MODELING ANXIETY DISORDERS FOLLOWING CHEMICAL EXPOSURES

The effects of kindling and inverse benzodiazepine receptor agonist be ta-carbolines on animal models of anxiety are briefly reviewed in rela tion to affective disorder associated with chemical exposure. Recent e xperimental results are described. In the present study, cars were giv en the inverse benzodiazepine receptor agonist, FG-7142, a powerful an xiogenic compound in humans and animals. Neural transmission in pathwa ys involved in defensive behavior in the cats was monitored using evok ed potential techniques. Change in these pathways was related to behav ioral changes induced by the drug. It was found that a single dose of FG-7142 lastingly increased defensive response to rodents for at least 40 days after drug administration. Behavioral change was specific to defensive response, since approach-attack behavior remained unchanged replicating previous studies. The benzodiazepine receptor antagonist F lumazenil, reversed the increase in defensiveness in a drug-dependent manner, replicating previous findings. Increased defensiveness was par alleled by a delayed onset potentiation of neural transmission between the amygdala and the medial hypothalamus of the left hemisphere. Pote ntiation in the left hemisphere was transient, decaying between 6 and 12 days after the drug. There was a longer lasting potentiation (LTP) of activity evoked in the left and right amygdalo-periacqueductal gray pathways and in the right amygdalo-medial hypothalamic pathway. Poten tiation in these pathways appeared at the time of behavioral change. P otentiation of the right amwygdalo-periacqueductal gray and right amyg dalo-medial hypothalamic pathways persisted until the end of the exper iment. In contrast, potentiation of the left amygdalo-periacqueductal gray pathway faded by 40 days after the drug. Flumazenil decreased pot entiation only in the right amygdalo-periacqueductal gray pathway, The se data strongly suggest that lasting affective change is mediated by lasting changes in particular efferents of the amygdala of the right h emisphere. Behavioral and physiological effects of FG-7142 were blocke d by the N-methyl-D-Aspartate (NMDA) receptor blocker, AP7. The data s uggest that failure of neural inhibition induced by FG-7142 engages NM DA receptor processes to produce lasting potentiation of transmission bl neural circuits that mediate defensive response with behavioral con sequences. Since FG-7142 interferes with GABA mediated neural inhibiti on and is proconvulsant, its action might mimic the action of other en vironmental chemicals with similar properties, such as chlorinated hyd rocarbon insecticides. The relationship of the present data to the lit erature on the neural and behavioral effects of insecticide exposure i s discussed. The significance of these findings for multiple chemical sensitivity disorder is also briefly discussed.