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Pharmacology and Behavior: Demystifying Neurotransmitters and Their Role

Karen L. Overall, MA, VMD, PhD, DACVB, ABS Certified Applied Animal Behaviorist

Introduction:

Acceptance of veterinary behavioral medicine has been aided by developments in neuropsychopharmacology and behavioral/neuropsychiatric genetics. The addition of psychotherapeutic agents to more general treatments, such as behavioral and environmental modification, has lead to better and faster treatment outcomes. In addition to facilitating better treatment of domestic animals and humans, psychopharmacological developments have permitted hypotheses about underlying mechanistic pathology to be tested. Mere treatment of non-specific behavioral complaints and signs is outdated and has been replaced with an approach that includes necessary and sufficient criteria for diagnosis and pursuit of treatment that addresses the specific mechanism underlying the neurochemical contribution to the pathology.

The use of medication should occur and is most effective as part of an integrated treatment program. There is no substitute for the hard work involved in behavior modification; however, some medications may be able to make it easier to implement the modification. Those seeking 'quick fix' solutions will doubtless be disappointed: inappropriate drug use will only blunt or mask a behavior without alteration of processes or environments that produced the behavior. Furthermore, the newer, more specific, more efficacious drugs have a relatively long lag time between initiation of treatment and apparent changes in the patient's behavior. This delay is due to the mechanism of action of the tricyclic antidepressants (TCAs) and the selective serotonin re-uptake inhibitors (SSRIs) which employ second messenger systems to alter transcription of receptor proteins.

Neurotransmitters and neurochemical tracts:

The neurotransmitters affected by behavioral medications are acetylcholine, serotonin, norepinephrine (noradrenaline), dopamine, gamma amino butyric acid (GABA), and excitatory amino acids. Common adverse effects of psychotherapeutic drugs are usually caused by a blockage of the muscarinic acetylcholine receptors, which have diffuse connections throughout the brain.

Serotonin (5-hydroxy-tryptamine [5-HT]): Serotonin receptors are all G-protein-coupled receptors. There are 14 identified classes of serotonin receptors. The 5-HT1 receptors are linked to the inhibition of adenylate cyclase and affect mood and behavior. Presynaptic 5-HT1A-receptors predominate in dorsal and median raphé nuclei; post-synaptic 5-HT1A-receptors predominant in limbic regions (hippocampus and septum) and some cortical layers. Activation of pre-synaptic receptors by agonists results in decreased firing of serotonergic neurons leading to transient suppression of 5-HT synthesis and decreased 5-HT release; activation of post-synaptic receptors decreases firing of post-synaptic cells. These are 'thermostatic' effects, not integrated outcomes of receptor activation. The overall effect depends on regulation of second messengers (cAMP, Ca2+, cGMP, IP3) and their effects on protein kinases which then alter neuronal metabolism and receptor protein transcription. The subclasses of 5-HT receptors vary in their affects. 5-HT1A receptors affect mood and behavior. 5-HT1D receptors affect cerebral blood vessels and appear to be involved in the development of migraine. These last two classes of receptor subtypes are the primary focus of many behavioral drugs. Urinary excretion of 5-HIAA (5-hydroxy indoleacetic acid) is a measure of 5-HT turnover and has been used to assess neurochemical abnormalities in human psychiatric patients, and has potential in this regard for veterinary behavioral medicine.

Noradrenaline / norepinephrine (NE): The most prominent collection of noradrenergic neurons is found in the locus coeruleus of the grey matter of the pons and in the lateral tegmental nuclei. There is also a cluster in the medulla. NE has been postulated to affect (1) mood [NE decreases in depression and increases in mania], (2) functional reward systems, and (3) arousal.

Dopamine: The distribution of dopamine in the brain is non-uniform, but is more restrictive than that of NE. Dopaminergic nuclei are found primarily in: (1) the substantia nigra pars compacta which projects to the striatum and is largely concerned with coordinated movement; (2) the ventral tegmental area which projects to the frontal and cingulate cortex, nucleus acumbens, and other limbic structures; and (3) the arcuate nucleus of the hypothalamus which projects to the pituitary. A large proportion of the brain's dopamine is found in the corpus striatum, the part of the extrapyramidal system concerned with coordinated movement.

