Abstract

A survey was sent to zoologic institutions housing gorillas questioning the use of psychoactive drugs to control aggression. Survey results, as well as a brief discussion of the types of drugs used for behavior modification, are presented.

Introduction

In recent years, psychoactive drugs have been a rapidly expanding component of modern veterinary practice for domestic animals as well as laboratory animals.¹ It is important to remember that the use of these drugs is extra-label and the pharmacologic, toxicologic, and behavioral effects seen may vary greatly from animal to animal. Because many of these drugs have side effects on multiple systems, a complete physical examination is recommended before commencing treatment. A complete behavioral analysis should also be performed, and a set of targeted problem behaviors clearly identified. Oversimplification of a complex behavioral problem may lead to errors that may be dangerous.

All psychoactive drugs are thought to have their effects through five main neurotransmitters in the brain. These neurotransmitters are acetylcholine, dopamine, norepinephrine, serotonin, and γ-aminobutyric acid (GABA). It is important to know which neurotransmitters are affected by each drug class in order to understand the possible related side effects.⁶ Acetylcholine is produced from choline and is inactivated by anticholinesterase. Cholinergic receptors have numerous behavioral and physiologic effects that should be understood before initiating treatment with this class of drugs. Many psychoactive drugs affect acetylcholine producing anticholinergic side effects. These may include dry mouth, dilated pupils, GI stasis, and cardiac side effects, which may be of particular concern in captive gorillas.³ Dopaminergic neurotransmission can occur by at least five subtypes of dopamine receptors, located both pre and post-synaptically. Dopaminergic antagonists may produce behavioral changes without the side effects of cortical depression. Norepinephrine is the precursor of epinephrine and a central neurotransmitter. Norepinephrine agonists are stimulating and increase arousal through several mechanisms, including the reticular activating system. Serotonin (5-hydroxytryptamine) is produced in the brain from tryptophan. There are at least nine serotonin receptor types, both pre and post-synaptically, and all with different behavioral effects. Serotonin is thought to be an important neurotransmitter in the regulation of sleep, pain, aggression, thermoregulation, appetite, and sexual behavior. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter produced from glutamate and is widely distributed throughout the brain. It is thought to have numerous behavioral and metabolic effects.

Psychoactive Drug Groups

Most psychopharmaceuticals used fall into the following four groups: antidepressants, mood stabilizers, antipsychotics (neuroleptics), and anxiolytics.

Antidepressants are generally organized into three classes: the tricyclic antidepressants, the selective serotonin-reuptake inhibitors, and the atypical antidepressants.⁶ The antidepressants tend to have a wide range of behavioral effects and can be used to treat other psychologic disorders as well as depression. Tricyclic antidepressants: The tricyclic antidepressants are labeled for use in human medicine to treat depression, but also have been noted to have additional usefulness in treating panic disorders and agoraphobia.⁶ They have long half-lives, a narrow therapeutic index, and there is a considerable risk of toxicity when overdosed. These antidepressants appear to block norepinephrine and serotonin presynaptic neurotransmitter receptors in the brain, reducing norepinephrine and serotonin turnover, thereby increasing their actions. Tricyclic antidepressants can have numerous side effects including cardiovascular side effects, which can be of particular concern in great apes.³ Other side effects seen include anticholinergic effects. Selective serotonin-reuptake inhibitors (SSRI): have a wide therapeutic index with a low incidence of side effects. In human medicine, they have been used to treat depression, obsessive-compulsive disorders, eating disorders, and panic disorders.⁶ The SSRI enhance central serotonin by blocking presynaptic input at serotonin receptors. They may also act through an increased output or increased post-synaptic receptor sensitivity. They rarely produce sedation and the most commonly seen side effects are gastrointestinal signs, including anorexia, nausea, and diarrhea. Anxiety, agitation, and insomnia have also been seen in humans.⁶ Atypical Antidepressants: contain drugs that are different from both tricyclic antidepressants and selective serotonin-reuptake inhibitors.

