. Both the GALR1 [86] and GALR3 [87,88] subtypes are
present in the DRN and are known to mediate an inhibitory
relationship between galanin and 5-HT in which hyperpolarisation of
DRN neurons decreases the release of 5-HT [48, 89]. Galaninergic
neurons project from the DRN to the medial and lateral thalamus
[78] and regions of the cortex [77,90].
The amygdala: Galaninergic neurons project from the AMG to the
HYP via the stria terminalis [91] and research has shown that
galanin microinfusion (0.3 µl) into both the AMG and PVN increased
food intake in Sprague-Dawley rats [92]. In this study,
microinfusion of two galanin receptor antagonists, C7 and M40 (0.3
µl), ceased galanin-induced feeding, thereby confirming a role for
galanin in feeding behaviour via its action in the AMG [92]. The
neurotransmitter GABA also co-exists with galanin in the CeA [93],
which suggests a possible role for galanin in response to fear or
stress. Neurons of the BST have also been identified as sites that
release galanin in response to stress [94].
The hippocampus: Galanin and the neurotransmitter ACh
(acetylcholine) are co-expressed in the rat ventral hippocampus
[32], where galanin acts to inhibit ACh release [95]. High levels
of ACh in the HIP contribute to learning and memory consolidation
[96,97]. So
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 4 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
it is conceivable that galanin may interfere with memory
processes in drug addiction such as associative learning [for
review see 98].
The ventral tegmental area: It is speculated that galaninergic
projections exist from the LC to the VTA to modulate NA release in
the VTA [76]. This connection provides an important link between
galanin and the MDS (mesolimbic dopamine system), which plays a
crucial role in mediating addictive behaviours and reward following
consumption of drugs of abuse. NA in the VTA stimulates firing of
dopaminergic neurons that project to regions of the forebrain and
limbic structures [99] and it has been shown that galanin injection
(1 nmol) into the VTA increases DA accumulation in regions of the
CPu and NAc in Wistar rats [69].
The Mesolimbic Dopamine SystemGalanin and the mesolimbic
dopamine system
As previously mentioned, galanin modulates DA activity within
limbic regions. The MDS is often called the ‘reward circuit’ of the
brain because of the pivotal role it plays in the reinforcement of
pleasurable experiences. Both endogenous mediators and exogenous
substances
introduced into the body including foods, alcohol and other
drugs of abuse are capable of activating the MDS, and it is widely
accepted that this system plays a role in the habit-forming actions
of all drugs of abuse [12,100,101].
Figure 1 illustrates the regions of the brain that are involved
in reward function including the VTA, NAc and PFC (pre-frontal
cortex) [101]. Neuronal cell bodies located in the VTA produce DA
and project into the PFC, CPu and the NAc, with reciprocal
projections from the NAc to the AMG and other regions of the limbic
system [12,100,102]. The NAc is a critical site for reinforcing the
pleasurable sensations associated with alcohol and other drugs of
abuse [102,103], while the AMG plays a role in learning and
conditioned reward [15,104]. Projections from the LC to the VTA
provide a direct link for galaninergic innervation of the MDS via
the release of NA.
The MDS in food and alcohol consumption
The overlap in the role of circuits involving the HYP and the
MDS and their contribution to excess food and alcohol consumption
has recently been reviewed in detail [105]. Neuronal activity
in
Treatment / condition Dose / concentration Species Route of
adminis-tration
Physiological or behav-ioural effect
Primary target Reference
Galanin 1 and 3 nmol Sprague-Dawley rat Microinjection into the
third ventricle
Increase in voluntary ethanol consumption
[116]
M40 (non-selective galanin receptor antagonist)
1 nmol Sprague-Dawley rat Microinjection into the third
ventricle
Blocked galanin-induced increased in voluntary ethanol
consumption
[116]
Galanin 1 nmol Sprague-Dawley rat Microinjection into the
PVN
Increase in voluntary ethanol consumption
[126]
M40 (non-selective galanin receptor antagonist)
1 nmol Sprague-Dawley rat Microinjection into the PVN
Reversal of galanin-induced increase in voluntary ethanol
con-sumption
[126]
Ethanol 1.0 g/kg Sprague-Dawley rat Intraperitoneal
injection
Increased galanin pep-tide mRNA expression
Hypothalamic PVN [127]
Ethanol 0.8 g/kg Sprague-Dawley rat Intraperitoneal
injection
Increased galanin pep-tide mRNA expression
Hypothalamic DMN, PVN, PLH
[125]
SNAP 37889 (GALR3 antagonist) 30 mg/kg iP rat Intraperitoneal
injection
Decreased operant responding for ethanol
GALR3 [133]
Co-superfusion of galanin with ethanol
1 µM C57Bl/6J mouse Brain slices in vitro Increased IPSPs in CeA
neurons
GALR3 [132]
Co-superfusion of galanin with ethanol
1 µM C57Bl/6J mouse Brain slices in vitro Decreased IPSPs in CeA
neurons
GALR2 [132]
Co-superfusion of galanin with ethanol and SNAP 37889
1 µM; 200nM C57Bl/6J mouse Brain slices in vitro Prevented a
galanin-in-duced increase in IPSPs in CeA neurons
GALR3 [132]
Voluntary ethanol consumption 9% v/v (12 hour limited access
schedule for 28-30 days)
Sprague-Dawley rat Oral Increased galanin pep-tide
expression
Hypothalamic PVN [127]
Voluntary ethanol consumption 2% w/w (12 hour limited access for
5 days)
Sprague-Dawley rat Oral Increased galanin pep-tide
expression
Hypothalamic PVN [128]
Voluntary ethanol consumption 9% w/w (12 hour limited access for
20 days)
Sprague-Dawley rat Oral Increased galanin pep-tide mRNA
expression and increased galanin immunoreactivity
Hypothalamic PVN, DMN
[125]
Voluntary ethanol consumption 15% w/w (ad libitum access;
concentration incrementally increased over 16 days)
Male GAL-OE mouse Oral Increased voluntary ethanol intake and
increased preference for ethanol
[131]
Voluntary ethanol consumption 15% w/w (ad libitum access;
concentration incrementally increased over 16 days)
Male and female GAL-KO mouse
Oral Decreased voluntary ethanol intake and decreased preference
for ethanol
[130]
Abbreviations: GAL-KO, Galanin knockout; GAL-OE, Galanin
over-expressing.
Table 1: Experimental interactions between galanin,
galanin-receptor regulators and alcohol
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 5 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
mesocorticolimbic structures including the PFC, CPu and VTA was
reported to be greater in brains of heavy drinkers following
exposure to the taste of alcohol [106]. In addition, this study
also reported activation of the same MDS structures following the
taste of pleasant tasting non-alcoholic drinks such as fruit juice
[106]. This further provides evidence of a link between the
motivation to drink and brain structures that control drug-seeking,
which overlap with structures that control food intake and
nutrition. Repeated exposure to highly palatable food is thought to
be similar to repeated drug exposure in that both actions are
driven by the rewarding consequences that follow. In both
instances, neural circuits become sensitised and the reinforcing
effects of both food and drug intake increase DA in limbic regions
[reviewed by 107].
The reinforcing effects of dopamine
DA (dopamine) is one of the most important neurotransmitters
involved in the brain reward pathway and increased levels of DA in
the NAc are associated with the pleasurable effects experienced
following drug self-administration [12,101]. Another positive link
between food, alcohol and galanin, is that all three act to
stimulate the release of DA into the NAc [for review see 108].
Microinjection of galanin (300 pmol) into the NAc specifically
stimulates the release of DA in the NAc and decreases ACh release
in the NAc in Sprague-Dawley rats [65]. Increases in both DA and NA
concentrations in the VTA have been observed following alcohol
consumption in mice [109] and given that the main noradrenergic
input to the VTA comes from the LC, galanin may contribute
indirectly to an increase in alcohol consumption via this pathway.
Previous research has indicated a strong relationship between
galanin and DA, as injection of galanin directly into the PVN
increases DA release into the NAc [65]. DA is released by neurons
projecting from the VTA into the NAc, causing increased levels of
DA in the NAc [103,104]. DA antagonists injected
directly into the NAc reduce ethanol consumption in animal
models [for reviews see 110,111]. Indeed, evidence supports a
possible modulatory effect of galanin on DA release within limbic
regions, which may contribute to altered alcohol consumption.
Pre-Clinical Research into Galanin and AddictionTable 1
summarises the most important findings to date from
pre-clinical studies that have confirmed a link between galanin,
galanin receptors and alcohol consumption. Interactions between
other galanin, galanin receptors and other drugs of abuse,
including nicotine, opiates, cocaine and amphetamine are summarised
in Table 2.
Galanin and alcohol
Research into a proposed link between galanin and alcohol began
more than 20 years ago [112] but the first published study to
report a positive link between galanin and alcohol was in 2001 by
Hauge and colleagues [113]. An increased density of galaninergic
nerves (along with other neuropeptides) was reported in biopsies of
small intestine taken from chronic alcoholics, indicative of an
increase in galanin expression in response to heavy alcohol
consumption [113]. More recently, research has looked at the effect
of alcohol on galanin-serum levels in alcohol-dependent humans
[114] and it was reported that galanin serum levels were
significantly lower during the early stages of alcohol withdrawal
with the cause of this decrease remaining unexplained [114].
