Second Edition

Sharon L. Crowell‐Davis, DVM, PhD, DACVB

Professor of Behavioral Medicine
Department of Veterinary Biosciences and Diagnostic Imaging
College of Veterinary Medicine
University of Georgia
Athens, GA, USA

Leticia Mattos de Souza Dantas DVM, MS, PhD, DACVB

Clinical Assistant Professor of Behavioral Medicine
University of Georgia Veterinary Teaching Hospital
Department of Veterinary Biosciences and Diagnostic Imaging
College of Veterinary Medicine
University of Georgia,
Athens, GA, USA

Mami Irimajiri BVSc, PhD, DACVB

Synergy General Animal Hospital
Animal Behavior Service
Saitama, Japan
Adjunct Professor
Kitasato University
College of Veterinary Medicine
Towada, Aomori, Japan

Thomas F. Murray, PhD

Provost,
Creighton University
Department of Pharmacology
Omaha, NE, USA

Niwako Ogata BVSc, PhD, DACVB

Associate Professor of Veterinary Behavior Medicine Purdue University
College of Veterinary Medicine
West Lafayette, IN, USA

Lynne Seibert DVM, MS, PhD, DACVB

Veterinary Behavior Consultants
Roswell,
GA, USA

The first edition of this book grew out of a series of phone calls that Dr. Crowell‐Davis received over the years from various veterinarians wanting information about their patients’ behavior problems and the psychoactive medications that might help them. What were appropriate drugs for given problems? What were appropriate doses? What side effects should be watched for? The first answer to this steadily accumulating set of questions was a continuing education course in psychopharmacology specifically organized for veterinarians. The course was first presented at the University of Georgia in November of 2001 and is now part of UGA’s Outpatient Medicine annual Continuing Education, as Behavioral Medicine has become integrated with all other specialties of our teaching hospital. From the original courses, taught by Dr. Murray and Dr. Crowell‐Davis and the assistance from the clinical residents at the time (Dr. Lynne Seibert and Dr. Terry Curtis), the next logical step was a textbook so that practicing veterinarians would have a resource to turn to for the answers to their various questions. Years later, Dr. Crowell‐Davis and Dr. Dantas felt an urgent need to update the book and add several new drugs that more recently are used by diplomates of the American College of Veterinary Behaviorists, so this knowledge could be available to general practitioners. Where studies were available, we tried to make this edition purely evidence‐based and avoided including personal communications and short publications as much as possible. As this edition goes to print, we are already planning for the third as new information and protocols in veterinary mental health care keep being tested and developed.

Information on the effects of various psychoactive drugs in dogs, cats, and other veterinary patients comes from two major sources. First, animals were often used to test and study the actions of various drugs during their initial development. Thus, the reader who peruses the references will find papers published as early as the 1950s, when major breakthroughs in psychopharmacology were being made to much newer publications in human and veterinary neuroscience. With the establishment of the American College of Veterinary Behaviorists in 1993 and the overall rapid development of the field of Clinical Behavioral Medicine, there has been increasing research on the efficacy of various medications on the treatment of various mental health and behavioral/psychiatry disorders of companion animals, zoo animals, and other nonhuman animals.

There are often huge gaps in our knowledge, and the reader may note them throughout the book. While we can glean bits and pieces of pharmacokinetic and other data from studies done on dogs and cats during early drug development, the quality and quantity of the information are highly variable. Studies of teratology and carcinogenicity are typically done on rats, mice, and rabbits, while comprehensive studies of all aspects of pharmacological activity in the body are done only in humans, the species that has historically been of interest. It is hoped that, as interest in this field continues to evolve, more comprehensive data will become available; new data will be supplied in future editions.

There is so much to be thankful for on this second edition of Veterinary Psychopharmacology. From all the veterinarians who request consults and always ask questions about psychoactive medications; reminding us of how important this resource is, to all of the students who push us to be updated, creative and enthusiastic about practicing and teaching. We dream of a time where mental health and psychiatry care will be fully integrated into the standard of care in veterinary medicine across the globe and part of the curriculum of every veterinary medicine school. To all of you that are eager to learn and provide the best care for your patients, we thank you. You are leading the way in our profession and this book is for you.

We wanted to keep the acknowledgments from the first edition to the many people who, besides the authors, contributed to the work involved in bringing together the information presented at that time. Of particular assistance were Linda Tumlin, Wendy Simmons, and Lucy Rowland. In their capacity as librarians and reference librarians they were invaluable in locating and obtaining much of the information provided in our first edition.

