Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry

It is speculated that specific hindbrain transmitter pathways centred on th e periaqueductal gray and locus coeruleus are an important integrative neur al substrate for the expression of anxiety and the somatic symptoms and car diovascular changes that accompany severe anxiety states, such as in panic disorder. Here we investigated the effects of various drugs, known to induc e panic in humans and to be anxiogenic in animals, on Fos expression in the periaqueductal gray, locus coeruleus and other parts of the rat hindbrain. The drugs tested were the benozodiazepine inverse agonist FG-7142, the alp ha(2)-adrenoceptor antagonist yohimbine, the non-selective 5-hydroxytryptam ine(2C) receptor agonist m-chlorophenyl piperazine, the adenosine antagonis t caffeine and the cholecystokinin analogue BOC-CCK4. A clear-cut finding w as that administration of each anxiogenic drug caused a striking region-spe cific pattern of Fos expression within the hindbrain. In particular, the dr ugs commonly increased Fos-like immunoreactivity in the periaqueductal gray and locus coeruleus. Increased Fos expression in the periaqueductal gray w as specific to the rostral dorsolateral and caudal ventrolateral regions. A ll the anxiogenic drugs also increased Fos-like immunoreactivity in the lat eral parabrachial nucleus and nucleus of the solitary tract and all but one (BOC-CCK4) increased Fos in the dorsal raphe nucleus. Rats habituated to t he test environment and injected with saline vehicle displayed little or no Fos-like immunoreactivity in the hindbrain areas investigated. In summary, each of the anxiogenic drugs tested (FG-7142, yohimbine, m-chlo rophenyl piperazine, caffeine and BOC-CCK4) increased Fos expression in a r estricted number of hindbrain regions, including the periaqueductal gray an d locus coeruleus. Previous Fos studies have found that these same regions are activated by various fearful environmental stimuli. Therefore, a specif ic set of hindbrain circuits may be commonly involved in the processing of anxiety-related information evoked by pharmacological and environmental man ipulation. The present findings also raise the possibility that measurement of the effect of anxiogenic drugs on Fos expression might be a useful way to model hindbrain pathways activated by anxiety and possibly panic. (C) 20 00 IBRO. Published by Elsevier Science Ltd. All rights reserved.