Galanin is known to have an orexigenic effect, more specifically
in fat intake and alcohol consumption [115]. A similarity between
these two macronutrients is their high kilojoule content but one
notable difference is that alcohol is also a drug of abuse. Unlike
other drugs of abuse, alcohol has a rich caloric content and is
therefore postulated to interact with regions of the brain involved
in the control of appetite
Treatment / condition Dose / concentration Species Route of
administration Physiological or behavioural effect
Primary target Reference
Galnon 0.5 mg/kg BXD mouse Intraperitoneal injection Reversed
nicotine withdrawal signs
[139]
Nicotine withdrawal (pre-cipitated by
mecamylamine-hydrochloride)
2 mg/kg BXD mouse Subcutaneous injection Increased GALR1
expression NAc [139]
Nicotine 0.01 ml/g GAL-KO mouse Intraperitoneal injection
Decreased sensitivity to nicotine [138]Morphine 20 – 100 mg/kg
Galanin-LacZ mouse Subcutaneous injection Increased galanin
expression LC [141]Opiate withdrawal (precipi-tated by
naloxone)
1 mg/kg GALR1-KO mouse Subcutaneous injection More severe
withdrawal signs than wild-type
GALR1 [141]
Opiate withdrawal (precipi-tated by naltrexone)
1 mg/kg C57Bl/6 mouse Subcutaneous injection Upregulation of
galanin binding and GALR1 mRNA
LC [142]
Galnon 2 mg/kg C57Bl/6 mouse Intraperitoneal injection Decreased
withdrawal symptoms and decreased preference for morphine
[143]
Opiate withdrawal (precipi-tated by naloxone)
1 mg/kg GAL-OE mouse Subcutaneous injection Increased withdrawal
signs of opi-ate withdrawal
[143]
Opiate withdrawal (precipi-tated by naloxone)
1 mg/kg GAL-KO mouse Subcutaneous injection Decreased withdrawal
signs of opiate withdrawal
[143]
Galnon 2 mg/kg GAL-KO mouse Intraperitoneal injection Blocked
cocaine-induced place preference
[145]
Cocaine 3 or 10 mg/kg GAL-KO mouse Intraperitoneal injection
Greater cocaine-induced increased place preference than
wild-type
[145]
Amphetamine 3 mg/kg GAL-KO mouse Injection Smaller increase in
amphetamine induced locomotor activity than galanin wild-type
[147]
Abbreviations: GALR1-KO, galanin-1 receptor knockout; GAL-KO,
Galanin knockout; GAL-OE, Galanin over-expressing.
Table 2: Experimental interactions between galanin,
galanin-receptor regulators and other drugs of abuse
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 6 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
and feeding [for reviews see 108,111,116]. Interestingly, the
brain mechanisms that stimulate the intake of fat and ethanol are
similar, and somewhat cross-over in their roles. The
mesocorticolimbic system, which is known to regulate the
consumption of drugs of abuse [117] is also implicated in feeding
behaviour [118,119], and likewise, the HYP which controls the
intake of food [120] is also involved in alcohol consumption [52].
Furthermore, galanin is known to modulate both general feeding
behaviour [65,121-123] and ethanol intake [116,124,125] via
pathways involving many sub-regions of the HYP. In accordance with
these findings, injection of galanin directly into particular
hypothalamic regions produced a stimulatory effect on voluntary
ethanol intake in Sprague-Dawley rats [116,126]. More specifically,
microinjection of galanin (1 nmol) directly into the third
ventricle [116] and the PVN [126] increased voluntary alcohol
consumption in Sprague-Dawley rats, an effect that was reversed
following administration of the non-selective galanin antagonist
M40 (1 nmol) [126].
Galanin peptide expression in the PVN [127,128] and the LH
[125,128] of Sprague-Dawley rats has been shown to increase
following voluntary ethanol consumption. Voluntary consumption of
2% w/w ethanol by Sprague-Dawley rats has also been shown to
increase galanin peptide expression in the PVN [128]. In humans, it
has been reported that alcohol-dependent individuals often obtain
30-50% of their daily energy intake from alcohol [129]. Galanin may
contribute to this through the development of a positive feedback
loop, by which alcohol consumption triggers an increase in galanin
production, which in turn induces an increase in alcohol intake.
The promotion of excessive drinking as a result of this mechanism
is suggested to be a factor that may contribute to a physical
dependence on alcohol [108]. Further support of a stimulatory
relationship between galanin and alcohol comes from studies that
have used transgenic mice that over-express galanin, or
alternatively have a deletion of the galanin gene. Previous
research has shown that galanin knockout mice show a significant
decrease in voluntary ethanol intake and preference for ethanol
when compared with wild-type mice [130]. In contrast, galanin
over-expressing mice have been found to have an increased intake
and preference for ethanol when compared with wild-types, further
suggesting that galanin plays a role in stimulating ethanol
consumption [131].
Electrophysiological studies in C57Bl/6J mice have shown that
galanin, when superfused with ethanol increases IPSPs (inhibitory
post-synaptic potentials) in a subpopulation of neurons within the
CeA, and decreases IPSPs within another subpopulation of CeA
neurons [132]. The differential effects are speculated to be due to
activation of two different receptor subtypes. It was proposed that
galanin may act post-synaptically in neurons of the CeA via GALR2
to decrease the size of IPSPs and also via GALR3 to enhance IPSPs
[132]. As previously noted, galanin is co-expressed with GABA in
the AMG, so this may ultimately lead to increased GABAergic
transmission in the CeA, which highlights a role for GALR3
antagonism and GALR2 agonism in the CeA to reduce the synergistic
interaction between galanin and ethanol [132].
Despite the large amount of evidence to support a role for
galanin in the modulation of ethanol consumption, the relationship
between alcohol and specific galanin-receptor subtypes has not been
studied in great detail. Our laboratory has shown that
administration of the selective GALR3 antagonist, SNAP 37889 (30
mg/kg, i.p.), decreased preference for ethanol in rats that had
been chronically drinking as part of a fixed-ratio operant model
[133]. More recently, we have shown that the same GALR3 antagonist
reduced the breakpoint for alcohol
under a progressive ratio schedule (Ash, et al. 2011;
unpublished data). This finding validates the GALR3 as a potential
target in the treatment of alcohol dependence and warrants further
research to elucidate the exact mechanism by which GALR3 antagonism
alters alcohol-seeking behaviour.
A recent genomic study looked at two polymorphisms in the
galanin transcriptional start site; of which the weaker and less
active allele is suggested to alter food and alcohol preference
[134]. A single-nucleotide-polymorphism in the GALR3 gene has been
strongly associated with alcoholism, while there was no correlation
found between alcoholism and the GALR1 or GALR2 gene [135]. This
provides further evidence that the GALR3 mediates actions of
galanin that contribute to alcohol dependence. The GALR3 gene has
also been implicated in susceptibility to alcoholism in various
populations of very different backgrounds in terms of ethnicity and
country of origin [136].
Galanin and nicotine
A correlation between a single-nucleotide-polymorphism of the
GALR1 gene in humans and self-reported tobacco cravings during a
recent smoking cessation study suggested a link between the GALR1
genotype and nicotine dependence [137]. Another recent study used
mice that lacked the galanin peptide gene to investigate the
relationship between galanin and nicotine-seeking behaviour in a
conditioned place preference paradigm [138]. These mice were found
to require administration of a higher dose of nicotine than galanin
wild-type mice to induce conditioned place preference [138],
indicating that galanin decreases sensitivity to the rewarding
effects of nicotine and possibly also promotes nicotine-seeking
behaviour. Contradictory findings were reported in a different
study where nicotine withdrawal signs in BXD mice, which had been
induced by the nicotinic receptor antagonist mecamylamine (2mg/kg,
s.c.), were reversed following administration of galnon (0.5mgl/kg,
i.p.), a non-specific galanin receptor agonist [139]. This study
reported an increase in GALR1 expression in the NAc in conjunction
with decreased galanin expression in the ventral midbrain of mice
that had displayed increased withdrawal symptoms [139].
Collectively, this data supports a role for galanin signalling in
protecting against nicotine dependence, which is possibly mediated
via GALR1. The role of galanin in nicotine dependence and
withdrawal has not been extensively studied and differences in the
findings of the above-mentioned studies could evidently be due to
variation in mice strains and the possible involvement of GALR2
and/or GALR3. Indeed, there is evidence of a role for galanin in
nicotine dependence and further research will provide insight into
the use of galanin receptors as potential drug targets for nicotine
dependence.
