-
4NOREPINEPHRINE
GARY ASTON-JONES
This chapter reviews findings from basic research concern-ing
brain norepinephrine (NE) systems. The focus is onwork that is
relevant to the mechanisms of psychiatric disor-ders, or the
actions of drugs used to treat such disorders.The locus ceruleus
(LC) system receives most of the atten-tion here, but recent
findings concerning the role of the A2/A1 medullary cell groups in
drug abuse are also reviewed.Emphasis is placed on studies
published since the last ver-sion of this volume. Space limitations
prevent a thoroughreview of the involvement of any brain NE system
in mentalfunction and dysfunction, so that only a fraction of
therelevant research can be covered. Apologies are offered tothose
whose work could not be included.
MOLECULARGENETIC STUDIES
Previous studies have revealed molecular properties of NEneurons
and their effector systems that have extended ourunderstanding of
the function and pharmacology of thissystem. For example, Duman et
al. (1) have shown thatacute opiate administration decreases cyclic
adenosinemonophosphate (cAMP) and adenylate cyclase activity inLC
neurons, whereas long-term use of opiates or opiatewithdrawal
results in elevated activity in this secondmessen-ger mechanism.
Continuing studies in this vein have re-sulted in a more complete
picture of molecular events andproperties within LC neurons that
help regulate their dis-charge activity. Thus, the adenylate
cyclase/cAMP systemis up-regulated with chronic stress but
down-regulated withlong-term antidepressant treatment (2).
Additional studiesindicate that impulse activity of LC neurons may
be regu-lated in part by a nonspecific cation current that is
activatedby this second messenger system (2). These findings
suggesta molecular mechanism whereby the overall excitability ofLC
neurons may be modulated in accordance with long-term environmental
or pharmacologic conditions and may
G. Aston-Jones: Department of Psychiatry, University of
PennsylvaniaSchool of Medicine, Philadelphia, Pennsylvania.
be involved in the mechanisms of action of antidepressantand
other psychopharmacologic agents.
Recent genetic studies have also revealed important as-pects of
NE systems relevant to their role in psychopharma-cology. Xu et al.
(3) studied the brains of mice with a knock-out of the NE
transporter (3). These mice exhibitedcharacteristics of animals
treated with antidepressants (i.e.,prolonged clearance of NE and
elevated extracellular levelsof this catecholamine). In a test for
antidepressant drugs,the NE transporter knockouts behaved like
antidepressant-treated wild-type mice, being hyperresponsive to
locomotorstimulation by cocaine or amphetamine. Importantly,
theseanimals also exhibited dopamine D2/D3-receptor
supersen-sitivity. Thus, NE transporter function can alter
midbraindopaminergic systems, an effect that may be an
importantmechanism of action of antidepressants and
psychostimu-lants.
NEUROANATOMY
Chemoanatomy of the LC
The neuroanatomy of the major brain NE systems has beenrecently
reviewed in detail (4), and only the most salientfeatures are
described here. In the rat and primate (but notcat, guinea pig, and
most other species), virtually all neuronslocated within the
compact LC nucleus are noradrenergic. Itis notable that LC neurons
also often contain other possibleneurotransmitters (e.g.,
neuropeptides), and subsets of ratNE neurons can be distinguished
by neurotransmitter mole-cules that they co-localize (see ref. 4
for review). Additionalwork is needed to determine the functional
significance ofco-localization of other transmitter molecules
within LCneurons.
Peri-LC Dendritic Shell
A prominent feature of LC neurons in all species is thattheir
dendrites typically extend hundreds of micra from theparent cell
body. Our recent studies have revealed that thesedendrites in rat
are organized into two prominent collec-tions that project outside
the nuclear core in the caudodorsal
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Neuropsychopharmacology: The Fifth Generation of Progress48
and rostroventromedial directions (5). This work has
alsodemonstrated that these dendrites receive numerous synap-tic
contacts, indicating that the extranuclear peri-LC pro-cesses serve
as a substantial receptive surface for LC neu-rons.
Afferents to the LC
Prior studies indicated that prominent afferents to the
LCinclude the nucleus paragigantocellularis (PGi) and the
ven-tromedial aspect of the prepositus hypoglossi (PrH) in
therostroventrolateral and dorsomedial medulla, respectively(6,7).
These nuclei provide strong excitatory and inhibitoryinfluences on
LC neurons, respectively, and are also sourcesof several
neurotransmitter inputs to the LC nucleus (seebelow) (4,8).
