The Neurological and Pharmacological Basis for Fears and Anxieties

Debra F. Horwitz, DVM, Diplomate ACVB
Veterinary Behavior Consultations
St. Louis, Missouri

Introduction

Long gone is the assumption that animals are merely biologic machines that react in a predictable manner. We now know that both learning and environment work together to influence behavior. When we discuss fears and anxieties an understanding the neurological basis for the behavior allows us to use our knowledge of the brain, neurotransmitters and learning to formulate treatments and possible pharmacological interventions.

Physiological influences on fears and anxieties

Stress has long been thought to have metabolic effects and behavioral effects. When using the term stress when applied to humans and animals we are normally describing a situation where the environmental situations are having an adverse effect on the individual ¹ Often stress is difficult to quantify for companion animals, but most of us would agree that it can be a factor in behavioral disorders in companion animals. Stress can be identified by changes in certain physiologic measurements. One measure of stress is the change in adrenal corticosteroid output, which under stress can become abnormally high. In conditions that result in constant fear or anxiety abnormally high levels of corticosteroids can lead to general debilitation, weakness, gastrointestinal signs and cardiovascular changes ². Catecholamines may become elevated leading to changes in heart rate, trembling, tachypnea among other signs that occur due the activation of the "fight or flight" response ³. Neutrophil and lymphocyte ratios may be altered in white blood cell counts with long term stress. Finally, stress can result in disease in the affected animal. This might include metabolic alterations, inflammation, changes in immune function and gastrointestinal alterations¹.

Learning and memory are important in the formation and maintenance of fears and anxieties. Learning causes lasting biochemical and structural changes in the synapse ⁴. One of the changes is to bias synapses and pathways to reconstruct responses to earlier stimulus with the memory encoded in electrical activity ⁴. The results of neuronal learning allow for responses to become potentiated and create a sustained bias in transmission. The end of result is long term potentiating of post-synaptic responsiveness with the repetition of the same stimulus⁴. This memory potentiation may help account for some anxiety and fearful responses.

Naturally the brain has an important role in fears and anxiety. The locus ceruleus portion of the brain supplies norepinephrine to the limbic system and mediates a wide range of the physiologic responses seen in fearful and anxious behaviors^3. In humans, dysregulation of the locus ceruleous can lead to panic and phobias ⁵. The limbic system controls emotional and motivational activities. The limbic system consists of the hypothalamus, amgydala, septum, hippocampus and cingulate nucleus⁴. In humans changes in the HPA axis have been known to be correlated with panic attacks, it is unknown if this occurs in animals.

Several neurotransmitters are involved in the regulation of fears and anxieties. These include GABA, Dopamine, Serotonin, Acetylcholine and Norepinephrine³.

•  GABA

Gamma Aminobutyric acid. Generally considered an inhibitory neurotransmitter that is widely distributed in the brain ⁶. GABA is produced from glutamate and its effects are not well characterized.

•  Dopamine

Dopamine produces behavioral quieting and there are multiple receptors in the brain. Dopamine is thought to have a role in Cognitive Dysfunction ⁷ and in Cushings disease in dogs.

•  Serotonin

Produced in the brain from tryptophan. Multiple receptor subtypes in the brain. Thought to play a role in sleep, pain aggression, sexual behavior, anxiety, thermoregulation, food intake and social attachment.

•  Acetylcholine

Most widely distributed neurotransmitter in the brain and body. Produced from choline and inactivated by acetylcholinesterase. Responsible for numerous side effects with medications.

•  Norepinephrine

Precursor of epinephrine and also can act centrally. In behaviorally stimulating and increases arousal via activation of the reticular activating system.

Pharmacological intervention

The goal of pharmacological intervention in behavioral disorders is to alter neurotransmitters and aid in changing problem behavior. One can always hope that changing neurotransmitters will alter behavior, but rarely does this occur without concurrent behavior modification. The clinician hopes to work at the cellular level to change outward behavior. However several key principles are important; drugs alone rarely change behavior and you must have a behavioral diagnosis to pick the appropriate medication ⁸. Because medications are metabolized via hepatic and renal pathways, serum biochemistry screenings in patients is prudent. Few if any drugs are approved for use in companion animals for behavioral disorders so signed release and consent forms from owners are suggested.

Definitions

•  Agonist: a drug that mimics the action of the neurotransmitter ⁹. It binds with the receptor to initiate action and has affinity and intrinsic activity.

•  Antagonist: substances that block or reverse the action⁹.

•  Disinhibition: used in aggression to describe the loss of normal agonistic responses and therefore may increase the likelihood of aggression. May be seen with fear aggression in dogs and cats.

Classes of medications

•  Antipsychotics

Commonly used for tranquilization. Act as dopamine agonists and produce behavioral quieting ¹⁰. Most common veterinary drug is acepromazine, which is used for sedation and restraint. Responses to medication are non-specific and not particularly anxiolytic. Helpful in situational fears and anxieties such as veterinary visits and car rides. May see disinhibition. Common side effects include hypotension and hypothermia, reduction in seizure threshold and idiosyncratic increases in aggression.

•  Antidepressants

Encompasses tricyclic antidepressants, selective serotonin reuptake inhibitors and atypical antidepressants. Have been used in human psychiatry for some time. Mode of action is blocking reuptake of serotonin and/or norepinephrine. Reduce neurotransmitter turnover. All have a lag time until behavioral effect is seen¹⁰.

Tricyclic antidepressants: Most common ones are amitriptyline, clomipramine and doxepin. Side effects include increase heart rate, orthostatic hypotension, and anticholinergic effects. May have antihistaminic and noradrenergic effects. May take 7-10 days until effect.

Selective Serotonin reuptake inhibitors: Most common are Fluoxetine and paroxetine. Inhibit reuptake into the presynaptic neuron and may also increase post synaptic receptor sensitivity¹⁰. May take 7-10 days until effect. Most common side effects include changes in appetite, gastrointestinal effects. Inhibit liver P-450 enzymes so drug interactions are possible.

Monoamine oxidase inhibitors: Used rarely in veterinary medicine with the exception of Selegiline. Used in the USA for cognitive impairment in dogs (Canine Cognitive Dysfunction) and in Europe for other behavioral conditions.

•  Anxiolytics: Class of drugs used to decrease anxiety in certain situations. Includes benzodiazepines, azapirones, barbituates and antihistamines. The most common ones used in veterinary medicine are diazepam, buspirone, alprazolam and clorazepate.

Benzodiazepines: They act by binding to GABA receptors and enhance GABA mediated chloride influx. Usually they result in neuronal inhibition and may cause sedation and muscle relaxation. Can cause dependence and withdrawal symptoms. May also cause disinhibition of aggression. Often used in urine spraying in cats, phobias and fears in dogs. Fatal hepatotoxic reactions in cats have been reported ^11.

Buspirone: Blocks serotonin pre and post synaptically and acts as a dopamine agonist¹⁰. Used in generalized anxiety states. May take 7-30 days until effect. Useful in urine spraying in cats.

Conclusion

Drug therapy can be a useful adjunct to the treatment of fears and anxieties. Different medications have differing modes of actions, uses and side effects. Understanding what you want to accomplish along with a good diagnosis and treatment plan will help drug therapy to be a useful adjunct to behavioral therapy.