Galanin and opiates
A well established mechanism of addiction is the upregulation of
the cAMP messenger pathway following chronic administration of
drugs of abuse [9]. Upregulation of cAMP can indirectly contribute
to physical dependence, drug tolerance and withdrawal symptoms when
the site of cAMP upregulation projects to particular brain regions
that mediate physical dependence and withdrawal such as the LC and
VTA [9]. Chronic morphine administration in 129OlaHsd mice
increased cAMP activity and CREB phosphorylation [140]. Studies
have shown that galanin administration inhibits cAMP and decreases
CREB phosphorylation in the LC, which supports a role for galanin
agonists in opiate withdrawal [140]. Another study reported that
both morphine administration and withdrawal increased the
expression of
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 7 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
galanin within the LC of mice [141]. In addition, a positive
correlation was identified between increased galanin in the LC and
a reduction in withdrawal signs exhibited by the mice [141]. This
effect was suggested to be mediated through GALR1, as GALR1
knockout mice showed severe signs of withdrawal compared to
wild-type mice, while GALR2 knockout mice did not show a difference
in withdrawal signs when compared with their wild-type counterparts
[141]. Similarly, another study reported that opiate withdrawal in
C57Bl/6 mice resulted in an upregulation of both galanin binding
and GALR1 mRNA in the LC [142], further suggesting a role for GALR1
in opiate withdrawal.
In further support of a relationship between galanin and
opiates, another study reported that administration of galnon (2
mg/kg, i.p.), decreased preference for morphine and decreased
withdrawal symptoms from morphine in C57Bl/6 mice [143]. In
agreement with this finding, galanin over-expressing mice were
found to display increased withdrawal signs, while galanin knockout
mice displayed decreased signs of opiate withdrawal [143]. This
indicates that galanin acts to decrease behaviours relating to
opiate-dependence. In support of this finding, Wu and colleagues
found that there was a significant decrease in galanin-induced,
anti-nociceptive effects in morphine-tolerant rats, which further
implicates a role for galanin in morphine tolerance [144].
Galanin and cocaine
Only a smally number of studies that have looked at a role for
galanin in cocaine addiction. Cocaine has been shown to increase
conditioned place preference in galanin knockout mice compared with
galanin wild-type and this preference was reduced following the
administration of galnon [145]. In another study, cocaine-induced
hyperactivity was observed in both galanin wild-type and knockout
mice, however, administration of galnon failed to alter general
activity, which does not support a role for galanin in
cocaine-induced hyperactivity [146]. Furthermore, a different
experiment in the same study found that both wild-type and galanin
knockout mice acquired cocaine self-administration tasks, again
suggesting that galanin does not play a major role in
cocaine-seeking behaviour [146].
Galanin and amphetamine
One study looking at the role of galanin in relation to
amphetamine found that galanin over-expressing mice displayed a
smaller increase in locomotor activity that was induced by
amphetamine administration [147]. The connection between
amphetamine and galanin remains underexplored. Amphetamine and
cocaine are both classed as stimulants, so the lack of evidence of
a relationship with galanin would suggest that stimulant abuse may
be more strongly linked to other neuropeptides.
Roles for Individual Galanin Receptors in AddictionReceptor
functionality
Galanin exerts its effects via binding to one or more receptor
subtypes. In terms of receptor functionality, all galanin-receptor
sub-types are membrane bound G-protein coupled receptors but have
very different pharmacological profiles [20,148]. Galanin typically
acts as a neuromodulator at the pre-synaptic level, to inhibit the
post-synaptic release of neurotransmitters via the opening of
ATP-sensitive K+ (potassium) channels or closing of the Ca2+
(calcium) channels [95], however, some effects of galanin via GALR2
are of a stimulatory nature [88,132].
The GALR1 and GALR3 share similar signalling pathways in that
they are both coupled to Gi /Go-proteins to mediate an inhibitory
effect on neurotransmitter release via the inhibition of cAMP
turnover [20,149]. Activation of the GALR2 is associated with
coupling to Go/Gq which stimulates the turnover of inositol
phospholipid and increases intracellular levels of Ca2+ to mediate
a stimulatory effect on neurotransmitter release [88].
General patterns of receptor distribution
The unique distribution of galanin receptor subtypes (GALR1,
GALR2 and GALR3) through the central nervous system and periphery,
allows galanin to mediate a variety of physiological actions, with
some crossover due to localisation of multiple receptor subtypes
within the same regions [28]. Given that mRNA expression for the
subtypes is not necessarily reflective of the presence of the
receptor, the exact patterns of receptor distribution in the rat
brain remains undetermined. The lack of selective radioligands and
selective antibodies [150,151] for galanin receptors has meant that
mRNA expression has been relied upon in terms of speculating about
receptor distribution patterns; however, these reported patterns of
mRNA distribution have been fairly consistent with presumptions
made in the literature [38,150], along with confirmed
immunoreactivity in the mouse brain [38].
GALR1 distribution
GALR1 mRNA is found primarily in regions of the rat brain
involved with the processes of feeding, addiction, nociception and
memory [20]. According to multiple studies that have looked at
GALR1 mRNA expression in the rat brain, the general consensus is
that the PFC [152], some hippocampal regions, AMG [39,153], some
hypothalamic nuclei [39,86,152,153] and thalamic nuclei [152,153]
exhibit the highest levels of GALR1 mRNA expression, followed by
moderate levels within the LC [86,153] and DRN [86]. The pattern of
GALR1 immunoreactivity in the mouse brain, was largely reflective
of rat GALR1 mRNA distribution with the highest levels in the VTA,
SN (substantia nigra), LC, some hippocampal regions [38] and
moderate levels observed in the NAc, CPu, BST, AMG and hypothalamic
regions [38]. There is limited information available on GALR1 mRNA
distribution in the human brain, but what has been reported is high
GALR1 mRNA distribution in the PFC, AMG and SN [86]. GALR1 mRNA in
the human cortex [86] and ventral hippocampus [153] is supportive
of a role for the GALR1 in memory and learning processes. The high
distribution in the NAc highlights a possible role for GALR1 in DA
function. Early pre-clinical evidence exists for GALR1 mediation of
opiate withdrawal [reviewed by 154]. GALR1 immunoreactivity in the
NAc, VTA and SN was comparatively higher than GALR2 and GALR3
immunoreactivity [38] indicating a stronger role for drug-reward
mediated through GALR1 in these regions.
Early evidence exists for a stimulatory role of GALR1 in the
intake of food, as shown by increased consumption of high-fat milk
following administration of a selective GALR1 agonist in
Sprague-Dawley rats [155]. This opens the possibility of GALR1
antagonists for potential use in the treatment of alcoholism, given
the high energy content of alcohol and the previously described
regulatory role of the HYP on alcohol consumption. In addition, the
high density of GALR1 in the HYP validates further research into
the effect of GALR1 antagonism on ethanol consumption.
GALR2 distribution
GALR2 is the most abundantly distributed galanin receptor
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 8 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
within both the CNS (central nervous system) and PNS (peripheral
nervous system) [20]. In the rat brain, GALR2 mRNA is expressed at
the highest levels within regions of the HIP [156], followed by
moderate to high expression in the HYP [156] and the AMG [156-158],
and moderate expression in the PAG (periaqueductal gray) and
olfactory bulbs [159]. GALR2 immunoreactivity in the mouse brain is
very similar to that of rat, with high expression in hippocampal
regions, moderate expression in the PFC, HYP, AMG and PAG [38] and
lower levels reported in the LC, VTA and NAc [38]. Borowsky and
colleagues reported human GALR2 mRNA to be abundantly expressed in
the HYP and HIP [160] which is in agreement with GALR2 mRNA in the
rat and mouse brain [88]; however, the overall distribution pattern
differs greatly between rodents and humans. GALR2 seems to have
more importance in peripheral neuron functions according to the
high distribution of GALR2 in the PNS, relative to the CNS. Dense
expression of GALR2 is found within the heart, kidney, small
intestine, liver [160], injured bone [161], prostate, uterus,
ovary, pancreas, stomach and large intestine [156] indicating a
crucial role for the GALR2 in the regulation of cardiovascular,
neuroendocrine, bone remodelling, reproductive and digestive
functions.
Despite the large number of studies that have identified GALR2
mRNA within brain regions involved in addiction, it appears that a
possible relationship between GALR2 and addictive behaviours it yet
to be studied. Localisation of GALR2 within the HYP and HIP
supports a possible role in the modulation of feeding, learning and
memory, however we can only speculate about GALR2 involvement in
the modulation of addictive behaviours as a recent search of the
literature failed to find any evidence of a relationship between
the GALR2 and any drug of dependence.
GALR3 distribution
GALR3 mapping studies in the brain are limited in comparison to
GALR1 and GALR2 until recent years, due to a lack of GALR3
selective antibodies. GALR3 mRNA is highest in the rat brain within
the HYP, specifically detected in the ventromedial, dorsomedial,
paraventricular [87,162], Arc and supraoptic nuclei [162] which
strongly supports a major role for GALR3 in feeding behaviours.
High GALR3 mRNA expression has also been reported in the DRN, LC,
PFC [87,88] preoptic area, BST [87], olfactory bulb [149] various
hippocampal regions [162], and moderate expression in the CPu
[149,162], NAc, AMG, SN [162]. Mouse brain patterns of GALR3
immunoreactivity reflect that of rat GALR3 mRNA distribution with
high levels of expression reported in the SN, VTA, PAG, NAc, some
thalamic nuclei and moderate levels in the NAc [38]. Overall, the
distribution pattern of GALR3 in the brain suggests that major
physiological effects would be highly likely to include feeding,
reward, memory and emotion.
