Nicotinic activation of CRH neurons in extrahypothalamic regions of the rat brain

Nicotine is known to have multiple effects on neuroendocrine, autonomic, and behavioral responses. Its neuroendocrine effect on the stress-responsive hormone, ACTH, depends on central pathways that act on corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN). Other CRH neurons throughout the brain also are involved in coordinating aspects of the stress response, but very little is known about the effect of nicotine on CRH neurons in extrahypothalamic regions that are involved in the autonomic and behavioral responses to stress. The current study sought to determine the extent of nicotinic activation of extrahypothalamic CRH neurons, since these neurons may be involved in mediating the central effects of nicotine. Freely moving rats were pretreated with a low dose of colchicine, infused with nicotine (0.045 mg/kg/30 s or 0.135 mg/kg/90 s, i.v.), and cardiac perfused 1 h later. Double-label immunocytochemistry identified the activated (positive for cFos protein) CRH neurons in limbic structures (bed nucleus of the stria terminalis [BNST] and central nucleus of the amygdala [CNA]), the dorsal raphe (DR), and Barrington's nucleus (BN); comparisons were made to the PVN. In all of these areas, nicotine activated CRH neurons in a dose-dependent manner, showing differential sensitivity and efficacy with respect to region. CNA CRH neurons were most responsive and were maximally stimulated by the low dose of nicotine (62% of CRH neurons were cFos+, compared to 10-27% of the CRH population in other regions, including the PVN). Although the BNST also was activated by the low dose, only the non-CRH+ neurons were involved; in contrast, 41% of the BNST CRH neurons responded to the higher dose. Nicotinic activation of DR neurons was dose-dependent, with 22% of the CRH neurons activated by the high dose. Few BN neurons were activated by the low dose of nicotine, but 26% of the CRH population responded to the higher dose. These results indicate that the effect(s) of nicotine on the brain may be mediated, in part, by the selective activation of specific extrahypothalamic regions containing CRH neurons that also are involved in autonomic and behavioral responses to stress. The large fraction of CRH neurons responding to the low dose of nicotine in the CNA suggests that this limbic region may be particularly important in mediating these CNS effects of nicotine.