However, as previously stated, LC dendritesthat extend outside the
LC nucleus proper provide a promi-nent receptive surface for inputs
to LC neurons (5). Studiesof inputs to these peri-LC dendritic
zones indicate severaladditional possible strong inputs to LC
neurons, includingthe periaqueductal gray, medial preoptic nucleus,
prefrontalcortex, and hypothalamus (4,8). Recent work has
confirmedsome of the proposed inputs, showing direct contacts
ontoperi-LC dendrites from amygdala (9) and nucleus
tractussolitarius (NTS) (10). Additional work is needed to testsome
of the other possible inputs to LC distal dendrites.These dendritic
inputs are important in revealing additionalfunctional circuitry
linked to the LC system (e.g., limbic,autonomic, and cognitive
functions).
A host of immunohistochemically defined fibers havebeen found in
LC afferents (see ref. 4 for review). Thesources of some of these
inputs have been determined.Strong glutamate (11) and epinephrine
inputs (12) originatein the PGi, -aminobutyric acid (GABA) inputs
arise fromthe PrH (13), and strong enkephalin projections to the
LCoriginate in both the PGi and the PrH (14). Histaminefibers
innervate the LC, presumably originating in the tub-eromammillary
nucleus (15). A particularly dense innerva-tion by serotonin fibers
also exists; the origin of this projec-tion has not been
determined. Ultrastructural analyses haveshown that several of
these inputs directly innervate LCneurons (1620).
Most recently, the novel neuropeptide hypocretin (syn-onymous
with orexin) has been shown to innervate the LCdensely in rats
andmonkeys (2124) (Fig. 4.1). This projec-tion presumably
originates in the hypothalamus (the solelocation of
hypocretin-producing cells) and is mirrored bydense projections to
other nuclei associated with sleep andarousal functions (e.g., the
raphe serotonin neurons, tubero-mammillary histamine cells, and
cholinergic neurons of thebrainstem). Initial studies of this
peptide suggested a role infeeding (24,25). However, more recent
work has stimulatedconsiderable interest in this neurotransmitter
by closelylinking its function to sleep regulation. Specifically,
muta-tions of the gene that makes a hypocretin receptor (26),
or
FIGURE4.1. Photomicrograph showing dense innervation of thelocus
ceruleus (LC) by hypocretin/orexin Fibers. Low-power (A)and
high-power (B) photographs of frontal sections through therat LC
after staining with antibodies for hypocretin and
tyrosinehydroxylase (TH). Note the proximity of numerous black,
punctatehypocretin fibers and brown TH-positive NE somata and
den-drites. (From Horvath TL, Peyron C, Sabrina D, et al. Strong
hypo-cretin (orexin) innervation of the locus coeruleus
activatesnoradrenergic cells. J Comp Neurol 1999;415:145159,
withpermission.) See color version of figure.
of another gene that makes hypocretin itself (27),
producednarcolepsy symptoms in animals. This finding supports
thelong-standing belief that the LC system is important
insleepwaking processes (28) and indicates that sleep disor-ders
may involve anomalies in this hypocretin projection tothe LC. These
findings also offer a novel target for pharma-cologic manipulation
of the LC and other systems involvedin sleep function.
The functions of the different inputs to LC neurons ortheir
dendrites are being revealed in behavioral and neuro-physiologic
studies. Stimulation of the PGi strongly excitesLC neurons (11).
The PGi has strong autonomic functions,an observation consistent
with the marked parallel foundbetween LC and sympathetic activities
(29). These findings,together with the strong cortical projections
of LC neurons,suggest that the LC acts as a cognitive component of
a globalsympathetic system (8). In contrast, strong inhibition is
pro-duced by PrH stimulation (13); the functional significanceof
this input is unclear. That inhibitory adrenergic inputalso arises
from the PGi is revealed when the strong gluta-mate input is
antagonized pharmacologically (30). Inputsto distal LC dendrites
from the amygdala (9) or NTS (10)may convey limbic/emotional or
autonomic information tothe LC, respectively, although an influence
of activity inthese afferents on LC activity has not yet been found
(8,31). Our unpublished studies in monkey indicate that theanterior
cingulate cortex strongly innervates the LC (32).Some of our other
recent results suggest that this input maymodulate the mode of LC
activity and thereby its influenceon cognitive performance
(described below) (33). Finally,our recent studies using
transsynaptic retrograde tracing re-veal that the suprachiasmatic
nucleus is a prominent indirectafferent to the LC (3436). This is
the first demonstrationof a circuit that links the circadian
suprachiasmatic nucleusmechanism with the arousal/alerting LC
system. Inasmuchas other studies have linked circadian disturbances
with
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Chapter 4: Norepinephrine 49
depression (37), and the LC system is also associated
withdepression and other mood disorders (38), this pathwaymay also
be important for affective function.
