Acetylcholine and dopamine systems: Outlining the pharmacological issues for motor disorders

Thomas Austin Acetylcholine and

dopamine systems

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Acetylcholine and dopamine systems: Outlining the

pharmacological issues for motor disorders

Completed as part of a BSc Psychology degree.

Submission: 7/01/2014

Word Count: 2811


dopamine systems

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Acetylcholine and dopamine systems: Outlining the pharmacological issues

for motor disorders

Abstract

An explorative review of literature of pharmacological aspects of acetylcholine

(ACh) and dopamine (DA) neurotransmitter systems on the methods of causation of

motor dysfunction, ranging from dyskinesia to tremulous jaw movements. The

current author comments on the ACh system with reference to nicotinic ACh receptor

(nAChR) blockade, competitive antagonism and tacrine-induced jaw tremor

research. The DA system implication is also reviewed and raises current topical

issues models of neuro-circuitry and ACh-DA interactions. To conclude, the ACh and

DA systems and their interactions require future research to establish concrete

mechanisms and the complexities of these system interactions to be explored in

relation to dysfunctional motor behaviour.


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1. Introduction

Acetylcholine (ACh) and dopamine (DA) are two neurotransmitters that

inhabit the brain and despite their differences are related in many neurological

structures (Parent & Hazrati, 1995) and behaviours (Nunes, Randall, Podurgiel,

Correa, & Salamone, 2013).

ACh is involved in the autonomic nervous system and can be observed in the

peripheral and central nervous systems. Initially ACh was found in cardiovascular

tissue, in which it is inhibitory but research has progressed the documentation of the

neurotransmitter in the brain and on other motor behaviours (Edwards, Dolezal,

Zemkova, & Vyskocil, 1985).

The ACh system is based upon two main types of receptor; nicotinic

(nAChRs) and muscarinic (mAChRs) receptors. The nAChRs are ligand-gated

channels comprised of five subunits; α1 to α6, β1 to 4, γ, δ, and ε. There are many

nAChR variants as the receptors can be hetero- or homo-pentamers, with each

variant expressing a unique affinity for the possible agonist and antagonist agents

(Papke & Porter Papke, 2002). Muscarinic receptors are metabotropic and therefore

use G proteins as their method of signalling, caused by ACh binding to one of seven

transmembrane areas.(Ishii & Kurachi, 2006). This receptor only has five types (M1-

M5), despite M5 being pharmacologically elusive but genetically identified (Caulfield

& Birdsall, 1998) The role of mAChR antagonists in parkinsonian symptomology is

easily documented as several agents are used in the parkinsonian treatment

(Langmeand, Watson, & Reavill, 2008).


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DA is a neurotransmitter with complex roles in behaviour, from addiction

(Diana, 2011) to Parkinson’s disease (Merims & Giladi, 2008). Many psychological

disorders are attributed to dopamine-related abnormality such as schizophrenia and

attention deficit hyperactivity disorder (ADHD). DA is also secreted and has purpose

outside the brain.

DA receptors (DARs) are split into two families; D1-like (D1 and D5) and D2-

like (D2, D3 and D4) subtypes. Postulation surrounding a sixth and seventh subtypes

(D6 and D7) was expressed, however there is considerable lack of supporting

research (Contreras et al., 2002).

2. Acetylcholine

2.1. Movement disorders

Research that implicates ACh as playing a major role in movement disorders

uses a wide range of techniques and experiment types. Research with animals,

stemming from agricultural toxicology research into livestock disease, where as other

research utilises a pharmacological and behavioural paradigm. A toxicological

article–regarding the nAChR antagonists (deltaline and methyllycaconitine (MLA))

and agonists (nicotine and anabasine) from Delphinium and Nicotiana species,

respectively– indicates support for AChs involvement in motor disorders (Aiyar et al.,

1979).

