Modelling anxiety disorders following chemical exposures.
The effects of kindling and inverse benzodiazepine receptor agonist beta-carbolines on animal models of anxiety are briefly reviewed in relation to affective disorder associated with chemical exposure. Recent experimental results are described. In the present study, cats were given the inverse benzodiazepine receptor agonist, FG-7142, a powerful anxiogenic compound in humans and animals. Neural transmission in pathways involved in defensive behavior in the cat was monitored using evoked potential techniques. Change in these pathways was related to behavioral 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, Flumazenil, reversed the increase in defensiveness in a drug-dependent manner, replicating previous findings. Increased defensiveness was paralleled by a delayed onset potentiation of neural transmission between the amygdala and the medial hypothalamus of the left hemisphere. Potentiation 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. Potentiation in these pathways appeared at the time of behavioral change. Potentiation of the right amygdalo-periacqueductal gray and right amygdalo-medial hypothalamic pathways persisted until the end of the experiment. In contrast, potentiation of the left amygdalo-periacqueductal gray pathway faded by 40 days after the drug. Flumazenil decreased potentiation ony in the right amygdalo-periacqueductal gray pathway. These data strongly suggest that lasting affective change is mediated by lasting changes in particular efferents of the amygdala of the right hemisphere. Behavioral and physiological effects of FG-7142 were blocked by the N-methyl-D-Aspartate (NMDA) receptor blocker, AP7. The data suggest that failure of neural inhibition induced by FG-7142 engages NMDA receptor processes to produce lasting potentiation of transmission in neural circuits that mediate defensive response with behavioral consequences. Since FG-7142 interferes with GABA mediated neural inhibition and is proconvulsant, its action might mimic the action of other environmental chemicals with similar properties, such as chlorinated hydrocarbon insecticides. The relationship of the present data to the literature on the neural and behavioral effects of insecticide exposure is discussed. The significance of these findings for multiple chemical sensitivity disorder is also briefly discussed.
Adamec
R
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Department of Psychology, Basic Medical Science, Memorial University of Newfoundland, Canada.
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001008:Anxiety Disorders / Q000139:chemically induced*; D001522:Behavior, Animal / Q000187:drug effects*; D002243:Carbolines / Q000633:toxicity*; D002415:Cats; D005442:Flumazenil / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007306:Insecticides / Q000633:toxicity; D007696:Kindling, Neurologic / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018777:Multiple Chemical Sensitivity / Q000523:psychology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D000596:Amino Acids; D002243:Carbolines; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007306:Insecticides; D016194:Receptors, N-Methyl-D-Aspartate; D005442:Flumazenil; C035874:FG 7142; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid