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Published with the permission of LAVC

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PHARMACOLOGY OF BEHAVIOR
Kathy R. Gaughan, DVM, ABVP
Franktown Animal Clinic
Franktown, CO USA
INTRODUCTION
Modification of behavior is necessary for resolution of behavior problems in dogs and cats. Drug
therapy 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 lecture
is to provide the general practitioner with an overview of the mechanism and application of medications
used to treat behavior problems in animals.
NEUROTRANSMITTERS AND SPECIFIC DRUGS
This discussion will be limited to two classes of neurotransmitters, amino acid transmitters (AAT) and
biogenic amines (BA). Glutamate (excitatory) and GABA (inhibitory) are the primary AATs and are present
in 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) and
barbiturates. These receptors act like an ON OFF SWITCH. To alter neurotransmission at GABA receptors
a drug can either increase frequency of channel opening (BZD, neurosteroids) or prolong duration of
channel 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 associated
with aggression, panic, urine marking in cats and amnesia. BZD commonly used for behavior problems
include 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 - 0.25
mg / kg q 8 - 12 h]. Side effects of BZD include sedation, ataxia, impaired learning, disinhibition of fearful
aggression, paradoxical excitement, and idiopathic hepatic necrosis. Administration of high doses of BZD
immediately after a traumatic event may effectively scramble memory pathway. Caution should be used
when 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 neurotransmission
is slow. This discussion will focus primarily on the BA, serotonin (5HT). The brain must make 5HT from
dietary tryptophan, thus diets low in tryptophan mean less serotonin in the brain. Tryptophan competes
with other amino acids for absorption so diets high in protein do not necessarily increase plasma tryptophan
levels.
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 high
degree of reuptake signals the presynaptic neuron to STOP production of serotonin. 5HT1A receptors are
present on the postsynaptic neuron and the cell body of the presynaptic neuron. The 5HT1A receptor on
the cell body signal the neuron to slow down serotonin transmission. The 5HT1B receptor is located on
the 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 concentration
and function of serotonergic receptors. Monoamine oxidase degrades 5HT as well as other biogenic
amines (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 in
depression, anxiety and panic disorders, compulsive disorders and aggressive disorders. For animals,
the facilitation of serotonin transmission is indicated in disorders of anxiety, panic, compulsion, feline
house soiling (due to anxiety or social conflict) and aggression. Drugs that facilitate serotonin transmission
include 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 response
to chronic stimulation.
SSRIs block the reuptake and recycling of serotonin in the presynaptic neuron. This allows serotonin
to accumulate in the synaptic cleft for action on the postsynaptic neuron. Fluoxetine, paroxetine and
sertraline are examples of SSRIs. Starting dosages for these SSRIs are as follows: Dogs: 0.5 - 1 mg / kg
once daily; Cats: 0.25 1.0 mg / kg once daily to every 3rd day. Side effects include sedation, change in
appetite, 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. Side
effects 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 in
patients 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 and
lactating 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 antihistaminic
effects than clomipramine and may be useful for animals with dermatologic issues [Dog: 1 6 mg / kg q
12 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 production
and in timid cats. Timid cats will become more confident and stand up to bully cats when buspirone is
administered. 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 antagonistic
properties. The mechanism of action is not clear. Reported indications include treatment of urine spraying
and 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 and
should 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. In
the U.S, the MAOI-B selegiline (ANIPRYL) is approved for canine cognitive dysfunction [CCD] and the
control 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 SELECTION
Appropriate 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 critical
to obtain a detailed behavioral and medical history and minimum data base (complete blood count, serum
chemistry, urinalysis, +/- serum thyroxine levels). Ask about other medications pet is currently receiving,
including nonprescription medications and supplements. The veterinarian must consider the following to
make 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 risk
of 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 behavioral
response or until signs of toxicity arise
Adverse events include the development of serotonin syndrome, or excessive serotonin transmission.
This syndrome can lead to changes in mentation, neuromuscular activity, and autonomic activity (including
cardiorespiratory and GI signs). The treatment of serotonin syndrome requires the discontinuation of all
medications 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 controlled
studies. Indications for stopping or changing drugs include undesirable side effects and a lack of the

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desired behavioral response. First, try a different drug within the same class before changing to a different
class 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 prior
to initiating drug B. It is important to note that fluoxetine has active metabolites for 4 5 weeks beyond
cessation of therapy.
DURATION OF THERAPY
Remember that most drugs take time to produce an effect. The goal is improvement in the animals
behavioral response. Owners should be instructed to keep a journal (written or video). Frequent rechecks
are recommended to document responses. Effective drug therapy should be maintained throughout the
behavior modification program. It is also important to note that many animals may require life-long drug
therapy 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 the
primary targets of most behavioral therapy in small animals. Drugs can be used to alter neurotransmission
and 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 individual
patient.

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The Latin American Veterinary Conference TLAVC 2006