We also could not have developed and run the Behavioral Medicine Service and the didactic program at the University of Georgia to this date without the continuing support of various administrators over the years. In the first edition, Dr. Royce Roberts, Dr. Crowell‐Davis’ department head of many years was acknowledged. On this edition, we would like to thank Dr. Stephen Holladay for all his encouragement and support to both of us. Dr. David Anderson, Dr. Keith Prasse, Dr. Bob Lewis, and Dr. Jack Munnell have also facilitated Dr. Crowell‐Davis’ continuing work in this field previously. In the past 10 years, our service has had major support from our hospital director, Dr. Gary Baxter, to whom Dr. Dantas is incredibly grateful as he has supported and allowed for the service’s revitalization, allowing for a more competitive and business‐oriented approach to her practice.

Finally, this book is for all animals who co‐exist with humankind, providing us with so much affection, companionship and even health benefits, but who have to adapt to our lifestyle and often undergo significant mental suffering that can remain ignored, undiagnosed, and untreated. Our mission is to heal and to improve the quality of life of all patients we have the privilege to treat; and increase the awareness in our society that the mental and emotional suffering of animals matters.

Drug Action

Pharmacology is the science of drug action, and a drug is defined as any agent (chemical, hormone, peptide, antibody, etc.) that, because of its chemical properties, alters the structure and/or function of a biological system. Psychopharmacology is a sub‐discipline of pharmacology focused on the study of the use of drugs (medications) in treating mental disorders. Most drugs used in animals are relatively selective. However, selectivity of drugs is not absolute inasmuch as they may be highly selective but never completely specific. Thus, most drugs exert a multiplicity of effects.

Drug action is typically defined as the initial change in a biological system that results from interaction with a drug molecule. This change occurs at the molecular level through drug interaction with molecular target in the biologic system (e.g. tissue, organ). The molecular target for a drug typically is a macromolecular component of a cell (e.g. protein, DNA). These cellular macromolecules that serve as drug targets are often described as drug receptors, and drug binding to these receptors mediates the initial cellular response. Drug binding to receptors either enhances or inhibits a biological process or signaling system. Of relevance to the field of psychopharmacology, the largest group of receptors are proteins. These include receptors for endogenous hormones, growth factors, and neurotransmitters; metabolic enzymes or signaling pathways; transporters and pumps; and structural proteins. Usually the drug effect is measured at a much more complex level than a cellular response, such as the organism level (e.g. sedation or change in behavior).

Drugs often act at receptors for endogenous (physiologic) hormones and neurotransmitters, and these receptors have evolved to recognize their cognate signaling molecules. Drugs that mimic physiologic signaling molecules at receptors are agonists, that is, they activate these receptors. Partial agonist drugs produce less than maximal activation of activation of receptors, while a drug that binds to the receptor without the capacity to activate the receptor may function as a receptor antagonist. Antagonists that bind to the receptor at the same site as agonists are able to reduce the ability of agonists to activate the receptor. This mutually exclusive binding of agonists and antagonists at a receptor is the basis for competitive antagonism as a mechanism of drug action. One additional class of drugs acting at physiologic receptors are inverse agonists. At physiologic receptors that exhibit constitutive activity in the absence of activation by an endogenous agonist, inverse agonists stabilize an inactive conformation and therefore reduce the activation of the receptor. Thus, inverse agonists produce responses that are the inverse of the response to an agonist at a given receptor. Theoretical log concentration‐response curves for these four classes of drugs are depicted in Figure 1.1.

Dose Dependence of Drug Interaction with Receptors

Receptor occupancy theory assumes that drug action is dependent on concentration (dose) and the attendant quantitative relationships are plotted as dose‐ or concentration‐response curves. Dose–response analysis is typically reserved to describe whole animal drug effects, whereas concentration‐response curves describe in vitro drug action where the actual concentration of the drug interacting with a receptor is known. Inspection of dose–response relationships reveals that for any drug, there is a threshold dose below which no effect is observed, and at the opposite end of the curve there is typically a ceiling response beyond which higher doses do not further increase the response. As shown in Figure 1.2, these dose‐ or concentration‐response curves are typically plotted as a function of the log of the drug dose or concentration. This produces an S‐shaped curve that pulls the curve away from the ordinate and allows comparison of drugs over a wide range of doses or concentrations.

