Behavioral sensitization effected by variable anxiogenic challenge and psychogenic stressor exposure in anxiety and motivational paradigms in CD-1 mice: In situ hybridization and immunohistochemical determinations in selective mesocorticolimbic sites

It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Arguments for behavioural and neurochemical conditioning and sensitization have been proposed in documentation pertaining to the vulnerability of clinical populations to relapse, the history of such relapses and symptom exacerbation, over protracted intervals. A role for cholecystokinin (CCK) in the induction and persistence of anxiety and major depression in infrahuman and human subjects appears to be conspicuous. While increased cerebrospinal (CSF) CCK has been associated with motivational loss, anticipatory anxiety and panic increased enkephalin (ENK) availability in humans has been associated with coping and mood elevation. The present series of experiments provide behavioral evidence for a CCK-ENK interface in the modulation of anxiety and motivation following psychogenic and pharmacological stressor applications. In particular, exposure of CD-1 mice to predator odors increased anxiety in the light-dark box immediately following odor exposure. Anxiety was associated with increased CCK mRNA and decreased ENK mRNA from sub-areas of the amygdala and nucleus accumbens. These changes in CCK and ENK gene expression were transient and were not associated with protracted levels of anxiety. In contrast, repeated exposure of CD-1 mice to the startle stimulus following varying durations of predator exposure resulted in an exaggeration of startle reactivity for up to one week following odor exposure. In contrast to enhanced anxiety in the light-dark box and startle paradigms, predator exposure did not influence reward thresholds among mice responding for brain stimulation from the dorsal aspects of the VTA. The experimental parameters underlying the manifestation of fear and anxiety in CD-1 mice following psychogenic stressor challenge were paralleled by pharmacological assessment of the anxiogenic and anxiolytic influence of central CCK and enkephalin administration, respectively, within these identical paradigms. In pharmacological investigations, the sensitizing effect of a previous anxiogenic dose of CCK-8 sulfated (CCK-8S) to a CCK challenge dose was blocked by coactivation of μ and δ receptors by the enkephalin agonist DALA in an ICSS but not an exploration paradigm among CD-1 mice. Interestingly, administration of intraventricular CCK-8S or systemic Boc CCK-4 increased acoustic startle in mice dependent upon the stressor history of the animal. These data parallel other studies evaluating the propensity of traditional anxiolytic and antidepressant agents to counteract the sensitization process. Evidently, the light dark task, acoustic startle, ICSS and exploration paradigms appear to be differentially sensitive to diverse stressor applications and site specific alterations in mesocorticolimbic ENK and CCK may underlie the expression of anxiety-like behavior within these paradigms. In effect, while CCK induces relatively protracted behavioral disturbances in both infrahuman and human subjects following stressor applications, μ/δ receptor activation may change the course of psychopathology. Potential anxiogenic and mnemonic influences of mesocorticolimbic CCK and ENK availability as well as the time course and underlying neuronal substrates of long-term behavioral disturbances (i.e., behavioral sensitization) as a result of stressor manipulations are discussed.