Galanin receptors make a good site for potential therapeutic
intervention in addiction as the normal inhibitory action of
galanin can be somewhat manipulated via GALR1 and GALR3; where the
role of these receptors in this context is supported by the
literature. Immunoreactivity for both the GALR1 and GALR3 in the LC
are very high in comparison to GALR2 [38], indicating a role in
noradrenergic transmission from the LC to regions of the forebrain.
The location of these two receptor subtypes shows that they are
well situated for inclusion in processes of motivation and
reward.
A Role for the Galanin-3 Receptor in Mood DisordersIn addition
to new therapies for addiction, many studies have
highlighted the potential for mood disorders, which often occur
co-morbidly with drug abuse, to be treated via the galanin system
[reviewed by 163], most likely via modulation of GALR3 function
[28,164]. The occurrence of mood-disorders in drug users is of
major concern, particularly depression [165,166] and anxiety [167],
for which the prevalence is reported to be significantly higher in
drug-dependent patients than the general population [168,169]. The
pattern of GALR3 distribution in areas involved with emotion such
as the LC [87,95,169] and AMG [162], along with the co-localisation
of galaninergic neurons with 5-HT in the DRN [32] suggests a role
for galanin via the GALR3 in aspects of mood disorders.
Early experimental animal models indicate that GALR3 may be an
effective target for reducing depressive and anxiety-like symptoms
[170,171]. In 2005, the first specific GALR3 antagonist that was
able to cross the blood brain barrier was synthesised [172] and
administered by Swanson et al. to examine the role of GALR3 in
behaviours related to anxiety and depression [167]. Two selective
GALR3 antagonists, SNAP 37889 and SNAP 398299, reduced anxiety and
depressive-like symptoms across a broad range of species [171].
Both of these GALR3 antagonists were found to have a very high
binding affinity for GALR3 and were highly selective for GALR3 over
GALR1 and GALR2 [171]. A different study using another novel GALR3
selective antagonist,
3-(3,4-dichlorophenylimino)-1-(6-methoxypyridin-3-yl)indolin-2-one,
also reported antidepressant-like effects in mice and rats in a
variety of behavioural paradigms [170]. Our laboratory has shown
that administration of the GALR3 antagonist, SNAP 37889 (30 mg/kg,
i.p.), did not alter anxiety-like behaviour in the elevated plus
maze and light-dark paradigms [133]. However, this finding should
not exclude the possibility of GALR3 as a target in the treatment
of anxiety and depression. Our study used a single dose to
primarily investigate the effect of GALR3 antagonism on alcohol
consumption, so it is feasible that alternative doses may have
altered anxiety and depressive-like behaviours. Overall, GALR3
antagonists appear to be a promising target in the treatment of
affective disorders that are often present in conjunction with
drug-abuse.
In terms of the role of GALR1 or GALR2 in anxiety and
depression, there is very little information to suggest a strong
role for these receptors in the mediation of mood-disorders. One
study reported that GALR1 did not play a role in mediating
depression in GALR1 receptor knockout mice as antidepressant
responses were unchanged in the tail suspension test [170]. A
literature search for the specific involvement of GALR2 did not
disclose any published findings to indicate a role for this
receptor in mood regulation.
ConclusionsThe distribution of galanin receptors and coexistence
of galanin
with classical neurotransmitters in brain regions involved in
addiction make the galanin system and its receptors viable targets
for addiction pharmacotherapy. Galanin appears to modulate a
drug-induced neurochemical response for a wide range of drugs of
abuse; however, the effect of galanin is not uniform for each class
of drug. Pre-clinical research indicates that galanin stimulates
alcohol-seeking behaviour, whereas galanin counteracts dependence
and withdrawal signs from opiates. Conflicting evidence exists as
to whether galanin has an inhibitory or stimulatory effect on
nicotine dependence. Furthermore, the treatment of co-morbid
affective disorders often associated with drug dependence may be
modulated via the galanin system.
The varied effects of galanin are suggested to be via the
activation
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 9 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
of different galanin-receptor subtypes, in particular, GALR1 and
GALR3. Pre-clinical research indicates that the modulation of
nicotine dependence and opiate withdrawal most likely occur via
GALR1 and alterations in alcohol-seeking behaviour and emotional
states via GALR3. In accordance with these findings, it is
appropriate to suggest that GALR1 agonists and GALR3 antagonists
may be favourable as novel treatments. Further understanding of the
relationship between galanin receptors and drugs of abuse will
provide the framework for developing effective therapies for
addiction.
References
1. Christmon K (1995) Historical Overview of Alcohol in the
African American Community. JBS 25: 318-330.
2. Roth T, Roehrs T, Zorick F Conway W (1985) Pharmacological
effects of sedative-hypnotics, narcotic analgesics, and alcohol
during sleep. Med Clin North Am 69: 1281-1288.
3. Australian Institute of Health and Welfare (2007) Statistics
on drug use in Australia 2006. Canberra: AIHW.
4. Australian Institute of Health and Welfare (2008) 2007
National Drug Strategy Household Survey: detailed findings.
Canberra: AIHW.
5. Roxburgh A Degenhardt L (2008) Characteristics of
drug-related hospital separations in Australia. Drug Alcohol Depend
92: 149-155.
6. Collins D, Lapsley H (2008) The costs of tobacco, alcohol and
illicit drug abuse to Australian society in 2004/05. Australian
Government Department of Health and Ageing, Canberra.
7. Rehm J, Patra J (2010) Chapter 1: Psychoactive substance use:
epidemiology and burden of disease. ATLAS on substance use (2010) -
Resources for the prevention and treatment of substance use
disorders. Geneva, Switzerland: World Health Organization,
2010.
8. Hyman SE (2005) Addiction: a disease of learning and memory.
Am J Psychiatry 162: 1414-1422.
9. Nestler EJ (2001) Molecular neurobiology of addiction. Am J
Addict 10: 201-217.
10. Nestler EJ, Aghajanian GK (1997) Molecular and cellular
basis of addiction. Science 278: 58-63.
11. Nestler EJ, Malenka RC (2004) The addicted brain. Sci Am
290: 78-85.
12. Stahl SM (2000) Essential Psychopharmacology. 2. Cambridge
University Press, Cambridge.
13. Everitt BJ, Robbins TW (2005) Neural systems of
reinforcement for drug addiction: from actions to habits to
compulsion. Nat Neurosci 8: 1481-1489.
14. Hyman SE, Malenka RC (2001) Addiction and the brain: the
neurobiology of compulsion and its persistence. Nat Rev Neurosci 2:
695-703.
15. Kalivas PW, O’Brien C (2008) Drug addiction as a pathology
of staged neuroplasticity. Neuropsychopharmacology 33: 166-180.
16. Liu X, Weiss F (2002) Additive effect of stress and drug
cues on reinstatement of ethanol seeking: exacerbation by history
of dependence and role of concurrent activation of
corticotropin-releasing factor and opioid mechanisms. J Neurosci
22: 7856-7861.
17. Berke JD, Hyman SE (2000) Addiction, dopamine, and the
molecular mechanisms of memory. Neuron 25: 515-532.
18. Nestler EJ (2002) From neurobiology to treatment: progress
against addiction. Nat Neurosci 5: 1076-1079.
19. Picciotto MR (2008) Galanin and addiction. Cell Mol Life Sci
65: 1872-1879.
20. Branchek TA, Smith KE, Gerald C, Walker MW (2000) Galanin
receptor subtypes. Trends Pharmacol Sci 21: 109-117.
21. Hokfelt T (2005) Galanin and its receptors: introduction to
the Third International Symposium, San Diego, California, USA,
21-22 October 2004. Neuropeptides 39: 125-142.
22. Tatemoto K, Rokaeus A, Jornvall H, McDonald TJ, Mutt V
(1983) Galanin - a novel biologically active peptide from porcine
intestine. FEBS Lett 164: 124-128.
23. Evans HF, Shine J (1991) Human galanin: molecular cloning
reveals a unique structure. Endocrinology 129: 1682-1684.
24. Evans HF, Huntley GW, Morrison JH, Shine J, Paxinos G (1992)
Localization of preprogalanin mRNA in the monkey hippocampal
formation. Neurosci Lett 146: 171-175.
25. Melander T, Hokfelt T, Rokaeus A (1986) Distribution of
galaninlike immunoreactivity in the rat central nervous system. J
Comp Neurol 248: 475-517.
26. Kaplan LM, Spindel ER, Isselbacher KJ, Chin WW (1988)
Tissue-specific expression of the rat galanin gene. Proc Natl Acad
Sci U S A 85: 1065-1069.
27. Mensah ET, Volkoff H, Unniappan S (2011) Galanin systems in
non-mammalian vertebrates with special focus on fishes. EXS 102:
243-262.
28. RM, Holmes A (2006) Galanin as a modulator of anxiety and
depression and a therapeutic target for affective disease. Amino
Acids 31: 231-239.
29. Robinson JK, Brewer A (2008) Galanin: a potential role in
mesolimbic dopamine-mediated instrumental behavior. Neurosci
Biobehav Rev 32: 1485-1493.
30. Brewer A, Echevarria DJ, Langel U, Robinson JK (2005)
Assessment of new functional roles for galanin in the CNS.