Topography of LC Efferents
It is well-known that LC axons are highly branched andhave
extensive efferents that ramify throughout the centralnervous
system, providing NE innervation at all levels ofthe neuraxis (see
ref. 4 for review). Previous studies havefound topography among
these efferent projections (39),but the degree of specificity for
projections of different LCneurons appears to be quite limited.
Recent studies bySimpson et al. (40) have revealed topography of a
noveltype. They report that LC neurons selectively collateralizeto
different nuclei of the somatosensory system, so that indi-vidual
neurons are more likely to send branches to thalamicand cortical
areas within the somatosensory system than to,e.g., a somatosensory
thalamic nucleus and a visual corticalarea. This functional
topography for projections of indi-vidual LC neurons provides a new
dimension for the ana-tomic organization of this ubiquitous brain
system and mayindicate a means for coordination or synchronization
of NErelease along relays in serial functional pathways.
A2 NE Neurons of the Caudal Medulla
Norepinephrine neurons in the A2 group (caudal NTS)have recently
been implicated in behavioral functions ofpsychiatric importance.
Previously relegated solely to auto-nomic and visceral control
(e.g., see ref. 41), the strongascending projections of these NE
cells to forebrain areassuch as the hypothalamus (42), bed nucleus
of the striaterminalis (BNST) (43), nucleus accumbens (44),
andamygdala (45,46) have now been shown also to be impor-tant in
affective and cognitive processes (43,47). As de-scribed below,
these findings identify new circuits for under-standing affective
and mnemonic functions.
NEUROPHYSIOLOGY
Several recent findings regarding the neurophysiology of
LCneurons have extended our understanding of this system.Notably,
integration of studies at the cellular and behaviorallevels
indicates a potentially important role of couplingamong LC
neurons.
Electrotonic Coupling
Experiments by Christie and Williams and colleagues(4850) showed
that LC neurons may be regulated by elec-trotonic coupling, not
only during development but also inadults. Additional studies by
these workers indicate thatsuch coupling may be modulated by inputs
to LC neurons
that alter cAMP (51). This is significant because
electrotoniccoupling allows rapid, powerful cell-to-cell
communication(electrically and biochemically) via large
transmembranechannels between neurons (called gap junctions). Once
rele-gated to the domain of the esoteric but unimportant,
elec-trotonic coupling is now being demonstrated in an increas-ing
number of central neurons. Of great interest is the factthat such
coupling is readily modulated by other inputs tocoupled cellsfor
example, in the retina, coupling isstrongly attenuated by dopamine
inputs in a cAMP/proteinkinase A manner. This line of work is very
promising inneuropsychopharmacology because it suggests a novel
setof targets (receptors that regulate electrotonic coupling)
thatcould be used to develop new drugs to modulate the func-tion of
systems important in mental function and dysfunc-tion (such as the
LC). Our recent work (described below)shows how modulation of such
coupling can have profoundinfluences on behavior and cognitive
performance (33). Itis noteworthy that electrotonic coupling has
been reportedamong striatal neurons in a dopamine-modulated
manner(see Chapter 9, this volume), as well as among interneuronsin
the cerebral cortex (52,53).
LC Activity, Electrotonic Coupling, andCognitive Performance in
BehavingMonkeys
A possible role for electrotonic coupling among LC neuronsin
cognitive performance was revealed by combining ourrecordings of LC
neurons in monkeys performing a signaldetection task with neural
network modeling (33). In theserecordings, LC neurons exhibited
twomodes of activity dur-ing task performance: a phasic mode, in
which LC cellsresponded phasically to target stimuli, and a tonic
mode,in which the tonic baseline activity of LC neurons was highbut
responses to target cues were absent. Moreover, the pha-sic mode
corresponded closely to focused attention andgood task performance,
whereas the tonic mode was associ-ated with scanning attentiveness
and poor performance inthis task, which requires focused attention.
