Case studies in behavioral pharmacological therapy (Proceedings)

Our knowledge of the brain on the neurochemical, genetic and molecular level is increasing steadily each year. Despite this, little is definitively known about the neurochemical correlates of various disease processes. Much of our knowledge concerning the etiology of mental illness comes from response to pharmacological intervention. The neurotransmitter systems interact with each other, and with other signaling systems such as hormones, in complex ways. This makes it difficult to hypothesize on the effects of any particular drug as well as to predict response to therapy.

There are only three drugs labeled for use in treating animal behavioral disorders. Most drugs are used in an extralabel fashion based on information extrapolated from humans and laboratory animal models, which may or may not accurately mimic clinical disease. Data provided on drug interaction and CYP hepatic enzyme systems are also extrapolated from human data. There is little data on the effects of these drugs on CYP systems in dogs and cats, and even less on horses. As with humans, there is likely to be high genetic variability in CYP systems in animals.

Nevertheless, it is important to understand what is known concerning chemical transmission in the brain in order to study psychopharmacology. Keep in mind that receptors for these chemicals are usually found in somatic tissues as well as in the brain; hence, psychotropic drugs may have peripheral effects as well. Some of these peripheral effects may actually be part of the therapeutic profile for the psychological disturbance.

There are many substances that function in neurotransmission in the brain. The neurotransmitters (NT) most commonly manipulated by drug therapy include dopamine (DA), serotonin (5HT), norepinephrine (NE), acetylcholine (Ach), γ-aminobutyric acid (GABA), and the excitatory amino acids such as glutamate (Glu).

Neurotransmission

Receptors occur presynaptically and postsynaptically. Presynaptic receptors are either autoreceptors or heteroreceptors. Heteroreceptors bind NTs that are different from those released by the terminal bouton of that neuron. Both receptors serve to modify the release of the NT into the synaptic cleft. Receptors can be up-regulated (increased in number) or down-regulated (decreased in number). Receptors can also change in sensitivity – sensitized or desensitized. Keep in mind that some texts and references use down-regulation and desensitization interchangeably although they are different phenomena. Although receptors are specific for certain neurotransmitters, these NTs sometimes can have effects on other receptors but usually at less affinity.

Acetylcholine is formed from choline and acetyl Coenzyme A and is one of the most widely distributed NT in the brain. There are two classes of receptors: muscarinic and nicotinic. Cholinergic receptors are involved in cognition, memory, sensory processing, motor coordination, and ANS and PNS functions.

Norepinephrine is formed from the amino acid tyramine. It is degraded by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). It is also inactivated by a NE reuptake transport pump which clears excess NT from the synaptic cleft. There are two basic classes of receptors (alpha and beta) with various subtypes: Alpha 1 and 2, Beta 1, 2, 3. Alpha 2 receptors occur presynaptically as autoreceptors. Cell bodies are located primarily in the locus ceruleus in the brain stem. Noradrenergic neurons are involved in attention, vigilance, learning/memory, anxiety, and autonomic function.

Serotonin is formed from the amino acid tryptophan. It is degraded by MAO and a reuptake transporter. At least 18 subtypes of receptors have been identified both centrally and peripherally. Presynaptic autoreceptors include 5HT1A which is a somatodendritic autoreceptor that slows impulse flow through the neuron. The 5HT1D receptor is a terminal autoreceptor that inhibits 5HT release from the terminal. Chronic stimulation of these receptors downregulates and desensitizes them leading to a loss of negative feedback. This results in a return of 5HT activity to baseline or above baseline levels. The major postsynaptic receptors are 5HT1A, 5HT1D; 5HT2A, 5HT2C – stimulation of these receptors produce agitation and restlessness, as well as anorexia and sleep loss. The 5HT3 is the only ionotropic 5HT receptor; it is involved in emesis. Chronic treatment with serotonin modulators leads to downregulation of postsynaptic 5HT2A receptors. Other late adaptations include indirect enhancement of NE output, increases in cAMP, and increases in cyclic AMP-response element binding protein (CREB) and brain derived neurotrophic factor (BDNF).

Serotonergic neurons also have noradrenergic heteroreceptors: α2 on axon terminals in the cortex — which inhibit serotonin release, and α1 on cell bodies in brain stem – which enhance 5HT release.

Serotonin is important in the treatment of many mental disorders. Transmission is complex and interrelated to other NTs especially DA and NE. Serotonergic cell bodies are located in the raphe nucleus in the brain stem. The serotonergic system is involved in anxiety, panic, depression, compulsive disorders, sleep, and appetite. Drugs that influence the serotonergic system represent the largest group of drugs used for behavior therapy in veterinary medicine.

Dopamine is formed from amino acid tyrosine and degraded by MAO and COMT; it is eliminated through the DA reuptake transporter. Dopaminergic transmission is involved in psychosis, stereotypies, reward/reinforcement, and fine motor control.

GABA is formed from glutamate and degraded by GABA T enzyme. There are two classes of receptors: GABAA which is a ligand gated chloride ion channel and GABAB which is metabotropic. GABA is the major inhibitory NT in the brain. GABA has binding sites for various allosteric modulators including benzodiazepines (BZP), barbiturates, and alcohol. There are at least 5 different BZP receptors mediating various effects. GABAergic transmission is involved in anxiety, panic, and anticonvulsant effects.

This lecture will review several case studies in mono- and combination drug therapy for common behavioral disorders. Recommendations for drug usage for situations such as nocturnal restlessness, car travel, boarding, veterinary visits, storm phobia, etc will also be covered.