The authors studied the agents’ method of mechanism in the body and found

deltaline and MLA in excessive amounts to cause competitive antagonism-induced

paralysis via blockade of nAChRs at post-synaptic neuromuscular sites. However,

the experiment was a descriptive exploration of the method of action, rather than

adhering to a pharmacological paradigm.


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However, the psychopharmacological implications of these nAChR

antagonists and agonists’ methods of action were not commented upon in the

publication. A recent study (Welch, Pfister, Lima, Green, & Gardner, 2013) applied

Aiyar et al.’s work by studying the action of both nAChR antagonists and agonists, of

the Delphinium species, in pharmacological experiments on mice to further define

the chemical actions on the neurology of the subjects.

Welch et al. used non-lethal doses of the two isolated toxins in the

Delphinium species: deltaline and MLA, as well as nicotine and anabasine. However,

Welch et al. uses the substances to specifically evaluate the effect on motor

coordination in the subject using a battery of assorted motor performance tasks; a

balance beam, a grip strength, a rotarod, open field analysis and featured a tremor

monitor.

The results showed significance between the non-lethal dose agonists and

antagonists used and acute movement and coordination dysfunction, and then the

subject undergoes a brief period of inactivity. This illustrates the control of ACh and

the endogenous receptors on movement signalling on a neuronal level, agonist and

antagonists of nAChRs can both cause motor dysfunction. The study holds an

agricultural rationale by explaining the connection between Delphinium toxicity and

the loss of livestock due to poisoning (paralysis). However, the aforementioned study

(Welch et al., 2013) can be criticised due to the lack of generalisation of results to a

human population as the subjects were mice.


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To elucidate; the methodology features the use of a median lethal dose

(LD50) of the administered agents for mice to find the non-lethal dose. The non-

lethal dose was calculated by finding 75% of the LD50. However, the LD50 relies on

many factors such as metabolic rate, agent-associated cytoarchitectual damage and

many environmental and genetic factors regarding receptor frequency, sensitivity

and physical distribution. Therefore, the results cannot be used to represent a

human population as it may result in an over/under pronounced or otherwise skewed

effect on motor dysfunction and/or nAChR activity.

Acetylcholine (ACh)

nAChR

Agonists

nAChR

Antagonists

Diagram 1. Illustration of the antagonists (deltaline and methyllycaconitine (MLA)) and agonists (nicotine and

anabasine) that were used in research (Welch et al., 2013). The 2D ACh chemical has been added to represent

the ACh system.


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Furthermore, the pharmacokinetics of deltaline and MLA have not been

evaluated and remains unclear. This information would aid pharmacological

interpretation of results.

Anabasine has been found to cause sustained muscle paralysis in adult and

embryo-stage animals, in-utero, thus causing teratogenic effects by manipulation of

the nACh system triggering motor dysfunction in (Green, Lee, Panter, & Brown,

2012) teratogenic effects are due to the motor dysfunction in critical stages of foetal

development (Weizweig et al., 2008).

Furthermore, a study supporting the postulation of ACh enrolment in motor

dysfunction symptomology used an indirect study design, focusing on nicotine as an

AChR agonist; nicotine initially stimulates nAChRs in the ACh system (Wang & Sun,

2005). However after prolonged and persistence agonism the receptors cause

tachyphalaxis, a sudden reduction in receptor sensitivity. Further evidence of AChs

role in movement disorders comes from a review of tacrine, an acetylcholinesterase

and an Alzheimer’s disease treatment, and links with tremulous jaw movements

(TJMs)(Cousins et al., 1999). The TJM is a type of tremor, a dysfunctional movement

disorder characteristic of parkinsonian syndrome (Keltner, 1994).

The authors accompanied the review with three experiments to determine the

extent, if any, that ventrolateral striatal ACh modulates TJMs in-vivo (rats, n=89).

