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The Latin American Veterinary Conference TLAVC 2006

PHARMACOLOGY OF BEHAVIORKathy R. Gaughan, DVM, ABVP

Franktown Animal ClinicFranktown, CO USA

INTRODUCTION Modification of behavior is necessary for resolution of behavior problems in dogs and cats. Drugtherapy is often necessary to facilitate behavior modification and speed resolution of behavior problems. However, very few drugs are labeled for behavioral use in companion animals. The purpose of this lectureis to provide the general practitioner with an overview of the mechanism and application of medicationsused to treat behavior problems in animals.

NEUROTRANSMITTERS AND SPECIFIC DRUGS This discussion will be limited to two classes of neurotransmitters, amino acid transmitters (AAT) andbiogenic amines (BA). Glutamate (excitatory) and GABA (inhibitory) are the primary AATs and are presentin very high levels in the brain. These neurotransmitters have very rapid signaling, thus fast transmission. GABAA receptors utilize chloride ion channels and are the primary target for benzodiazepines (BZD) andbarbiturates. These receptors act like an ON OFF SWITCH. To alter neurotransmission at GABA receptorsa drug can either increase frequency of channel opening (BZD, neurosteroids) or prolong duration ofchannel opening (barbiturates). Drugs that facilitate GABA transmission tend to work quickly. GABA regulates level of awareness /vigilance (sedation), level of anxiety (anxiolytic), memory and learning (amnesia), and muscle tension(anticonvulsant). Clinical applications for facilitating GABA transmission include fear that is not associatedwith aggression, panic, urine marking in cats and amnesia. BZD commonly used for behavior problemsinclude diazepam [Dog: 0.5 2.0 mg / kg q 4 - 12 h; Cat: 0.2 0.4 mg / kg q 12 -24 h] and alprazolam[Dog: 0.01 0.1 mg / kg q 4 8 h or 0.10 1 mg / kg q 12 h (do not exceed 4 mg / day); Cat: 0.0125 - 0.25mg / kg q 8 - 12 h]. Side effects of BZD include sedation, ataxia, impaired learning, disinhibition of fearfulaggression, paradoxical excitement, and idiopathic hepatic necrosis. Administration of high doses of BZDimmediately after a traumatic event may effectively scramble memory pathway. Caution should be usedwhen dispensing BZD due to development of tolerance and potential for abuse. The biogenic amines (BA) are present in relatively low levels in the brain. The rate of neurotransmissionis slow. This discussion will focus primarily on the BA, serotonin (5HT). The brain must make 5HT fromdietary tryptophan, thus diets low in tryptophan mean less serotonin in the brain. Tryptophan competeswith other amino acids for absorption so diets high in protein do not necessarily increase plasma tryptophanlevels.

The primary 5HT receptors include the reuptake transporter, 5HT1A receptor and 5HT1B receptor. The reuptake transporter removes 5HT from the synaptic cleft and back into presynaptic neuron. A highdegree of reuptake signals the presynaptic neuron to STOP production of serotonin. 5HT1A receptors arepresent on the postsynaptic neuron and the cell body of the presynaptic neuron. The 5HT1A receptor onthe cell body signal the neuron to slow down serotonin transmission. The 5HT1B receptor is located onthe terminus of the presynaptic neuron and signals the neuron to slow serotonin production. Many factors affect serotonergic function, including 5HT production and breakdown and the concentrationand function of serotonergic receptors. Monoamine oxidase degrades 5HT as well as other biogenicamines (dopamine, norepinephrine and acetylcholine). Serotonin is the chemical responsible for general awareness, facilitation of appropriate social interactions,the ability to adopt a passive attitude and coping and adaptation. Serotonin dysfunction is implicated indepression, anxiety and panic disorders, compulsive disorders and aggressive disorders. For animals,the facilitation of serotonin transmission is indicated in disorders of anxiety, panic, compulsion, felinehouse soiling (due to anxiety or social conflict) and aggression. Drugs that facilitate serotonin transmissioninclude selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) and azapirones. These drugs require administration of 4 8 weeks before effective alteration of 5HT transmission occurs. Effective alteration is due to the desensitization of the presynaptic 5HT1A receptor which occurs in responseto chronic stimulation. SSRIs block the reuptake and recycling of serotonin in the presynaptic neuron. This allows serotoninto accumulate in the synaptic cleft for action on the postsynaptic neuron. Fluoxetine, paroxetine andsertraline are examples of SSRIs. Starting dosages for these SSRIs are as follows: Dogs: 0.5 - 1 mg / kgonce daily; Cats: 0.25 1.0 mg / kg once daily to every 3rd day. Side effects include sedation, change inappetite, GI upset and, rarely, anxiety, irritability, aggression (very uncommon in animals), insomnia, tremors,mania, and seizures.