Task perfor-mance could be improved by systemic or local
(intra-LC)injection of clonidine during poor performance, which
indi-cates a causal influence of these patterns of LC activity
onperformance. A neural network model was constructed toinvestigate
mechanisms involved in generating these modesof LC activity and the
corresponding task performance.Space limitations prohibit a full
discussion of the findings,which are reported and reviewed in
recent publications (33,54). In brief, the model showed that
modulated electrotoniccoupling among LC neurons could produce the
patternsof LC firing observed in the monkeys, and that
knownmodulatory effects of NE could then translate these modesof LC
activity into corresponding levels of task performance,also
observed in the monkeys (Figs. 4.2 and 4.3). Thesefindings have a
number of implications for neuropsycho-
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Neuropsychopharmacology: The Fifth Generation of Progress50
A,B
C,D
FIGURE 4.2. Simulation of locus ceruleus (LC) activity
bymodulated electrotonic coupling.Upper: Post-stimulus
timehistograms (PSTHs) for LC activity during the visual
discrimi-nation task. A,B: Response for targets. C,D: Response
fordistractors. A,C: Periods of good performance (phasic LCmode).
B,D: Poor behavioral performance (false alarm ratetypically 7%;
tonic LC mode). Stimuli occur at time zero.All histograms are
normalized to a standard of 100 trials.Note that the phasic LC mode
is found during periods ofgood performance, and that the tonic mode
corresponds topoor performance on this task. Bin width, 10 ms.
Lower:A,BSimulation of LC responses. A,B: Response to targets.
C,D:Response to distractors. A,C: Coupling among LC neurons.B,D:No
coupling among LC neurons. These simulation PSTHsare normalized for
100 trials, as for the empiric data. Notethat coupling reduces
tonic (baseline) LC activity but in-creases phasic (transient)
response to target stimuli, captur-ing the phasicmode of LC neurons
in our recordings. See Fig.4.3 for corresponding behavioral
simulation results. (FromUsher M, Cohen JD, Rajkowski J, et al. The
role of locusC,Dcoeruleus in the regulation of cognitive
performance. Sci-ence 1999;283:549554, with permission.)
FIGURE 4.3. Simulation of behavioral performance by modu-lated
coupling among locus ceruleus (LC) neurons. Left: Graphsshowing
higher rate of false alarm errors (% FA) during epochsof poor
versus good performance by monkeys in the visual dis-crimination
task (33). No differences were noted in the percent-age of hit
responses during the various levels of performance,as misses were
rare. Right: Graphs showing higher % FA in thesimulated data from
our model (33) during epochs of low versushigh coupling among LC
neurons. Note similarity to empiric dataat left. See Fig. 4.2 and
ref. 33 for further details.
pharmacology. First, they support the view that the LC hasan
important role in attentional processes, and that pathol-ogy in LC
function could contribute to mental disorderswith attentional
components [e.g., attention-deficit/hyper-activity disorder (ADHD),
stress disorders, schizophrenia].These results also indicate that
alterations in couplingamong widely projecting neurons can have
profoundmentaland behavioral consequences, offering a new dimension
foranalyzing the function of highly divergent modulatory
brainsystems. Finally, these results, in view of other findings
thatelectrotonic coupling can be rapidly modulated by
neuro-transmitter inputs (55), indicate that coupling may be
avaluable new target for pharmaceutical development in
neu-ropsychopharmacology.
Opiate Withdrawal
A long series of studies has implicated the LC system inopiate
withdrawal (see ref. 56 for review). Recent work has
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Chapter 4: Norepinephrine 51
shed light on molecular and cellular changes that occur inLC
neurons during long-term opiate exposure that may un-derlie their
strong activation during withdrawal (reviewedabove). It is
generally acknowledged that the bulk of thishyperactive LC response
is mediated by glutamate inputsfrom the PGi (11,57,58). However, a
possible intrinsicsource of withdrawal-induced hyperactivity in LC
neuronshas been somewhat controversial. Although some studiesfind
no evidence for withdrawal-induced activation of LCneurons in
slices taken from morphine-dependent rats (59,60), others have
presented evidence for such intrinsicallymediated withdrawal
responses in LC (6164). Our studyof local intra-LC microinfusion of
opiate antagonists inmorphine-dependent rats has confirmed the
likelihood thatintrinsic changes with dependence contribute to the
hyper-activity of these neurons during withdrawal (65).