A drug‐receptor interaction is typically reversible and governed by the affinity of the drug for the receptor. The affinity essentially describes the tightness of the binding of the drug to the receptor. The position of the theoretical S‐shaped concentration‐response curves depicted in Figure 1.2 reveals the potency of these drugs. The potency of a drug is a function of its affinity for a receptor, the number of receptors, and the fraction of receptors that must be occupied to produce a maximum response in a given tissue. In Figure 1.2, Drug A is the most potent and Drug C is least potent. The efficacy of all three drugs in Figure 1.2, however, is identical in that they all act as full agonists and produce 100% of the maximal effect. As a general principle in medicine, for drugs with similar margins of safety, we care more about efficacy than potency. The comparison of potencies of agonists is accomplished by determining the concentration (or dose) that produces 50% of the maximum response (Effective Concentration, 50% = EC₅₀). In Figure 1.2, the EC₅₀ values are 10⁻⁸, 10⁻⁷, and 10⁻⁶ M, respectively, for Drugs A, B and C; hence, the rank order of potency is Drug A > Drug B > Drug C, with Drug A being the most potent since its EC₅₀ value is the lowest. Figure 1.3 depicts three additional theoretical concentration‐response curves for drugs with identical potencies but different efficacies. In this example, Drug A is a full agonist, producing a maximum response, whereas Drugs B and C are partial agonists, producing responses, respectively, of 50% and 25% of the maximum. Similar to receptor antagonist drugs, partial agonists can compete with a full agonist for binding to the receptor. Increasing concentrations of a partial agonist will inhibit the full agonist response to a level equivalent to its efficacy, whereas a competitive antagonist will completely eliminate the response of the full agonist.

Structural Features of the Central Nervous System (CNS) and Neurotransmission

The cellular organization of the mammalian brain is more complex than any other biologic tissue or organ. To illustrate this complexity, consider that the human brain contains 10¹² neurons, 10¹³ glia, and 10¹⁵ synapses. Understanding how this complex information processor represents mental content and directs behavior remains a daunting biomedical mystery. Recent reconstruction of a volume of the rat neocortex found at least 55 distinct morphological types of neurons (Makram et al. 2015). The excitatory to inhibitory neuron ratio was estimated to be 87:13, with each cortical neuron innervating 255 other neurons, forming on average more than 1100 synapses per neuron. This remarkable connectivity reveals the complexity of microcircuits within even a small volume of cerebral cortex.

Most neuron‐to‐neuron communication in the CNS involves chemical neurotransmission at up to a quadrillion of synapses. The amino acid and biogenic amine neurotransmitters must be synthesized in the presynaptic terminal, taken up, and stored in synaptic vesicles, and then released by exocytosis, when an action potential invades the terminal to trigger calcium influx. Once released into the synaptic cleft, transmitters can diffuse to postsynaptic sites where they are able to bind their receptors and trigger signal transduction to alter the physiology of the postsynaptic neuron. Just as exocytotic release of neurotransmitters is the on‐switch for cell‐to‐cell communication in the CNS, the off‐switch is typically a transport pump that mediates the reuptake of the transmitter into the presynaptic terminal or uptake into glia surrounding the synapse. A schematic of a presynaptic terminal depicted in Figure 1.4 illustrates the molecular sites that regulate neurotransmission. Once synthesized or provided by reuptake, the neurotransmitter is transported into the synaptic vesicle for subsequent exocytosis. The pH gradient across the vesicular membrane is established by the vacuolar H⁺‐ATPase, which uses ATP hydrolysis to generate the energy required to move H⁺ ions into the vesicle (Lohr et al. 2017). This movement of H⁺ ions creates the vesicular proton gradient and establishes an acidic environment inside the vesicle (pH of ~5.5). Specific reuptake transporters are localized on the plasma membrane where they recognize transmitters and transport them from the synaptic cleft into the cytoplasm of the terminal (Torres et al. 2003). These transporters have evolved to recognize specific transmitters such as dopamine, serotonin, norepinephrine, glutamate, and gamma‐aminobutyric acid (GABA). In all cases, these presynaptic transporters regulate the extracellular concentration of transmitters and therefore a mechanism for termination of their respective synaptic actions. The monoamine transporters (dopamine, norepinephrine, and 5‐hydroxytryptamine) are the pharmacological targets for antidepressants and psychostimulants.

Presynaptic terminals also express neurotransmitter autoreceptors that function as local circuit negative feedback inhibitor mechanisms to inhibit further exocytotic release of the transmitter when its synaptic concentration is elevated.