Neuropeptides 39: 323-326.
31. Skofitsch G, Sills MA, Jacobowitz DM (1986) Autoradiographic
distribution of 125I-galanin binding sites in the rat central
nervous system. Peptides 7: 1029-1042.
32. Melander T, Hokfelt T, Rokaeus A, Cuello AC, Oertel WH, et
al. (1986) Coexistence of galanin-like immunoreactivity with
catecholamines, 5-hydroxytryptamine, GABA and neuropeptides in the
rat CNS. J Neurosci 6: 3640-3654.
33. Melander T, Staines WA, Rokaeus A (1986) Galanin-like
immunoreactivity in hippocampal afferents in the rat, with special
reference to cholinergic and noradrenergic inputs. Neuroscience 19:
223-240.
34. Sweerts BW, Jarrott B, Lawrence AJ (1999) Expression of
preprogalanin mRNA following acute and chronic restraint stress in
brains of normotensive and hypertensive rats. Brain Res Mol Brain
Res 69: 113-123.
35. Kohler C, Chan-Palay V (1990) Galanin receptors in the
post-mortem human brain. Regional distribution of 125I-galanin
binding sites using the method of in vitro receptor
autoradiography. Neurosci Lett 120: 179-182.
36. Kohler C, Persson A, Melander T, Theodorsson E, Sedvall G,
et al. (1989) Distribution of galanin-binding sites in the monkey
and human telencephalon: preliminary observations. Exp Brain Res
75: 375-380.
37. Gai WP, Geffen LB, Blessing WW (1990) Galanin immunoreactive
neurons in the human hypothalamus: colocalization with
vasopressin-containing neurons. J Comp Neurol 298: 265-280.
38. Hawes JJ, Picciotto MR (2004) Characterization of GalR1,
GalR2, and GalR3 immunoreactivity in catecholaminergic nuclei of
the mouse brain. J Comp Neurol 479: 410-423.
39. Jungnickel SR, Gundlach AL (2005) [125I]-Galanin binding in
brain of wildtype, and galanin- and GalR1-knockout mice: strain and
species differences in GalR1 density and distribution. Neuroscience
131: 407-421.
40. Becker EE, Kissileff HR (1974) Inhibitory controls of
feeding by the ventromedial hypothalamus. Am J Physiol 226:
383-396.
41. Dailey MJ, Bartness TJ (2009) Appetitive and consummatory
ingestive behaviors stimulated by PVH and perifornical area NPY
injections. Am J Physiol Regul Integr Comp Physiol 296:
R877-R892.
42. Dayas CV, Buller KM, Day TA (1999) Neuroendocrine responses
to an emotional stressor: evidence for involvement of the medial
but not the central amygdala. Eur J Neurosci 11: 2312-2322.
43. Fekete EM, Zhao Y, Li C, Sabino V, Vale WW, et al. (2009)
Social defeat stress activates medial amygdala cells that express
type 2 corticotropin-releasing factor receptor mRNA. Neuroscience
162: 5-13.
44. Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral
hypothalamic orexin neurons in reward seeking. Nature 437:
556-559.
45. Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G
(2007) Lateral hypothalamic orexin neurons are critically involved
in learning to associate an environment with morphine reward. Behav
Brain Res 183: 43-51.
46. M, Aston-Jones G, Herzog E, Manzoni O, Georges F (2009) Role
of the
http://www.jstor.org/pss/2784640http://www.ncbi.nlm.nih.gov/pubmed/2866287http://www.ncbi.nlm.nih.gov/pubmed/17884302http://www.health.gov.au/internet/drugstrategy/publishing.nsf/Content/34F55AF632F67B70CA2573F60005D42B/$File/mono64.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/16055762http://www.ncbi.nlm.nih.gov/pubmed/11579619http://www.ncbi.nlm.nih.gov/pubmed/9311927http://www.ncbi.nlm.nih.gov/pubmed/14981881http://books.google.co.in/books?hl=en&lr=&id=_G0su6j9qqYC&oi=fnd&pg=PR11&dq=Stahl+SM+%282000%29+Essential+Psychopharmacology.&ots=o93QjR7zxR&sig=KocVlc6l1RLDB2aAeqmP-01Azbg#v=onepage&q&f=falsehttp://www.ncbi.nlm.nih.gov/pubmed/16251991http://www.ncbi.nlm.nih.gov/pubmed/11584307http://www.ncbi.nlm.nih.gov/pubmed/17805308http://www.ncbi.nlm.nih.gov/pubmed/12223538http://www.ncbi.nlm.nih.gov/pubmed/10774721http://www.ncbi.nlm.nih.gov/pubmed/12403990http://www.ncbi.nlm.nih.gov/pubmed/18500649http://www.ncbi.nlm.nih.gov/pubmed/10689365http://www.ncbi.nlm.nih.gov/pubmed/15908000http://www.ncbi.nlm.nih.gov/pubmed/6197320http://www.ncbi.nlm.nih.gov/pubmed/1714839http://www.ncbi.nlm.nih.gov/pubmed/1283450http://www.ncbi.nlm.nih.gov/pubmed/2424949http://www.ncbi.nlm.nih.gov/pubmed/2448788http://www.ncbi.nlm.nih.gov/pubmed/21299073http://www.ncbi.nlm.nih.gov/pubmed/16733616http://www.ncbi.nlm.nih.gov/pubmed/18632153http://www.ncbi.nlm.nih.gov/pubmed/15944029http://www.ncbi.nlm.nih.gov/pubmed/2436195http://www.ncbi.nlm.nih.gov/pubmed/2432203http://www.ncbi.nlm.nih.gov/pubmed/2431348http://www.ncbi.nlm.nih.gov/pubmed/10350643http://www.ncbi.nlm.nih.gov/pubmed/1705678http://www.ncbi.nlm.nih.gov/pubmed/2721615http://www.ncbi.nlm.nih.gov/pubmed/1698834http://www.ncbi.nlm.nih.gov/pubmed/15514977http://www.ncbi.nlm.nih.gov/pubmed/15708483http://www.ncbi.nlm.nih.gov/pubmed/4811195http://www.ncbi.nlm.nih.gov/pubmed/19193934http://www.ncbi.nlm.nih.gov/pubmed/10383620http://www.ncbi.nlm.nih.gov/pubmed/19358876http://www.ncbi.nlm.nih.gov/pubmed/16100511http://www.ncbi.nlm.nih.gov/pubmed/17599478http://www.ncbi.nlm.nih.gov/pubmed/19616054
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 10 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
bed nucleus of the stria terminalis in the control of ventral
tegmental area dopamine neurons. Prog Neuropsychopharmacol Biol
Psychiatry 33: 1336-1346.
47. Kim SM, Frank LM (2009) Hippocampal lesions impair rapid
learning of a continuous spatial alternation task. PLoS One 4:
e5494.
48. Kyrkouli SE, Strubbe JH, Scheurink AJ (2006) Galanin in the
PVN increases nutrient intake and changes peripheral hormone levels
in the rat. Physiol Behav 89: 103-109.
49. Nadel L, Moscovitch M (1997) Memory consolidation,
retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol
7: 217-227.
50. Patterson M, Murphy KG, Thompson EL, Smith KL, Meeran K, et
al. (2006) Microinjection of galanin-like peptide into the medial
preoptic area stimulates food intake in adult male rats. J
Neuroendocrinol 18: 742-747.
51. Puente N, Elezgarai I, Lafourcade M, Reguero L, Marsicano G,
et al. (2010) Localization and function of the cannabinoid CB1
receptor in the anterolateral bed nucleus of the stria terminalis.
PLoS One 5: e8869.
52. Schick RR, Samsami S, Zimmermann JP, Eberl T, Endres C, et
al. (1993) Effect of galanin on food intake in rats: involvement of
lateral and ventromedial hypothalamic sites. Am J Physiol 264:
R355-R361.
53. Walker DL, Toufexis DJ, Davis M (2003) Role of the bed
nucleus of the stria terminalis versus the amygdala in fear,
stress, and anxiety. Eur J Pharmacol 463: 199-216.
54. Walker JR, Ahmed SH, Gracy KN, Koob GF (2000)
Microinjections of an opiate receptor antagonist into the bed
nucleus of the stria terminalis suppress heroin self-administration
in dependent rats. Brain Res 854: 85-92.
55. Wang J, Akabayashi A, Yu HJ, Dourmashkin J, Alexander JT, et
al. (1998) Hypothalamic galanin: control by signals of fat
metabolism. Brain Res 804: 7-20.
56. Zhu W, Bie B, Pan ZZ (2007) Involvement of non-NMDA
glutamate receptors in central amygdala in synaptic actions of
ethanol and ethanol-induced reward behavior. J Neurosci 27:
289-298.
57. Paxinos G, Watson C (2005) The rat brain in stereotaxic
coordinates. Elsevier Academic Press,
58. Levin MC, Sawchenko PE, Howe PR, Bloom SR, Polak JM (1987)
Organization of galanin-immunoreactive inputs to the
paraventricular nucleus with special reference to their
relationship to catecholaminergic afferents. J Comp Neurol 261:
562-582.