Mood stabilizers include compounds that are dissimilar in make-up that have been used in human medicine to treat bipolar disorders, reduce impulsivity, emotional reactivity, and aggression.⁷ These drugs show some promise in great apes due to their effectiveness on aggression; however, careful monitoring of blood levels and side effects are needed.

Antipsychotics (neuroleptics or major tranquilizers) have been used in human medicine for many years.⁶ They tend to have marked effects on behavior with a low risk of toxic side effects. These drugs all act as dopamine antagonists and block dopamine receptors in the basal nuclei and the limbic system. They can produce behavioral quieting and decreased emotional reactivity with or without some sedation. The antipsychotics are subdivided into low-potency and high-potency drugs. Low-potency drugs tend to require higher doses and, therefore, tend to have more side effects such as increased sedation, cardiovascular effects, and anticholinergic effects but with a lower chance of producing extrapyramidal side effects. The high-potency drugs require relatively lower doses, have fewer side effects but have an increased incidence of extrapyramidal side effects. Some side effects seen when using antipsychotics include sedation, anticholinergic effects, and cx-adrenergic blocking effects. In humans on high-potency antipsychotics there is also a risk of extrapyramidal motor side effects such as Parkinsonism, dystonic reactions, akathisia, and rarely, neuroleptic malignant syndrome and tardive dyskinesia.

Anxiolytics have antianxiety properties and include benzodiazepines, azapirones, barbiturates, and antihistamines. Most of their use in great apes appeared to be as pre-medications before stressful events such as anesthesia, transport, or introductions. The benzodiazepines and azapirones were the most commonly used and will be discussed. Benzodiazepines: in human medicine, drugs in this category have been used to treat anxiety, panic disorders, epilepsy, and insomnia.⁷ Because benzodiazepines can have paradoxical effects due to disinhibiting suppressed behaviors, their use to treat aggression should be carefully weighed. Benzodiazepines are believed to act by binding γ-aminobutyric acid (GABA) receptors in the central nervous system. Their anxiolytic properties seem to result from GABA like activity in the cerebral cortex and the limbic system. Some side effects that may be observed when using benzodiazepines include sedation, cortical depression, and muscle relaxation. There is little effect on the respiratory or cardiovascular system, although they may potentiate respiratory depression produced by other sedatives. Benzodiazepines have amnesic properties and may interfere with learning conditioned responses. Azapirones: buspirone was reported in great apes and is a non-sedating antianxiety drug that takes approximately one week to initial effect. It has an antianxiety effect gained by blocking serotonin pre-synaptic and post-synaptic receptors. Buspirone causes down regulation of serotonin receptors and also acts as a dopamine agonist in the brain. This drug lacks sedative, muscle relaxant, or anticonvulsant activities and does not impair motor function. Other Drugs have been used in veterinary medicine to treat behavioral problems such as barbiturates, antihistamines, narcotic antagonists, and progestin hormones.⁷ Beta-blockers reduce signs of fearfulness in humans and have helped in one gorilla case. Androcur and deslorelin implants have also shown promise in aggression problems (Table 1).

Survey Results

A summary of all of these survey results is presented in Table 1. Doses, dosages, and results are listed as given. All animals listed are adults unless otherwise specified.

Table 1. Results of survey

Conclusions

While the use of behavior modifying drugs may aid in the resolution of a problem, environmental management and behavioral modification are also needed in most cases. Veterinarians must understand the ethical issues surrounding how and when to use these drugs in order to maximize their effectiveness. Survey results indicate that as a whole, psychoactive drugs used in great apes to try to curb aggression have not been successful. This could be due to several things including, but not limited to, misdiagnosis of behavioral problem type, multifactorial causes, incorrect dosing, inconsistent observations, and short treatment times. Certainly, more research is warranted in this field.

Literature Cited

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