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TCAs affect multiple neurotransmitters. TCAs block the reuptake of 5HT and norepinephrine. Sideeffects correlate with receptor activity and include antihistaminic and anticholinergic effects, GI signs,hypersalivation and nausea (due bitter taste), arrhythmias and seizures. TCAs should not be used inpatients with glaucoma, urine retention, cardiac or thyroid disease, seizure disorders or adrenal tumors. The dose of TCA should be reduced in patients with hepatic and renal disease, as well as pregnant andlactating animals. Specific TCAs include clomipramine, which is somewhat selective for serotonin activity[Dog: 1 4 mg / kg q 12 h; Cat: 0.25 2.0 mg / kg q 24 h], and amitriptyline, which has more antihistaminiceffects than clomipramine and may be useful for animals with dermatologic issues [Dog: 1 6 mg / kg q12 24 h; Cat: 0.5 2.0 mg / kg q 12 24 h]. Buspirone, an azapirone, is a presynaptic 5HT1A agonist and partial postsynaptic 5HT1A agonist. Buspirone acts like serotonin at these receptors and is useful for animals with little or no serotonin productionand in timid cats. Timid cats will become more confident and stand up to bully cats when buspirone isadministered. Dosages are as follows: Dog: 0.5 2.0 mg / kg q 8 24 h; Cat: 2.5 7.5 mg / cat q 12 h,OR 0.5 1.0 mg / kg q 12 h. Other medications include cyproheptadine, which is an antihistaminic drug with 5HT antagonisticproperties. The mechanism of action is not clear. Reported indications include treatment of urine sprayingand masturbation in cats. It is also used for appetite stimulation. The dose for cats is 2 mg PO q 12 h. Monoamine oxidase inhibitors [MAOI] prevent the breakdown of endogenous and dietary amines andshould be used with caution. Concurrent use of MAOI and other agents [TCA, SSRI, herbal / homeopathics,parasiticides] that affect neurochemical transmission can result in severe side effects and even death. Inthe U.S, the MAOI-B selegiline (ANIPRYL) is approved for canine cognitive dysfunction [CCD] and thecontrol of clinical signs associated with pituitary dependent hyperadrenocorticism. Dose for CCD is: Dog:0.5 1.0 mg / kg daily in the morning; Cat: 0.5 1.0 mg / kg daily in the morning.

DRUG SELECTIONAppropriate drug selection is guided by the behavioral diagnosis. Because drugs will not help an

animal with medical disease and many medical diseases may manifest as a behavior problem, it is criticalto obtain a detailed behavioral and medical history and minimum data base (complete blood count, serumchemistry, urinalysis, +/- serum thyroxine levels). Ask about other medications pet is currently receiving,including nonprescription medications and supplements. The veterinarian must consider the following tomake an educated decision with regards to drug therapy: . Pre-existing disease considerations. Pet response to previous behavior drugs. Onset of action (can we manage pet until effects are noted?). Dosing frequency. Can owner administer meds safely?. Ability to dose accurately availability of appropriate dose. Pet compliance. Expense. Veterinarian preference (comfort zone). Potential side effects. Potential for drug abuse

COMBINATION DRUG THERAPY A combination of drugs may be necessary to achieve an adequate behavioral response.Consideration must be given to the action and degradation of each medication in order to reduce the riskof adverse events. Some guidelines include: . Combining drugs that work at different receptor sites . Reducing the dose in animals with hepatic / renal disease. Starting at low doses and gradually increase dose (one drug at a time) to achieve desired behavioralresponse or until signs of toxicity ariseAdverse events include the development of serotonin syndrome, or excessive serotonin transmission. This syndrome can lead to changes in mentation, neuromuscular activity, and autonomic activity (includingcardiorespiratory and GI signs). The treatment of serotonin syndrome requires the discontinuation of allmedications and the initiation of supportive care, including fluid therapy.

STOPPING OR CHANGING DRUGS Behavioral drug therapy is often requires a trial and error approach as there are limited controlledstudies. Indications for stopping or changing drugs include undesirable side effects and a lack of the

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The Latin American Veterinary Conference TLAVC 2006

desired behavioral response. First, try a different drug within the same class before changing to a differentclass of drugs (for example, switch from amitriptyline to clomipramine both are TCAs). When possible,the dose should be tapered 25% every 1 2 weeks until off the initial drug, A. If the second drug, B,has a similar mode of action (i.e. serotonergic), a washout period of 1 4 weeks may be necessary priorto initiating drug B. It is important to note that fluoxetine has active metabolites for 4 5 weeks beyondcessation of therapy.

DURATION OF THERAPY Remember that most drugs take time to produce an effect. The goal is improvement in the animalsbehavioral response. Owners should be instructed to keep a journal (written or video). Frequent rechecksare recommended to document responses. Effective drug therapy should be maintained throughout thebehavior modification program. It is also important to note that many animals may require life-long drugtherapy or intermittent therapy to maintain the appropriate behavioral response.

TAKE HOME MESSAGE Multiple neurotransmitter systems play a role in behavioral expression. Serotonin and GABA are theprimary targets of most behavioral therapy in small animals. Drugs can be used to alter neurotransmissionand behavioral expression. Some drugs act fast (BZD) and some drugs act more slowly (SSRI, TCA,Azapirones). Knowledge of drug actions and interactions is essential to select the best drug for the individualpatient.

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