59. Meister B, Hokfelt T (1988) Peptide- and
transmitter-containing neurons in the mediobasal hypothalamus and
their relation to GABAergic systems: possible roles in control of
prolactin and growth hormone secretion. Synapse 2: 585-605.
60. Kinney GA, Emmerson PJ, Miller RJ (1998) Galanin
receptor-mediated inhibition of glutamate release in the arcuate
nucleus of the hypothalamus. J Neurosci 18: 3489-3500.
61. Tsai G, Coyle JT (1998) The role of glutamatergic
neurotransmission in the pathophysiology of alcoholism. Annu Rev
Med 49: 173-184.
62. Chaillou E, Tramu G, Thibault J, Tillet Y (1998) Presence of
galanin in dopaminergic neurons of the sheep infundibular nucleus:
a double staining immunohistochemical study. J Chem Neuroanat 15:
251-259.
63. Sun YG, Gu XL, Lundeberg T, Yu LC (2003) An antinociceptive
role of galanin in the arcuate nucleus of hypothalamus in intact
rats and rats with inflammation. Pain 106: 143-150.
64. Meister B, Villar MJ, Ceccatelli S, Hokfelt T (1990)
Localization of chemical messengers in magnocellular neurons of the
hypothalamic supraoptic and paraventricular nuclei: an
immunohistochemical study using experimental manipulations.
Neuroscience 37: 603-633.
65. Rada P, Mark GP, Hoebel BG (1998) Galanin in the
hypothalamus raises dopamine and lowers acetylcholine release in
the nucleus accumbens: a possible mechanism for hypothalamic
initiation of feeding behavior. Brain Res 798: 1-6.
66. Hagemann LF, Costa CV, Zeni LZ, Freitas CG, Marino-Neto J,
et al. (1998) Food intake after adrenaline and noradrenaline
injections into the hypothalamic paraventricular nucleus in
pigeons. Physiol Behav 64: 645-652.
67. Leibowitz SF, Roossin P, Rosenn M (1984) Chronic
norepinephrine injection
into the hypothalamic paraventricular nucleus produces
hyperphagia and increased body weight in the rat. Pharmacol Biochem
Behav 21: 801-808.
68. Swiergiel AH, Peters G (1987) Injection of noradrenaline
into the hypothalamic paraventricular nucleus produces vigorous
gnawing in satiated rats. Life Sci 41: 2251-2254.
69. Ericson E, Ahlenius S (1999) Suggestive evidence for
inhibitory effects of galanin on mesolimbic dopaminergic
neurotransmission. Brain res 822: 200-209.
70. Landry M, Roche D, Vila-Porcile E, Calas A (2000) Effects of
centrally administered galanin (1-16) on galanin expression in the
rat hypothalamus. Peptides 21: 1725-1733.
71. Kalra SP, Kalra PS (1996) Nutritional infertility: the role
of the interconnected hypothalamic neuropeptide Y-galanin-opioid
network. Front Neuroendocrinol 17: 371-401.
72. Tachibana T, Mori M, Khan MS, Ueda H, Sugahara K, et al.
(2008) Central administration of galanin stimulates feeding
behavior in chicks. Comp Biochem Physiol A Mol Integr Physiol 151:
637-640.
73. M, Kelley AE (2002) Intake of saccharin, salt, and ethanol
solutions is increased by infusion of a mu opioid agonist into the
nucleus accumbens. Psychopharmacology (Berl) 159: 415-423.
74. Vila-Porcile E, Xu ZQ, Mailly P, Nagy F, Calas A, et al.
(2009) Dendritic synthesis and release of the neuropeptide galanin:
morphological evidence from studies on rat locus coeruleus neurons.
J Comp Neurol 516: 199-212.
75. Hokfelt T, Xu ZQ, Shi TJ, Holmberg K, Zhang X (1998) Galanin
in ascending systems. Focus on coexistence with 5-hydroxytryptamine
and noradrenaline. Ann N Y Acad Sci 863: 252-263.
76. Grenhoff J, Nisell M, Ferre S, Aston-Jones G, Svensson TH
(1993) Noradrenergic modulation of midbrain dopamine cell firing
elicited by stimulation of the locus coeruleus in the rat. J Neural
Transm Gen Sect 93: 11-25.
77. Holets VR, Hokfelt T, Rokaeus A, Terenius L, Goldstein M
(1988) Locus coeruleus neurons in the rat containing neuropeptide
Y, tyrosine hydroxylase or galanin and their efferent projections
to the spinal cord, cerebral cortex and hypothalamus. Neuroscience
24: 893-906.
78. Lechner J, Leah JD, Zimmermann M (1993) Brainstem
peptidergic neurons projecting to the medial and lateral thalamus
and zona incerta in the rat. Brain Research 603: 47-56.
79. Seutin V, Verbanck P, Massotte L, Dresse A (1989) Galanin
decreases the activity of locus coeruleus neurons in vitro. Eur J
Pharmacol 164: 373-376.
80. Sevcik J, Finta EP, Illes P (1993) Galanin receptors inhibit
the spontaneous firing of locus coeruleus neurones and interact
with mu-opioid receptors. Eur J Pharmacol 230: 223-230.
81. Pieribone VA, Xu ZQ, Zhang X, Grillner S, Bartfai T, et al.
(1995) Galanin induces a hyperpolarization of
norepinephrine-containing locus coeruleus neurons in the brainstem
slice. Neuroscience 64: 861-874.
82. Lundstrom L, Sollenberg U, Brewer A, Kouya PF, Zheng K, et
al. (2005) A Galanin Receptor Subtype 1 Specific Agonist.
International Journal of Peptide Research and Therapeutics 11:
17-27.
83. Tsuda K, Tsuda S, Nishio I, Masuyama Y, Goldstein M (1992)
Modulation of norepinephrine release by galanin in rat medulla
oblongata. Hypertension 20: 361-366.
84. Xu ZQ, Hokfelt T (1997) Expression of galanin and nitric
oxide synthase in subpopulations of serotonin neurons of the rat
dorsal raphe nucleus. J Chem Neuroanat 13: 169-187.
85. Sharkey LM, Madamba SG, Siggins GR, Bartfai T (2008) Galanin
alters GABAergic neurotransmission in the dorsal raphe nucleus.
Neurochem Res 33: 285-291.
86. Sullivan KA, Shiao LL, Cascieri MA (1997) Pharmacological
characterization and tissue distribution of the human and rat GALR1
receptors. Biochem Biophys Res Commun 233: 823-828.
87. Mennicken F, Hoffert C, Pelletier M, Ahmad S, O’Donnell D
(2002) Restricted distribution of galanin receptor 3 (GalR3) mRNA
in the adult rat central nervous system. J Chem Neuroanat 24:
257-268.
88. Smith KE, Forray C, Walker MW, Jones KA, Tamm JA, et al.
(1997) Expression
http://www.ncbi.nlm.nih.gov/pubmed/19616054http://www.ncbi.nlm.nih.gov/pubmed/19424438http://www.ncbi.nlm.nih.gov/pubmed/16806319http://www.ncbi.nlm.nih.gov/pubmed/9142752http://www.ncbi.nlm.nih.gov/pubmed/16965292http://www.ncbi.nlm.nih.gov/pubmed/20111610http://www.ncbi.nlm.nih.gov/pubmed/7680542http://www.ncbi.nlm.nih.gov/pubmed/12600711http://www.ncbi.nlm.nih.gov/pubmed/10784110http://www.ncbi.nlm.nih.gov/pubmed/9729239http://www.ncbi.nlm.nih.gov/pubmed/17215388http://www.ncbi.nlm.nih.gov/pubmed/2440918http://www.ncbi.nlm.nih.gov/pubmed/2905536http://www.ncbi.nlm.nih.gov/pubmed/9570780http://www.ncbi.nlm.nih.gov/pubmed/9509257http://www.ncbi.nlm.nih.gov/pubmed/9860090http://www.ncbi.nlm.nih.gov/pubmed/14581121http://www.ncbi.nlm.nih.gov/pubmed/1701038http://www.ncbi.nlm.nih.gov/pubmed/9666056http://www.ncbi.nlm.nih.gov/pubmed/9817576http://www.ncbi.nlm.nih.gov/pubmed/6514770http://www.ncbi.nlm.nih.gov/pubmed/6514770http://www.ncbi.nlm.nih.gov/pubmed/3669922http://www.ncbi.nlm.nih.gov/pubmed/10082897http://www.ncbi.nlm.nih.gov/pubmed/11090928http://www.ncbi.nlm.nih.gov/pubmed/8905347http://www.ncbi.nlm.nih.gov/pubmed/18725311http://www.ncbi.nlm.nih.gov/pubmed/11823894http://www.ncbi.nlm.nih.gov/pubmed/19598284http://www.ncbi.nlm.nih.gov/pubmed/9928176http://www.ncbi.nlm.nih.gov/pubmed/8373553http://www.ncbi.nlm.nih.gov/pubmed/2454419http://www.ncbi.nlm.nih.gov/pubmed/7680939http://www.ncbi.nlm.nih.gov/pubmed/2474450http://www.ncbi.nlm.nih.gov/pubmed/7678551http://www.ncbi.nlm.nih.gov/pubmed/7538638http://www.springerlink.com/content/j08g6843157240u3/http://www.ncbi.nlm.nih.gov/pubmed/1381336http://www.ncbi.nlm.nih.gov/pubmed/9315967http://www.ncbi.nlm.nih.gov/pubmed/17973188http://www.ncbi.nlm.nih.gov/pubmed/9168941http://www.ncbi.nlm.nih.gov/pubmed/12406501http://www.ncbi.nlm.nih.gov/pubmed/9305929
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 11 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
cloning of a rat hypothalamic galanin receptor coupled to
phosphoinositide turnover. J Biol Chem 272: 24612-24616.