Several doses of tacrine were used; 2.5mg/kg and 5mg/kg. The first experiment

consisted of subject’s ventrolateral neostraitum micro-injected with an ACh synthesis

inhibitor (hemicholinium-3) in rats exhibiting tacrine-induced TJMs. The result of this

was a reduction in the TJM severity, alleviating the motor dysfunction by reducing

the ACh available for binding in the synapse.


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A repeat of the initial experiment was conducted, but was altered and used as

a control against the natural diffusion of hemicholinium-3 to other cortices in the

surrounding area and causing unwanted effects. The importance of the ventrolateral

neostriatum was supported by a previous study, using scopolamine and the

methylated derivative to reduce TJMs (Mayorga, Carriero, Cousins, Gianutsos, &

Salamone, 1997).

Fig1. A scatterplot illustrating the correlational relationship between ACh blood levels and number

of TJMs spotted. Circles mark each control group subjects; squares mark the 2.5mg/kg tacrine group

subjects; triangles mark 5.0mg/kg tacrine group subjects (Cousins et al., 1999, p.445).


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Cousins et al. then conducted a final experiment, tacrine-induced TJM

extracellular ACh levels were assessed using, a surgically placed, ventrolateral

striatum dialysis module (1999). The authors found a 5mg/kg tacrine dose to cause

acute increase in ventrolateral ACh levels, 324-fold of baseline. This increase of ACh

was statistically significant when correlated with TJMs (r =+.56, p< .0001). The

authors’ concluded that ventrolateral ACh system plays a substantial role in

tremulous movements and therefore in parkinsonian symptoms.

Despite Cousins et al.’s high standard of research methods, from meticulous

record keeping to an effective review of past literature, the study can be criticised on

several key points. Primarily, despite obtaining a significant overall effect, the groups

that received 2.5mg/kg of tacrine showed no significant relationship between

ventrolateral neostriatal ACh and TJMs. This highlights the possible reductionism of

the implied overall results as the spread of the significant correlations is not even.

The authors correlations are as follows; 5mg/kg (r= +.9, p< .001), 2.5mg/kg (r= + .45,

no significance), combination of 5mg/kg and 2.5mg/kg (r= + .56, p< .05). However,

the statistics conducted between the ventrolateral neostriatal ACh levels and TJMs in

the 2.5mg/kg and 5mg/kg tacrine-dosed groups were found to be significant.

Secondly, the authors’ comment on the possibility that tacrine’s alteration of ACh

levels may not be as presumed –as an acetylcholinesterase inhibitor— but from

several other methods of mechanism such as an increase of receptor sensitivity or

an encouragement of ACh release. The lack of generalisation of the results to a

human population hinders the results; however, Cousins et al. included and

discussed research regarding human in-vivo tacrine symptoms in Alzheimer patients.

This final issue can be overlooked as in-vivo human testing would be unethical and

rats are better than many other alternative populations due to brain similarities.


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In addition, an α4 nAChR mutation in mice was found to elicit akinesia,

muscle rigidity and tremor symptomology. This symptomology is recognised in

parkinsonian syndrome and other movement disorders. The pharmacological

blockade and genetic deletion of nAChRs does not affect movement. However,

genetic mutation on the coding gene for α4 nAChRs (Leu9’Ala) in dopaminergic

neurones in the dorsal striatum can result in hypersensitivity of α4 receptors when

agonised (Soll, Grady, Salminen, Marks, & Tapper, 2013). The authors compared

wild-type (WT) and Leu9’Ala genes in mice and used both groups with an α4β2

nAChR antagonist (dihydro-β-erythroidine; DHβE). In WT mice the DhβE cause no

motor behaviour affect, however when the α4 nAChR antagonism occurs in Leu9’Ala

mice reversible motor dysfunction is exhibited resulting in increased movement

speeds, akinesia, catalepsy and tremors. This outlines the relationship between

nAChRs and their role in mediation of parkinsonian-type symptoms and suggests

that genetic disposition can place vulnerabilities within a component of the ACh

system (genetics for one specific receptor subunit) instead of the entire system itself.