Differentstudies have suggested different mechanisms for this
locallymediated withdrawal effect. Lane-Ladd et al. (62) and
Nest-ler and Aghajanian (66) have presented evidence from
sliceexperiments consistent with the possibility that
long-termmorphine exposure causes a sustained increase in a
tetro-dotoxin-insensitive Na current, linked to the increase
incAMP, adenylate cyclase activity, and cAMP response
ele-ment-binding protein (CREB) that occurs in the LC
duringwithdrawal. In their view, this inward current causes
LChyperactivity when the inhibitory influence of morphineis removed
during withdrawal. Our recent in vitro studiessuggest a different
mechanism. These results indicate thatlong-term opiate
administration produces a decrease in K
conductance in LC cells that leads to a state of
increasedexcitability when the inhibitory influence of morphine
isremoved during withdrawal (63,64). The decreased K
conductance during long-term morphine administrationmay be a
direct compensatory response to the increased K
conductance evoked by acute opiates (49). In either case,
itseems clear that the local component of
withdrawal-inducedactivation of LC neurons is small compared with
the strongexcitation evoked by the increased glutamate input
fromthe PGi (see above).
Hypocretin/Orexin
As discussed above, the hypothalamic neuropeptide hypo-cretin,
which is strongly implicated in sleep regulation,densely innervates
the LC in rat and monkey (21). Recentstudies have revealed that
this peptide activates LC neuronsboth in vitro (21,67) and in vivo
(68). The activation isassociated with a mild depolarization but is
independent oftetrodotoxin and Ca2 (67). The results have led to
thetentative conclusion that hypocretin activates LC neuronsby
decreasing a resting potassium conductance (67). Over-all, the
results are important because they indicate a possiblepathway and
transmitter mechanism by which the LC be-comes activated during
arousal from sleep, which may inturn help to drive a
sleep-to-waking transition. This path-
way could be involved also in the psychiatric disorders
asso-ciated with sleep dysfunction (e.g., depression, stress
disor-ders, ADHD).
Cortical Influences on LC Activity
Tract-tracing studies have revealed that the prefrontal
cortexmay directly innervate LC neurons. Our retrograde and
an-terograde studies in rat find a projection from the
medialprefrontal cortex to the extranuclear peri-LC dendritic
zone(69). Another of our studies confirms a projection from
thecingulate cortex to the LC in the monkey (32). In linewith these
findings, additional experiments have revealedprominent effects of
cortical stimulation on LC activity. Asshown in Fig. 4.4, we found
that electric stimulation of themedial prefrontal cortex in rats
activates LC neurons; similarresults were obtained with chemical
stimulation (70). Wealso found this activation to be mediated by
glutamate re-lease within the LC, as would be expected for a direct
corti-cal (presumably glutamatergic) input (71). In contrast,
Saraand Herve-Minvielle (72) reported that medial
prefrontalstimulation in rats results in inhibition of LC activity.
Pro-cedural differences may underlie the different results.
Inparticular, the study by Sara and Herve-Minvielle used keta-mine
anesthesia, a potent glutamate antagonist. Thus, theresults may
indicate an underlying inhibitory effect of pre-frontal activation
on LC activity when the more potent glu-tamate-mediated excitation
is antagonized. In any case, theresults reveal that the prefrontal
cortex can strongly influ-ence activity of LC neurons.
Postsynaptic Actions of NE
The proposed role of the NELC system in arousal wasconfirmed by
Berridge and Foote (73), who showed thatlocal activation of LC
neurons by microinjection of betha-nechol produces EEG activation
in the halothane-anesthe-tized rat. Similar studies demonstrated
that LC inactivationby local microinfusion of clonidine decreases
EEG arousal(74). Additional experiments revealed that the arousing
ef-fects of LC stimulation are mimicked by stimulation of
adrenoceptors within the medial septum and are blockedby -receptor
antagonists infused into this area (75). Con-tinuing studies along
these lines confirmed that local LCstimulation in waking animals
increases EEG and behav-ioral indices of arousal (76). Additional
studies found, how-ever, that septal infusion of antagonists in
unanesthetizedanimals does not decrease arousal (77). Thus, in the
wakingrat, actions at other NE or non-NE receptors may also
benecessary for arousal. Together, these studies indicate thatLC
activity is an important regulator of EEG arousal, andthat these
effects are mediated, at least in part, by receptorsin the medial
septum area. Additional studies are neededto determine the precise
location of these actions and whatother systems and receptors may
be important for maintain-ing the alert state.