89. Xu ZQ, Zhang X, Pieribone VA, Grillner S, Hokfelt T (1998)
Galanin-5-hydroxytryptamine interactions: electrophysiological,
immunohistochemical and in situ hybridization studies on rat dorsal
raphe neurons with a note on galanin R1 and R2 receptors.
Neuroscience 87: 79-94.
90. Cortes R, Villar MJ, Verhofstad A, Hokfelt T (1990) Effects
of central nervous system lesions on the expression of galanin: a
comparative in situ hybridization and immunohistochemical study.
Proc Natl Acad Sci U S A 87: 7742-7746.
91. Gray TS, Magnuson DJ (1987) Galanin-like immunoreactivity
within amygdaloid and hypothalamic neurons that project to the
midbrain central grey in rat. Neurosci Lett 83: 264-268.
92. Corwin RL, Robinson JK, Crawley JN (1993) Galanin
antagonists block galanin-induced feeding in the hypothalamus and
amygdala of the rat. Eur J Neurosci 5: 1528-1533.
93. Cassell MD, Freedman LJ, Shi, C (1999) The intrinsic
organization of the central extended amygdala. Ann N Y Acad Sci
877: 217-241.
94. Barrera G, Echevarria DJ, Poulin JF, Laforest S, Drolet G,
et al. (2005) One for all or one for one: does co-transmission
unify the concept of a brain galanin “system” or clarify any
consistent role in anxiety? Neuropeptides 39: 289-292.
95. Kask K, Langel U, Bartfai T (1995) Galanin--a neuropeptide
with inhibitory actions. Cell Mol Neurobiol 15: 653-673.
96. Pych JC, Chang Q, Colon-Rivera C, Haag R, Gold PE (2005)
Acetylcholine release in the hippocampus and striatum during place
and response training. Learn Mem 12: 564-572.
97. Pych, JC, Chang Q, Colon-Rivera C, Gold PE (2005)
Acetylcholine release in hippocampus and striatum during testing on
a rewarded spontaneous alternation task. Neurobiol Learn Mem 84:
93-101.
98. Davis JA, Gould TJ (2008) Associative learning, the
hippocampus, and nicotine addiction. Curr Drug Abuse Rev 1:
9-19.
99. Anden N, Grabowska M (1976) Pharmacological evidence for a
stimulation of dopamine neurons by noradrenaline neurons in the
brain. Eur J Pharmacol 39: 275-282.
100. Anton RF (2001) Pharmacologic approaches to the management
of alcoholism. J Clin Psychiatry 62: 11-17.
101. Wise RA (1998) Drug-activation of brain reward pathways.
Drug Alcohol Depend 51: 13-22.
102. Appel SB, McBride WJ, Diana M, Diamond I, Bonci A, et al.
(2004) Ethanol Effects on Dopaminergic “Reward” Neurons in the
Ventral Tegmental Area and the Mesolimbic Pathway. Alcohol Clin Exp
Res 28: 1768-1778.
103. Weiss F, Porrino LJ (2002) Behavioral neurobiology of
alcohol addiction: recent advances and challenges. J Neurosci 22:
3332-3337.
104. Tomkins DM, Sellers EM (2001) Addiction and the brain: the
role of neurotransmitters in the cause and treatment of drug
dependence. CMAJ 164: 817-821.
105. Barson JR, Morganstern I, Leibowitz SF (2011) Similarities
in hypothalamic and mesocorticolimbic circuits regulating the
overconsumption of food and alcohol. Physiol Behav 104:
128-137.
106. Filbey FM, Claus E, Audette AR, Niculescu M, Banich MT, et
al. (2008) Exposure to the taste of alcohol elicits activation of
the mesocorticolimbic neurocircuitry. Neuropsychopharmacology 33:
1391-1401.
107. Volkow ND, Wang GJ, Fowler JS, Telang F (2008) Overlapping
neuronal circuits in addiction and obesity: evidence of systems
pathology. Philos Trans R Soc Lond B Biol Sci 363: 3191-3200.
108. Lewis MJ, Rada P, Johnson DF, Avena NM, Leibowitz SF, et
al. (2005) Galanin and alcohol dependence: neurobehavioral
research. Neuropeptides 39: 317-321.
109. Bailey CP, Andrews N, McKnight AT, Hughes J, Little HJ
(2000) Prolonged
changes in neurochemistry of dopamine neurones after chronic
ethanol consumption. Pharmacol Biochem Behav 66: 153-161.
110. Brodie MS (2002) Increased ethanol excitation of
dopaminergic neurons of the ventral tegmental area after chronic
ethanol treatment. Alcohol Clin Exp Res 26: 1024-1030.
111. Koob GF, Sanna PP Bloom FE (1998) Neuroscience of
addiction. Neuron 21: 467-476.
112. Roy A, Berrettini W, Adinoff B Linnoila M (1990) CSF
galanin in alcoholics, pathological gamblers, and normal controls:
a negative report. Biol Psychiatry 27: 923-926.
113. Hauge T, Persson J Sjolund K (2001) Neuropeptides in the
duodenal mucosa of chronic alcoholic heavy drinkers. Alcohol
Alcohol 36: 213-218.
114. Heberlein A, Muschler M, Frieling H, Lenz B, Wilhelm J, et
al. (2010) Decreased galanin serum levels are associated with
alcohol-craving during withdrawal. Prog Neuropsychopharmacol Biol
Psychiatry 35: 568-572.
115. Barson JR, Morganstern I, Leibowitz SF (2010) Galanin and
Consummatory Behavior: Special Relationship with Dietary Fat,
Alcohol and Circulating Lipids. EXS 102: 87-111.
116. Lewis MJ, Johnson DF, Waldman D, Leibowitz SF, Hoebel BG
(2004) Galanin microinjection in the third ventricle increases
voluntary ethanol intake. Alcohol Clin Exp Res 28: 1822-1828.
117. Koob GF, Volkow ND (2010) Neurocircuitry of addiction.
Neuropsychopharmacology 35: 217-238.
118. Bassareo V, Di Chiara, G (1999) Modulation of
feeding-induced activation of mesolimbic dopamine transmission by
appetitive stimuli and its relation to motivational state. Eur J
Neurosci 11: 4389-4397.
119. Leinninger GM, Jo YH, Leshan RL, Louis GW, Yang H, et al.
(2009) Leptin acts via leptin receptor-expressing lateral
hypothalamic neurons to modulate the mesolimbic dopamine system and
suppress feeding. Cell Metab 10: 89-98.
120. Williams KW, Elmquist JK (2011) Lighting up the
hypothalamus: coordinated control of feeding behavior. Nat Neurosci
14: 277-278.
121. Crawley JN, Robinson JK, Langel U, Bartfai T (1993) Galanin
receptor antagonists M40 and C7 block galanin- induced feeding.
Brain Res 600: 268-272.
122. Koegler FH, York DA, Bray GA (1999) The effects on feeding
of galanin and M40 when injected into the nucleus of the solitary
tract, the lateral parabrachial nucleus, and the third ventricle.
Physiol Behav 67: 259-267.
123. Leibowitz SF, Akabayashi A, Wang J (1998) Obesity on a
high-fat diet: role of hypothalamic galanin in neurons of the
anterior paraventricular nucleus projecting to the median eminence.
J Neurosci 18: 2709-2719.
124. Leibowitz SF (2005) Regulation and effects of hypothalamic
galanin: relation to dietary fat, alcohol ingestion, circulating
lipids and energy homeostasis. Neuropeptides 39: 327-332.
125. Leibowitz SF, Avena NM, Chang GQ, Karatayev O, Chau DT, et
al. (2003) Ethanol intake increases galanin mRNA in the
hypothalamus and withdrawal decreases it. Physiol Behav 79:
103-111.
126. Rada P, Avena NM, Leibowitz SF, Hoebel BG (2004) Ethanol
intake is increased by injection of galanin in the paraventricular
nucleus and reduced by a galanin antagonist. Alcohol 33: 91-97.
127. Chang GQ, Karatayev O, Ahsan R, Avena NM, Lee C, et al.
(2007) Effect of ethanol on hypothalamic opioid peptides,
enkephalin, and dynorphin: relationship with circulating
triglycerides. Alcohol Clin Exp Res 31: 249-259.
128. Karatayev O, Barson JR, Carr AJ, Baylan J, Chen YW, et al.
(2010) Predictors of ethanol consumption in adult Sprague-Dawley
rats: relation to hypothalamic peptides that stimulate ethanol
intake. Alcohol 44: 323-334.