The proposed phenomenon uses the desensitivity of the genetically altered α4

nAChR as a basis for motor dysfunction but the authors have linked this, indirectly,

to the dopaminergic motor pathway circuit (i.e. D1-5 agonism) (Soll et al., 2013).


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2.3. Conclusion

In conclusion, research regarding nAChR antagonism (Aiyar et al., 1979;

Welch et al., 2013) and agonism (Green et al., 2012; Wang & Sun, 2005) shows that

either activity at the nAChR site can cause motor dysfunction such as paralysis.

However, the method of action is complex and needs to be focused on: The ACh

system is not directly in control of movement dysfunction observed but is a result of

ACh mediation in brain areas enrolled in motor capabilities (Cousins et al., 1999;

Keltner, 1994; Mayorga et al., 1997). Some research supports the postulation that

genetics can play a role in nAChR-related motor dysfunction (Soll et al., 2013).


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3. Dopamine

3.1. Movement disorders

In a recent review of the pharmacology (2007) of L-DOPA, a parkinsonian

motor dysfunction treatment drug, and the neural circuitry involved in prolonged L-

DOPA-induced dyskinesia symptomology (Cenci). The motor dysfunction is

mediated by extracellular DA in the basal ganglia and striatal areas and causes a

cascade of alterations resulting in the expression of genes that cause predisposition

for long-term dyskinesia. This occurs primarily in the D1 DA subunit receptors in the

striatal neurones, which encourage inhibitory neurotransmitters (prodynorphin) and

inhibitory enzyme secretion, such as glutamic acid decarboxylase. As a result the

globus pallidus’ internal segment’s (GPi) and substantia nigra pars reticulate’s

inhibition causes dysfunctional neocortical activity produces dysfunctional movement

(Cenci, 2007). The researcher concluded that this cascade affects the GABA signal

projection into the basal ganglia, further producing abnormal activation in motor

structures. Cenci (2007) uses an extensive literature review to support the neuro-

circuitry model proposed. In summary; DA’s modulation of movement dysfunction in

L-DOPA-induced parkinsonian-type symptoms.

Moreover, Cenci’s review is based upon a paper (Parent & Hazrati, 1995) that

reviewed research on the cortical basal ganglia and cortico-thalamic loop. This

article further documented and commented upon the importance of basal ganglical

modulation of premotor neurones and psychomotor behaviours.


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Furthermore, in 2010, hindbrain pedunculopontine and laterodorsal tegmental

nuclei project into the midbrain DA neurons causing nACh and mACh receptor

neurone excitation within the substantia nigra and ventral tegmental structure

(Lester, Rogers, & Blaha); thus controlling the flow of dopamine into the dorso-

ventral striatum and prefrontal cortex areas. Forebrain DA modulation has been

recorded to stem from ACh neurones in the striatum, further implementing the area

in ACh and DA-related dysfunctional motor behaviour.

Hoebel, Avena, & Rada supported the link between ACh and DA activity

modulation of dysfunctional parkinsonian motor symptoms (2007).

An experiment in 1975 investigated the behavioural products of DA,

haloperidol (an inverse DA agonist), carbachol (AChR agonist) and atropine (mAChR

antagonist) injection in rhesus monkeys, individually and in combinations(Cools,

Hendricks, & Korten) . DA injections caused a dynamic phase (P1; non-dysfunctional

increase in manipulative movement), the expression of spasmodic torticollis –related

to dystonic movements) in the dystonic phase (P2) and the dyskinetic phase (P3)

where speech and other limb dyskinesia was produced. DA-induced P1 and P2 were

counteracted by haloperidol, but there was no effect on DA-induced P3. Carbachol-

induced P2 was enhanced by high DA dose, but P4 was eliminated in subjects.