Dopamine is metabolized by monamine oxidase (MAO) and catechol-O-methyl transferase (COMT) into dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA). HVA is used as a peripheral index of central dopamine turnover in humans, but this use has been little explored in veterinary medicine. All dopaminergic receptors are G-protein-coupled transmembrane receptors. The D1 receptors exhibit their post-synaptic inhibition in the limbic system and are affected in mood disorders and stereotypies. The D2, D3, and D4 receptors are all affected in mood disorders and stereotypies. Excess dopamine, as produced by dopamine releasing agents (amphetamines and dopamine agonists, like apomorphine) is associated with the development of stereotypies.

Gamma amino butyric acid (GABA): GABA, the inhibitory neurotransmitter found in short interneurons, is produced in large amounts only in the brain and serves as a neurotransmitter in ~30% of the synapses in the human CNS. The only long GABA-ergic tracts run to the cerebellum and striatum. GABA is formed from the excitatory amino acid (EEA) glutamate via glutamic acid decarboxylase (GAD), catalyzed by GABA-transaminase (GABA-T) and destroyed by transamination. There are two main groupings of GABA receptors - GABAA and GABAB. GABAA receptors, ligand-gated ion channels, mediate post-synaptic inhibition by increasing Cl- influx. Barbiturates and benzodiazepines are a potentiators of GABAA. GABAB receptors are involved in the fine-tuning of inhibitory synaptic transmission: presynaptic GABAB receptors inhibit neurotransmitter release via high voltage activated Ca++ channels; postsynaptic GABAB receptors decrease neuronal excitability by activating inwardly rectifying K+ conductance underlying the late inhibitory post synaptic potential.

GABA also has a variety of tropic effects on developing brain cells. During ontogeny GABAergic axons move through areas where other neurotransmitter phenotypes are being produced, and so may be related to later monoaminergic imbalances. The extent such ontogenic effects are relevant for behavioral conditions is currently unknown but bears investigating.

EAAs (glutamate, aspartate, and, possibly, homocysteate): EEAs have a role as central neurotransmitters and are produced in abnormal levels in aggressive, impulse, and schizophrenic disorders. The main fast excitatory transmitters in the CNS are EEAs. Glutamate, widely and uniformly distributed in the CNS, is involved in carbohydrate and nitrogen metabolism. It is stored in synaptic vesicles and released by Ca2+ dependent exocytosis, so calcium channel blockers may affect conditions associated with increased glutamate. Both barbiturates and progesterone suppress excitatory responses to glutamate. Pre-synaptic barbiturates inhibit calcium uptake and decrease synaptosomal release of neurotransmitters, including GABA and glutamate.

Other chemical mediators: Nitric oxide (NO) and arachidonic acid metabolites (e.g., prostaglandins) can mediate neurotransmitter release. These are synthesized on demand and released by diffusion, requiring no specialized vesicles or receptors. Like encapsulated neurotransmitters (i.e., ACh) that are extruded through exocytosis after binding with the synaptic membrane, these chemical mediators are activated by an increase in calcium, so may be affected by calcium channel blockers.

Roles for neuronal stimulation, synaptic plasticity, and receptor protein transcription and translation:

What makes TCAs and SSRIs special and why are they so useful for anxiety disorders? The key to the success of these drugs is that they utilize the same second messenger systems and transcription pathways that are used to develop cellular memory or to "learn" something. This pathway involves cAMP, cytosolic response element binding protein (CREB), brain derived neurotrophic factor (BDNF), NMDA receptors, protein tyrosine kinases (PTK) - particularly Src - which regulate activity of NMDA receptors and other ion channels and mediates the induction of LTP (long-term potentiation = synaptic plasticity) in the CA1 region of the hippocampus.

There are two phases of TCA and SSRI treatment: short-term effects and long-term effects. Short-term effects result in a synaptic increase of the relevant monoamine associated with re-uptake inhibition. The somatodendric autoreceptor of the pre-synaptic neuron decreases the firing rate of that cell as a thermostatic response. Regardless, there is increased saturation of the post-synaptic receptors resulting in stimulation of the $-adrenergic coupled cAMP system. cAMP leads to an increase in PTK as the first step in the long-term effects. PTK translocates into the nucleus of the post-synaptic cell where it increases CREB, which has been postulated to be the post-receptor target for these drugs. Increases in CREB lead to increases in BDNF and tyrosine kinases (e.g., trkB) which then stimulate mRNA transcription of new receptor proteins. The altered conformation of the post-synaptic receptors renders serotonin stimulation and signal transduction more efficient.

