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Pharmacology and Behavior: Neurochemistry of Anxiety and Aggression

Karen L. Overall, MA, VMD, PhD, DACVB, ABS Certified Applied Animal Behaviorist

Approaching complex situations

Diagnoses are not diseases; correlation is not causality. Conditions for which there is putative etiologic and pathophysiologic heterogeneity (multi-factorial disorders) are complex, and there is nowhere that this is more true than for the topic of fears, phobias, and anxieties. Diagnosis and treatment will be, by definition, complex. Fear and anxiety are probably closely related, but may not be identical at the neurophysiological level. It is worth remembering that when one diagnoses a problem related to fear, anxiety, or aggression one is doing so at the level of the phenotypic or functional diagnosis; when psychotropic medication is used such conditions are treated at the neurophysiological level. Phenotypic (functional, phenomenological) diagnoses are open to various mechanistic bases of all subsequent levels. Some of these more reductionistic levels can be tested using treatment (specific pharmacologic agents), but few phenotypic diagnoses can be specifically tested using behavior modification. Regardless, the logic for using very specific phenomenological diagnoses related to fear and anxiety is to (a) enumerate and identify the particular behavioral manifestation that needs to be altered or assessed, and (b) to identify areas where specific behavioral intervention can be useful.


Cautious and discrete use of terminology will lead to clear thinking. Diagnosis may not be as simple or clear-cut as a definition. We do not understand the manner in which "causal" levels interact to produce the problem - all we can evaluate is the phenotypic form in which interactions occur. Clear use of terminology can help to make apparent the parts of these phenotypic diagnoses that are consistent, so that we can understand and separate them from those that are more complex.

Neuroanatomy of fear, anxiety, and obsessive-compulsive disorder:

The extent to which learning and memory play roles in fear, anxiety, phobias, and OCD has been poorly studied because it is difficult to do so given the complexity of the neurochemical systems involved. What is know is that: (1) a functioning amygdala is required to learn fear, (2) a functioning forebrain is required to unlearn fear (i.e., to effect habituation), and (3) many human fears appear to be the result of the inability to inhibit a fear response. Accordingly, it has been hypothesized that fear is, in part, due to chronic amygdala over-reaction and, or failure of the amygdala to turn off after the threat has passed.

The specific neuroanatomy of a fear response involves the locus ceruleus (LC), the principal norepinerphrinergic (noradrenergic) nucleus in the brain. Dysregulation of the LC appears to lead to panic and phobias in humans. The LC directly supplies the limbic systems and may be responsible for many correlated "limbic" signs. Patients with true panic and phobic responses are more sensitive to pharmacologic stimulation and suppression of the LC than are controls.

Imaging techniques have been useful to study fears, anxieties, and phobias, although they are currently on limited therapeutic and diagnostic use. PET (positive emission tomography) scans have been used to study regional brain flow as a measure of neuroanatomical correlates of emotion. In these cases painful electric shock has been applied before, during, and after anticipation of it. Increases in blood flow in bilateral temporal poles during anticipatory anxiety have been noted. These same neuroanatomical regions are implicated in lactate-induced anxiety attacks in panic disorders, suggesting a mechanism for the development of panic in humans. The lactate test is an accepted test to provoke (and diagnose) panic attacks in people, but it has not been evaluated in pets. In human lactate responsive / susceptible patients, parahippocampal blood flow (a marker of neuronal activity), blood volume, and oxygen metabolism are asymmetric when evaluated by PET scans under resting, non-panic conditions. This suggests that the abnormality is both biochemical and structural. The biochemical abnormality is postulated to be due to an increase in norepinephrine output from the locus coereleus, which, in turn, stimulates parahippocampal "over-responsiveness".

The roles of arousal and reactivity

Some dogs respond either more quickly to a stimulus, or react more intensely to a given stimulus that other dogs. At some level this "hyper-reactivity" is probably truly pathological and represents yet another phenotypical manifestation of some neurochemical heterogeneity associated with anxiety. These dogs are different and it can be very difficult or impossible to interrupt them once they reach that level where they "fire" indiscriminantly. Intense anticipation is critical for these individuals.

Other animals just react with a higher level of intensity, but may still be workable. Behaviors that can be used to ascertain levels of reactivity or arousal include alertness (hyper-vigilance), restlessness (motor activity), vocalization, systemic effects (emesis, urination, or defecation), displacement or stereotypic behaviors, and changes in content or quantity of solicitous behaviors. Dogs with the above described truly pathological hyper-reactivity do not generally evince these signs.


1.  Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panic disorders. Arch Gen Psychiat 1984;43:1042-1058.

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3.  Free NK, Winget CN, Whitman RM. Separation anxiety in panic disorder. Am J Psychiatry 1983;150:595-599.

4.  Grunhaus L, Harel Y, Krugler T, Pande AC, Haskett RF. Major depressive disorder and panic disorder. Clin Neuropharmacol 1988;11:454-461.

5.  Kalin NH. The neurobiology of fear. Sci Am 1993;268(5):94-101.

6.  Ko GN, Elsworth JD, Roth RH, Rifkin BG, Leigh H, Redmond DE, Jr. Panic-induced elevation of plasma MHPG levels in phobic anxious patients. Arch Gen Psychiat 1983;40:425-430.

7.  Overall KL. Clinical Behavioral Medicine for Small Animals, At. Louis, Mosby, 1997.

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