Carbachol induced P1, P2 and P3 as well as an additional epileptic phase (P4),

characterised by generalised epileptic seizures. Finally, atropine countered P1, P2

and P4 but not P3. These finding suggest that the striatal ACh-DA interactions are

more complicated than the two-dimensional balance model but propose that the

model is involved in the mediation of generalised epileptoid seizures. The study also

highlighted a secondary method of action relating to speech dyskinesia behaviour;

implementing neurotransmitters other than DA.


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However, again the generalizability of studies that use animal subjects is an

issue with Cools, Hendricks and Korten’s study. This is because, despite numerous

similarities in neurology as well as behaviour, animals such as rhesus monkeys are

ultimately not human and may have different within-species variation of receptor

variables. Nevertheless, the results are link to human behavioural phenomena such

as parkinsonian-type motor dysfunction.

Despite this limitation, Cools, Hendricks and Korten have efficiently utilised

pharmacological methodology to support a less reductionist model of ACh-DA

interactions and effects on motor behaviour. Replications of this study should use a

wider range of pharmacological agents to test for further underlying mechanisms of

the brains motor areas.

The basal ganglia have been implicated as the main structure involved in the

interactions between ACh and DA systems in the brain. Lehmann and Langer

demonstrated the need for a balance between the two neurotransmitters. An

increase in ACh can be DA-induced and is associated with motor dysfunction, as

well as high levels of DA being attributed to hyperkinesia symptoms (Lehmann &

Langer, 1983).

Parkinsonian symptom progression has been correlated with DA neurone

terminal degradation, located in the basal ganglia, using a [18F]dopa-PET scan

technique and is used to monitor disease progression (Morrish, Sawle, & Brooks,

1996). However, this study has several main criticisms. Primarily, the issue of

reductionism, as ACh and other neurotransmitters are left out of the model used.

Secondly, a criticism regarding the sample being too small (n=10) for reliability is a

marker for future replication despite using clinical and PET scan methods.


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3.3 Conclusion

In conclusion, the link between DA systems and motor dysfunction is

thoroughly documented (Cenci, 2007; Cools et al., 1975; Lester et al., 2010) and

research has clarified the link between the DA-related dysfunction and modern day

motor disorders such as Parkinson’s disease (Morrish et al., 1996). However, Cools,

Hendricks and Korten (1975) have commented and refuted a reductionist

pharmacological mechanism of action model of DA and introduced a new, multi-

neurotransmitter model of motor dysfunction. A [18F]dopa-PET scan study (Morrish

et al., 1996) highlights the need for large sample size to avoid criticism of reliability.

However, the research methods employed are time demanding and restrictive,

hindering replicability but enhancing methodological precision.


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4. Summary

ACh and DA system models of mechanism should not be reduced and should

be fully explored pharmacologically. A range of neural structures are related to these

two neurotransmitters and should be link using future studies to parkinsonisan and

other motor dysfunction disorders. The applications of research into parkinsonian

and other motor dysfunction disorders can have great impact for design of

pharmacological treatments and would therefore increase the quality of life for those

who have Parkinson’s disease or tremor movements. Disorders that are motor-

related can cause immense impacts to individuals and their relations, but these

disorders can be induced by medication for already severe disorders. As seen in

Alzheimer patients who use tacrine (Keltner, 1994; Mayorga et al., 1997).

Future research should include a wide variety of experimental techniques to

further characterise the neural correlates of motor dysfunction structures using brain

mapping. However, the practicality of conducting neuro-imaging on a subject that

may have a lack of control of movement any result in unusable data. More research

using a wide range of ACh and DA agents should be combined to determine if the

differing receptor subtypes have different effects on behaviour. Subtype selective

agonists and antagonists should also be utilised to pharmacologically measure the

differences between each receptor type and elicited behaviour; the combination of

nACh inhibitors and one selective nAChR agonist could be used to investigate this.


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Acetylcholine and dopamine systems: Outlining the pharmacological issues for motor disorders

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