Knowledge of the molecular basis for the action of these drugs can aid in choosing treatment protocols. For example, the pre-synaptic somatodendritic autoreceptor is blocked by pindolol (a $-adrenoreceptor antagonist) so augmentation of TCA and SSRI treatment with pindolol can accelerate treatment onset. Long-term treatment, particularly with the more specific TCAs (e.g., clomipramine) and SSRIs, employs the same pathway used in LTP to alter reception function and structure through transcriptional and translational alterations in receptor protein. This can be thought of as a form of in vivo "gene therapy" that works to augment neurotransmitter levels and production thereby making the neuron and the interactions between neurons more coordinated and efficient. In some patients short-term treatment appears to be sufficient to produce continued "normal" functioning of the neurotransmitter system. That there are some patients who require life-long treatment suggests that the effect of the drugs is reversible in some patients, further illustrating the underlying heterogeneity of the patient population considered to have the same diagnosis.

Literature cited:

1.  Blier P. and de Montigny C. (1997) Current psychiatric uses of drugs acting on the serotonin system. In: Serotonergic Neurons and 5-HT Receptors in the CNS, ed. H.G. Baumgarten and M Gothert, pp 227-750. Berlin: Springer.

2.  Caccia S. and Garattini S. (1992) Pharmacokinetic and pharmacodynamic significance of antidepressant drug metabolites. Pharmacology Research 26, 317-329.

3.  Capella D., Bruguera M., Figueras A., and Laporte J-R. (1999) Fluoxetine - induced hepatitis: why is post-marketing surveillance needed? European Journal of Clinical Pharmacology 55, 545-546.

4.  Daniel H., Levenes C., and Crépel F. (1998) Cellular mechanisms of cerebellar LTD. Trends in Neuroscience 21, 401-407.

5.  deBoer T., Stoof J.C., and van Duijn H. (1982) The effects of convulsant and anticonvulsant drugs on the release of radio labeled GABA, glutamate, noradrenaline, serotonin, and acetylcholine from rat cortical slices. Brain Research 253, 153-160.

6.  Dodman N.H., Donnelly R., Shuster L., Mertens P., and Miczek K. (1996) Use of fluoxetine to treat dominance aggression in dogs. Journal of the American Veterinary Medical Association 209, 1585-1587.

7.  Kaplan H.I. and Sadock B.J. (1993) Pocket Handbook of Psychiatric Drug Treatment. Baltimore: William and Wilkins.

8.  Lauder J.M., Liu J., Devaud L., and Morrow A.L. (1998) GABA as a trophic factor for developing monamine neurons. Perspectives in Developmental Neurobiology 5, 247-259.

9.  Nattal S., Mittleman M. (1984) Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. Journal of Pharmacology and Experimental Therapeutics 231, 430-435.

10. Overall K.L. (1998a) Diagnosing feline elimination disorders. Veterinary Medicine 93, 350-362.

11. Overall K.L. (1998b) Tracing the roots of feline elimination disorders to aggression. Veterinary Medicine 93, 363-366.

12. Overall K.L. (1998c) Treating feline elimination disorders. Veterinary Medicine 93, 367-382.

13. Overall K.L. (1999a) Allow behavioral drugs ample time to take effect. Veterinary Medicine 94, 858-859.

14. Overall K.L. (1999b) Understanding and treating dominance aggression: An Overview. Veterinary Medicine 94, 976-979.

15. Overall K.L. (1999c) Behavioral approaches to canine dominance aggression. Part IV. The addition of medication. Veterinary Medicine 94, 1049-1055.

16. Overall K.L. (2000) Behavior modifying drugs: Neurochemistry and molecular biology. Proceedings of the 18th ACVIM Forum 18, 68-71.

17. Salter M.W. (1998) Src, N-methyl-D-aspartate (NMDA) receptors, and synaptic plasticity. Biochemical Pharmacology 56, 789-798.

18. Sohn R.S. and Ferrendelli J.A. (1976) Anticonvulsant drug mechanisms. Phenytoin, phenobarbital, and ethoxsuximide and calcium flux in isolated presynaptic endings. Archives of Neurology 33, 626-629.

19. Taubøll E. and Gjerstad L. (1993) Comparison of 5 "-pregnan-3"-01-20-one and phenobarbital on cortical synaptic activation and inhibition studied in vitro. Epilepsia 34, 228-235.

20. Trotti D., Danboldt N.C., and Volterra A. (1998) Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration. Trends in Pharmacological Sciences 19,328-334.

21. Waagepetersen H.S., Sonnewald U., and Schousboe A. (1999) The GABA paradox: multiple roles as metabolite, neurotransmitter, and neurodifferentiative agents. Journal of Neurochemistry 73, 1335-1342.


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