129. Lieber CS (1988) The influence of alcohol on nutritional
status. Nutr Rev 46: 241-254.
130. Karatayev O, Baylan J, Weed V, Chan, S, Wynick D, et al.
(2010) Galanin Knockout Mice Show Disturbances in Ethanol
Consumption and Expression of Hypothalamic Peptides that stimulate
ethanol intake. Alcohol Clin Exp Res 34: 72-80.
http://www.ncbi.nlm.nih.gov/pubmed/9305929http://www.ncbi.nlm.nih.gov/pubmed/9722143http://www.ncbi.nlm.nih.gov/pubmed/1699231http://www.ncbi.nlm.nih.gov/pubmed/2450313http://www.ncbi.nlm.nih.gov/pubmed/7506975http://www.ncbi.nlm.nih.gov/pubmed/10415652http://www.ncbi.nlm.nih.gov/pubmed/15944024http://www.ncbi.nlm.nih.gov/pubmed/8719035http://www.ncbi.nlm.nih.gov/pubmed/16322358http://www.ncbi.nlm.nih.gov/pubmed/15950501http://www.ncbi.nlm.nih.gov/pubmed/19630701http://www.ncbi.nlm.nih.gov/pubmed/185062http://www.ncbi.nlm.nih.gov/pubmed/11584870http://www.ncbi.nlm.nih.gov/pubmed/9716927http://onlinelibrary.wiley.com/doi/10.1097/01.ALC.0000145976.64413.21/abstracthttp://www.ncbi.nlm.nih.gov/pubmed/11978808http://www.ncbi.nlm.nih.gov/pubmed/11276551http://www.ncbi.nlm.nih.gov/pubmed/21549731http://www.ncbi.nlm.nih.gov/pubmed/17653109http://www.ncbi.nlm.nih.gov/pubmed/18640912http://www.ncbi.nlm.nih.gov/pubmed/15885773http://www.ncbi.nlm.nih.gov/pubmed/10837855http://www.ncbi.nlm.nih.gov/pubmed/10837855http://www.ncbi.nlm.nih.gov/pubmed/12170113http://www.ncbi.nlm.nih.gov/pubmed/9768834http://www.ncbi.nlm.nih.gov/pubmed/1691926http://www.ncbi.nlm.nih.gov/pubmed/11373257http://www.ncbi.nlm.nih.gov/pubmed/21199668http://www.ncbi.nlm.nih.gov/pubmed/21299064http://www.ncbi.nlm.nih.gov/pubmed/15608598http://www.ncbi.nlm.nih.gov/pubmed/19710631http://www.ncbi.nlm.nih.gov/pubmed/10594666http://www.ncbi.nlm.nih.gov/pubmed/19656487http://www.ncbi.nlm.nih.gov/pubmed/21346745http://www.ncbi.nlm.nih.gov/pubmed/7679604http://www.ncbi.nlm.nih.gov/pubmed/10477058http://www.ncbi.nlm.nih.gov/pubmed/9502828http://www.ncbi.nlm.nih.gov/pubmed/15944030http://www.ncbi.nlm.nih.gov/pubmed/12818715http://www.ncbi.nlm.nih.gov/pubmed/15528006http://www.ncbi.nlm.nih.gov/pubmed/17250616http://www.ncbi.nlm.nih.gov/pubmed/20692550http://www.ncbi.nlm.nih.gov/pubmed/3045703http://www.ncbi.nlm.nih.gov/pubmed/19860804
-
Citation: Ash BL, Djouma E (2011) Galanin Receptors as
Pharmacological Targets in the Treatment of Addiction. J Addict Res
Ther S4:003. doi:10.4172/2155-6105.S4-003
Page 12 of 12
ISSN:2155-6105 JART, an open access journal J Addict Res Ther
Behavioral Pharmacology
131. Karatayev O, Baylan J, Leibowitz SF (2009) Increased intake
of ethanol and dietary fat in galanin overexpressing mice. Alcohol
43: 571-580.
132. Bajo M, Madamba SG, Lu X, Sharkey LM, Bartfai T, et al.
(2011) Receptor subtype-dependent galanin actions on
gamma-aminobutyric acidergic neurotransmission and ethanol
responses in the central amygdala. Addict Biol,
10.1111/j.1369-1600.2011.00360.x.
133. Ash BL, Zanatta SD, Williams SJ, Lawrence AJ, Djouma E
(2011) The galanin-3 receptor antagonist, SNAP 37889, reduces
operant responding for ethanol in alcohol-preferring rats. Regul
Pept 166: 59-67.
134. Davidson S, Lear M, Shanley L, Hing B, Baizan-Edge A, et
al. (2011) Differential Activity by Polymorphic Variants of a
Remote Enhancer that Supports Galanin Expression in the
Hypothalamus and Amygdala: Implications for Obesity, Depression and
Alcoholism. Neuropsychopharmacology 36: 2211-2221.
135. Belfer I, Hipp H, Bollettino A, McKnight C, Evans C, et al.
(2007) Alcoholism is associated with GALR3 but not two other
galanin receptor genes. Genes Brain Behav 6: 473-481.
136. Belfer I, Hipp H, McKnight C, Evans C, Buzas B, et al.
(2006) Association of galanin haplotypes with alcoholism and
anxiety in two ethnically distinct populations. Mol Psychiatry 11:
301-311.
137. Lori A, Tang Y, O’Malley S, Picciotto MR, Wu R, et al.
(2011) The Galanin Receptor 1 Gene Associates with Tobacco Craving
in Smokers Seeking Cessation Treatment. Neuropsychopharmacology 36:
1412-1420.
138. Neugebauer NM, Henehan RM, Hales CA, Picciotto MR (2011)
Mice lacking the galanin gene show decreased sensitivity to
nicotine conditioned place preference. Pharmacol Biochem Behav 98:
87-93.
139. Jackson KJ, Chen X, Miles MF, Harenza J, Damaj MI (2011)
The Neuropeptide Galanin and Variants in the GalR1 Gene are
Associated with Nicotine Dependence. Neuropsychopharmacology 36:
2339-2348.
140. Hawes JJ, Narasimhaiah R, Picciotto MR (2006) Galanin
attenuates cyclic AMP regulatory element-binding protein (CREB)
phosphorylation induced by chronic morphine and naloxone challenge
in Cath.a cells and primary striatal cultures. J Neurochem 96:
1160-1168.
141. Holmes FE, Armenaki A, Iismaa TP, Einstein EB, Shine J, et
al. (2011) Galanin negatively modulates opiate withdrawal via
galanin receptor 1. Psychopharmacology (Berl),
10.1007/s00213-011-2515-x.
142. Zachariou V, Thome J, Parikh K, Picciotto MR (2000)
Upregulation of galanin binding sites and GalR1 mRNA levels in the
mouse locus coeruleus following chronic morphine treatments and
precipitated morphine withdrawal. Neuropsychopharmacology 23:
127-137.
143. Zachariou V, Brunzell DH, Hawes J, Stedman DR, Bartfai T,
et al. (2003) The neuropeptide galanin modulates behavioral and
neurochemical signs of opiate withdrawal. Proc Natl Acad Sci U S A
100: 9028-9033.
144. Wu X, Yu LC (2006) Alternation of galanin in nociceptive
modulation in the central nervous system of rats during morphine
tolerance: a behavioral and immunohistochemical study. Brain Res
1086: 85-91.
145. Narasimhaiah R, Kamens HM, Picciotto MR (2009) Effects of
galanin on cocaine-mediated conditioned place preference and ERK
signaling in mice. Psychopharmacology 204: 95-102.
146. Brabant C, Kuschpel AS, Picciotto MR (2010) Locomotion and
self-administration induced by cocaine in 129/OlaHsd mice lacking
galanin. Behav Neurosci 124: 828-838.
147. Kuteeva E, Hokfelt T, Ogren SO (2005) Behavioural
characterisation of young adult transgenic mice overexpressing
galanin under the PDGF-B promoter. Regul Pept 125: 67-78.
148. Walton KM, Chin JE, Duplantier AJ, Mather RJ (2006) Galanin
function in the central nervous system. Curr Opin Drug Discov Devel
9: 560-570.
149. Smith KE, Walker MW, Artymyshyn R, Bard J, Borowsky B, et
al. (1998) Cloned human and rat galanin GALR3 receptors.
Pharmacology and activation of G-protein inwardly rectifying K+
channels. J Biol Chem 273: 23321-23326.
150. Lu X, Bartfai T (2009) Analyzing the validity of GalR1 and
GalR2 antibodies
using knockout mice. Naunyn Schmiedebergs Arch Pharmacol 379:
417-420.
151. Michel MC, Wieland T, Tsujimoto G (2009) How reliable are
G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch
Pharmacol 379: 385-388.
152. Lu X, Mazarati A, Sanna P, Shinmei S, Bartfai T (2005)
Distribution and differential regulation of galanin receptor
subtypes in rat brain: effects of seizure activity. Neuropeptides
39: 147-152.
153. Parker EM, Izzarelli DG, Nowak HP, Mahle CD, Iben LG, et
al. (1995) Cloning and characterization of the rat GALR1 galanin
receptor from Rin14B insulinoma cells. Brain Res Mol Brain Res 34:
17