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Neuropsychopharmacology: The Fifth Generation of Progress52
FIGURE 4.4. Activation of locus ceruleus (LC) neuronby
stimulation of medial prefrontal cortex (PFC) in rat.A: Cumulative
post-stimulus time histogram (PSTH) forsingle-pulse electric
stimulation of the PFC. Stimulationpresented at arrow. B: PSTH for
train stimulation (20 Hzfor 0.5 s) given during the epoch
designated by smalldots. Bin width in each PSTH, 5 ms. C: Response
of anLC cell to stimulation of PFC with 100-mM glutamate(at bar
below). D: Response of an LC neuron to stimula-tion of PFC with
10-mM D,L-homocysteic acid plus 50-Mbicuculline (DLH bic; 60-nL
injection). (From JodoE, Chiang C, Aston-Jones G. Potent excitatory
influenceof prefrontal cortex activity on noradrenergic locus
coe-ruleus neurons. Neuroscience 1998;83:6380, with
per-mission.)
A B
C D
Studies in intact animals have shown that -receptoractivation
from the LC can induce plasticity in hippocampalresponses. Chaulk
and Harley (78) found that in vivo or invitro administration of -
or -receptor agonists signifi-cantly potentiates the population
spike amplitude recordedin the dentate gyrus in response to
perforant path stimula-tion. Because the LC is the sole source of
NE in the hippo-campus, these findings confirm previous results
that LCstimulation also potentiates such dentate gyrus
responses(79,80). These results indicate a role for NE from the
LCin plasticity in hippocampal activity, and may provide evi-dence
for a role of this system in memory consolidation(described
below).
BEHAVIOR
Opiate Withdrawal and the LC
Several recent studies in which behavioral
pharmacologictechniques were used have reexamined the role of the
LCsystem in opiate withdrawal and abuse. The results of
lesionstudies by Chieng and Christie (81), Caille et al. (82),
andDelfs et al. (43), in which different methods and approacheswere
used, all agree that the LC system is not necessaryfor physical
signs of morphine withdrawal (Fig. 4.4). Thisfinding contrasts with
previous ideas and represents a signif-icantly changed view of the
role of the LC system in with-drawal. Although some studies
involving microinjection ofagents that alter LC activity (83) or
molecular events withinLC neurons (62,84) implicate the LC in
withdrawal re-sponses, their results must be viewed with caution
becausediffusion of injected substances from the small LC nucleusto
adjacent areas that have been implicated in withdrawal,such as the
periacqueductal gray (85), difficult to rule out.Further studies
are needed to determine the behavioral con-sequences of LC
hyperactivity during opiate withdrawal.
Critical Role of A2 NE NeuronsInnervating the BNST in
AversionInduced by Opiate Withdrawal
Our recent work has demonstrated that NE innervation ofthe BNST
from A2 noradrenergic neurons is critical foraffective responses to
opiate withdrawal (43,86). We dem-onstrated that antagonists of
receptors injected into theBNST, or lesions of the ventral NE
bundle that carries fibersfrom the A2 group to the BNST, eliminate
aversive re-sponses to withdrawal (Fig. 4.5). Interestingly, these
samemanipulations had almost no effect on the physical with-drawal
response. These findings, and other results showingthat aversive
responses to withdrawal can occur in the ab-sence of somatic
responses (87,88), indicate that withdrawalaversion is not simply a
consequence of physical symptoms,and that separate pathways are
involved in physical andaffective withdrawal responses (Figs. 4.5
and 4.6). This isimportant for neuropsychopharmacology because the
affec-tive response during withdrawal is the most potent motiva-tor
of further drug seeking (89). Thus, studies to
developpharmacotherapies for opiate abuse should focus on
aversivewithdrawal responses specifically, rather than
examiningonly physical signs. Lesions of the LC system had no
effecton aversive or physical signs of withdrawal, findings
thatcorresponded to other recent results (discussed above).
Memory and the LC
Recent studies by Clayton andWilliams (90) have indicatednew
evidence for involvement of the NELC system inmemory. Inactivation
of the PGi (a major input to the LC,described above) with either
lidocaine or the GABA agonistmuscimol immediately after acquisition
in a one-trial inhib-itory avoidance task producedmarked deficits
on a retentiontest given 48 hours later. Conversely, chemical
stimulation
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Chapter 4: Norepinephrine 53
of the PGi with glutamate following training in either
aninhibitory avoidance or spatial delayed matching to sampleradial
maze task enhanced retention performance when as-sessed 48 or 18
hours later, respectively (91). Given theexcitatory connections
between PGi and LC, these findingssuggest that pharmacologic
manipulation of PGi neuronalactivity may affect memory formation
via influences on LCand subsequent NE release in brain systems
involved in theencoding of new information.