Figure 1.5 illustrates the comparison of presynaptic terminals for the biogenic amine neurons: dopamine, norepinephrine, and 5‐hydroxytryptamine (serotonin). The biosynthesis of each biogenic amine transmitter is indicated with uptake and storage in synaptic vesicles. The vesicular uptake of all three biogenic amines depicted is mediated by a common transporter, vesicular monoamine transporter 2 (VMAT2). VMAT2 is the vesicular monoamine transporter that transports dopamine, norepinephrine, and 5‐hydroxytryptamine into neuronal synaptic vesicles. VMAT2 is an H⁺‐ATPase antiporter, which uses the vesicular electrochemical gradient to drive the transport of biogenic amines into the vesicle (Lohr et al. 2017). In contrast to VMAT2 being expressed in all three biogenic amine neurons, each neurotransmitter neuron expresses a distinct plasma membrane transporter. These transporters are members of the SLC6 symporter family that actively translocate amino acids or amine neurotransmitters into cells against their concentration gradient using, as a driving force, the energetically favorable coupled movement of ions down their transmembrane electrochemical gradients. The dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT) are all uniquely expressed in their respective neurotransmitter neurons and couple the active transport of biogenic amines with the movement of one Cl⁻ and two Na⁺ ions along their concentration gradient. The ionic concentration gradient is created by the plasma membrane Na⁺/K⁺ ATPase and serves as the driving force for transmitter uptake. Examples of drugs that act as selective inhibitors for all three biogenic transporters are listed. The three monoamine transporters, DAT, NET, and SERT, represent important pharmacological targets for many behavioral disorders including depressive, compulsive and appetite‐related behavioral problems. The three neurotransmitter terminals also express unique presynaptic autoreceptors that regulate exocytotic release.

Biogenic Amine Neurotransmitters and Affective Disorders

The role of biogenic amines in affective disorders has a long history, beginning in the 1950s. The biogenic amine theory for affective disorders emerged as pharmacologists and psychiatrists began to explore the biologic basis for mental disorders. Initially, insights were gained from better understanding of the cellular actions of drugs and correlation of this knowledge of drug action with the therapeutic and behavioral responses to the same drugs in the clinic. In its original formulation, the biogenic amine theory for affective disorders stated that depression was due to a deficiency of biogenic amines in the brain, while mania was due to an excess of these transmitters. In the 1950s, iproniazid was used in the treatment of tuberculosis, and it was observed that in some patients with depressive symptoms, their mood improved over the course of a chronic regimen with iproniazid. Concurrently, preclinical research showed that iproniazid was an inhibitor of the enzyme monoamine oxidase (MAO). MAO catalyzes the degradation of dopamine (DA), norepinephrine (NE), and serotonin (5‐HT), and inhibition of MAO was found to elevate the levels of these transmitters in animal brains. Also, in the 1950s, reserpine was being used as an antihypertensive. Some patients treated with reserpine developed depressive symptoms severe enough in some cases to produce suicide ideation. Animals given reserpine also developed depression‐like symptoms consisting of marked sedation. Reserpine was shown to deplete the CNS of DA, NE, and 5‐HT by virtue of its ability to block the vesicular uptake of these monoamines. Blocking the vesicular uptake of monoamines leads to a depletion of the transmitters due to degradation by the mitochondrial enzyme MAO. Therefore, vesicular storage of monoamines is not only a prerequisite for exocytosis but also a means of preventing degradation of the transmitters in the cytosolic compartment. One other observation in the 1950s was that imipramine, developed initially as an antipsychotic drug candidate, elevated mood in a subpopulation of schizophrenic patients with comorbid depressive illness. Preclinical research revealed that imipramine, and other tricyclic antidepressants, were able to block monoamine transport into presynaptic terminals. This action would therefore produce an elevation of synaptic levels of biogenic amines. All these observations with iproniazid, reserpine, and imipramine were therefore consistent with the original formulation of the biogenic amine hypothesis for affective disorders.

Although today we continue to recognize the role of biogenic amines in depression, several discrepancies in the original hypothesis are appreciated. As an example, some clinically effective antidepressants do not block the presynaptic transport of monoamines and are not MAO inhibitors. However, importantly for a hypothesis that attempts to correlate synaptic levels of monoamines with mood, while synaptic levels of monoamines are elevated within a time domain of a few hours after antidepressant administration, the symptoms of depression do not resolve until several weeks of chronic therapy with antidepressant drugs. Contemporary hypotheses to explain the mechanism of action of antidepressant drugs therefore seek an appropriate temporal correlation between neurochemical drug action and the mitigation of the symptoms of depression. Rather than a focus on the synaptic levels of biogenic amines, contemporary views of the mechanism of action of antidepressants are focused on the regulation of receptor signaling.

References

1. Lohr, K.M., Masoud, S.T., Salahpour, A., and Miller, G.W. (2017). Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. European Journal of Neuroscience 45 (1): 20–33.
2. Makram, H., Muller, E., Ramaswamy, S. et al. (2015). Reconstruction and stimulation of neocortical microcircuitry. Cell 163: 456–492.
3. Torres, G.E., Gainetdinov, R.R., and Caron, M.G. (2003). Plasma membrane monoamine transporters: structure, regulation and function. Nature Reviews Neuroscience 4 (1): 13–25.