Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry.
Singewald N., Sharp T.
It is speculated that specific hindbrain transmitter pathways centred on the periaqueductal gray and locus coeruleus are an important integrative neural substrate for the expression of anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states, such as in panic disorder. Here we investigated the effects of various drugs, known to induce 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 alpha(2)-adrenoceptor antagonist yohimbine, the non-selective 5-hydroxytryptamine(2C) receptor agonist m-chlorophenyl piperazine, the adenosine antagonist caffeine and the cholecystokinin analogue BOC-CCK(4). A clear-cut finding was that administration of each anxiogenic drug caused a striking region-specific pattern of Fos expression within the hindbrain. In particular, the drugs commonly increased Fos-like immunoreactivity in the periaqueductal gray and locus coeruleus. Increased Fos expression in the periaqueductal gray was specific to the rostral dorsolateral and caudal ventrolateral regions. All the anxiogenic drugs also increased Fos-like immunoreactivity in the lateral parabrachial nucleus and nucleus of the solitary tract and all but one (BOC-CCK(4)) increased Fos in the dorsal raphe nucleus. Rats habituated to the 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-chlorophenyl piperazine, caffeine and BOC-CCK(4)) increased Fos expression in a restricted number of hindbrain regions, including the periaqueductal gray and locus coeruleus. Previous Fos studies have found that these same regions are activated by various fearful environmental stimuli. Therefore, a specific set of hindbrain circuits may be commonly involved in the processing of anxiety-related information evoked by pharmacological and environmental manipulation. 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.