Recent studies by Przybyslawski et al. (92) have also indi-cated
a role for the LCNE system in memory. These exper-iments indicate
that memories are normally reconsolidatedeach time they are
reactivated by relevant cues. They foundthat blockade of
adrenoceptors after memory reactivation,during the consolidation
process, produced impairment onfuture tests of the same memory.
These results indicate thatreactivation of memory produces a
receptor-dependentintracellular cascade that reenacts the
consolidation process
FIGURE 4.5. Effects of intra-BNST (bed nucleus of the stria
termi-nalis) injection of noradrenergic drugs on conditioned place
aver-sion and somatic signs of opiate withdrawal. AD: Effects of
the-antagonist cocktail betaxolol/ICI 118,551 (A,B) or
propranololisomers (C,D) on place aversion and somatic signs. E,F:
Effects ofST-91 on place aversion and somatic signs. TC, teeth
chatter; ET,eye twitch; WDS, wet dog shakes; JUMP, jumping; WR,
writhing;PG, penile grooming; PT, paw tremor. All data are
expressed asmean standard error of themean (n 6 to 8 animals per
dose).For AD, p .05, analysis of variance followed by Fishers
PLSDtest for multiple comparisons. For E,F, p .05, Students
t-test.(From Delfs J, Zhu Y, Druhan J, et al. Noradrenaline in the
ventralforebrain is critical for opiate withdrawal-induced
aversion. Na-ture 2000;403:430434, with permission.)
FIGURE 4.6. Effects of dorsal (DNAB) and ventral (VNAB)
nora-drenergic bundle lesions on aversive and somatic signs of
opiatewithdrawal. A,C: Aversion scores. Aversion score equals time
inthe naltrexone-paired side on the test day minus the
precondi-tioning day. B,D:Number of somatic counts in 30minutes.
See Fig.4.5 legend for details and abbreviations. Nondependent
lesionedanimals exhibited neither aversion nor somatic signs
followingnaltrexone (data not shown). All data are mean standard
errorof the mean (n 6 to 8 control, 10 to 11 lesioned animals
pergroup). p .05, analysis of variance followed by Fishers PLSDtest
for multiple comparisons. (From Delfs J, Zhu Y, Druhan J, etal.
Noradrenaline in the ventral forebrain is critical for
opiatewithdrawal-induced aversion. Nature 2000;403:430434,
withpermission.)
responsible for the initial memory acquisition. This
NE-dependent lability of active memory traces indicates a
novelmechanism to target in pharmacologic manipulation
ofmemory-related disorders, such as posttraumatic stress dis-order
and Alzheimers disease.
Studies by Mao et al. (93) have found a role for 1and 2 NE
receptors in the dorsolateral prefrontal cortex inmemory. Infusion
of 1 agonists into the monkey prefrontalcortex produced deficits in
working memory (93), whereassimilar treatments with 2 agonists
improved memory per-formance (94).
Memory and the A2 NE System
Studies by McGaugh (95) during the last several years
haveestablished a role for NE stimulation of receptors in
theamygdala in the strong memories that are established
foremotionally salient events. Recently, this line of work hasshown
that the NTS is involved in this process, as lidocaineanesthesia of
the NTS prevents the memory-enhancing ef-fects of peripheral
epinephrine (47). Because the A2 neurons
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Neuropsychopharmacology: The Fifth Generation of Progress54
of the NTS strongly innervate the amygdala, this
findingindicates that the A2 neurons may be importantly involvedin
memory modulation. These studies suggest that a cen-tral nervous
systemperipherycentral nervous systemlong-loop circuit may be
involved, in which descendingactivity in response to emotional
events produces a periph-eral response (e.g., epinephrine release);
this response inturn stimulates receptors on vagal afferents that
then stimu-late the NTS to release NE in its hypothalamic and
forebraintargets. This possible route for enhancement of
emotionalmemories and other cognitive processes has received
littleattention previously. Such a loop may also be involved inthe
activation of A2 neurons during opiate withdrawal thatleads to the
corresponding aversive response (describedabove) (43). This is
potentially important clinically and psy-chopharmacologically
because peripheral receptors on vis-ceral afferent fibers that may
be involved in mental disordersrepresent a novel mechanism and
target for new pharmaco-therapies.
PSYCHOPATHOLOGY
Depression
Recent work by Miller et al. (96) has increased our
under-standing of the role of NE systems in depression. In
theirstudies, reduction of NE metabolites (presumably
reflectingdecreased NE turnover) after treatment with
-methyl-p-tyrosine (AMPT) caused no change in scores on the
Hamil-ton Depression Rating Scale in normal human subjects.
Incontrast, AMPT administration and reductions in NE turn-over in
patients in remission from depression after treatmentwith
desipramine or mazindol significantly increased theHamilton
Depression Rating Scale measures of depressivesymptoms (97). This
change was not seen in patients undertreatment with serotonin
antidepressants (fluoxetine or ser-traline). The results indicate
that monoamine deficiencyalone may not produce depressive symptoms,
but that dif-ferent types of depression exist that respond to
manipula-tions of different monoamine systems.
Advances in understanding the actions of antidepressantdrugs
have highlighted the possible role of NE systems indepression. New
drugs such as venlafaxine, which inhibitsreuptake of both serotonin
and NE, have been found tobe effective, particularly in refractory
depression (98). Inaddition, the highly effective antidepressant
paroxetine,which was previously thought to act selectively to
blockserotonin reuptake, has recently been found also to inhibitNE
reuptake (99,100). These findings confirm long-heldbeliefs that NE
is importantly involved in depression, andindicate that blockers of
NE uptake, including drugs thatselectively act at the NE
transporter, such as reboxetine(101,102), may be effective in
treating at least certain typesof affective illness (103).
Anxiety
Brain NE has long been implicated in anxiety disorders(104). Our
studies with cocaine- and morphine-dependentanimals have provided
new evidence for a role of centralNE systems in anxiety. By means
of a place-conditioningparadigm, we found that withdrawal from
long-term ad-ministration of morphine or cocaine is associated
withstrong anxiety, measured by the conditioned burying para-digm
(105). Importantly, the anxiogenic response to drugwithdrawal is
strongly attenuated by administration of the-receptor antagonist
propranolol, and by similar doses ofthe lipophobic 1 antagonist
atenolol, which is believed toact primarily peripherally. These
findings indicate that atleast some types of anxiety involve
stimulation of peripheral adrenoceptors.
ADHD
The firing patterns of LC neurons in behaving monkeysindicate
that this system plays an important role in attentionand
performance (reviewed above) (33,54,106). In particu-lar, one mode
of LC activity, characterized by elevated tonicdischarge,
corresponds to poor performance on a continu-ous performance task
that requires focused attention, witha high rate of false alarm
errors. These and other resultshave led us to propose that this
tonic mode of LC activitypromotes high behavioral flexibility and
disables focusedor selective attention (33,54). This view also
implies thatattentional disorders may be associated with LC
dysregula-tion in which the proper mode of activity is not
engagedadaptively for the context at hand. Specifically, several
paral-lels have been noted between behaviors in monkeys duringthe
tonic mode of LC activity and symptoms of ADHD,including
hypervigilance, irritability, poor focused atten-tiveness, and a
high false alarm rate in continuous perfor-mance tasks. These
findings indicate that the LC may playan important role in ADHD,
and that drugs that modulateLC mode, or switching between modes,
may be helpful intreating this disorder. In fact, many of the
stimulants thatare effective in treating ADHD decrease tonic LC
activity.
A role for the LCNE system in attentional disorders isalso
indicated by behavioral pharmacology experiments byArnsten and
colleagues (107). These investigators havefound that
overstimulation of 1 receptors in the prefrontalcortex produces
deficits in behaviors that depend on pre-frontal function (107).
Because ADHD includes symptomsof prefrontal dysfunction, these
findings raise the possibilitythat an overactive LC system may
contribute to ADHD byoverstimulation of 1 receptors in prefrontal
areas (108).
CONCLUSIONS
An impressive amount of research on NE systems has beenperformed
since the previous edition of this volume was
-
Chapter 4: Norepinephrine 55
published. This work is revealing an increasingly importantrole
for brain NE in mental function and dysfunction.Mechanisms by which
NE systems are involved in cognitive,addictive, stress-related, and
other behavioral functions arebeing elucidated. This progress not
only reinforces the im-portance of this system for
neuropsychopharmacology, butalso indicates that NE systems
represent a promising areafor discovering new and fruitful
approaches to developingtreatments for psychiatric disorders.
ACKNOWLEDGMENTS
This work was supported by PHS grants NS24698,DA06214, DA10088,
MH55309, and MH59978. Com-ments on the manuscript by Drs. Glenda
Harris and JonDruhan are greatly appreciated.
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