NICOTINIC ACTIVATION OF CRH NEURONS IN EXTRAHYPOTHALAMIC REGIONS OF THE RAT-BRAIN

Nicotine is known to have multiple effects on neuroendocrine, autonomi c, and behavioral responses. Its neuroendocrine effect on the stress-r esponsive hormone, ACTH, depends on central pathways that act on corti cotropin-releasing hormone (CRH) neurons in the paraventricular nucleu s of the hypothalamus (PVN). Other CRH neurons throughout the brain al so are involved in coordinating aspects of the stress but very little is known about the effect of nicotine on CRH neurons in extrahypothala mic regions that are involved in the autonomic and behavioral response s to stress. The current study sought to determine the extent of nicot inic activation of extrahypothalamic CRH neurons, since these neurons may be involved in mediating the central effects of nicotine. Freely m oving 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, iv), and cardiac perf used 1 h later. Double-label immunocytochemistry identified the activa ted (positive for cFos protein) CRH neurons in limbic structures (bed nucleus of the stria terminalis [BNST] and central nucleus of the amyg dala [CNA]), the dorsal raphe (DR), and Barrington's nucleus (BN); com parisons were made to the PVN. In all of these areas, nicotine activat ed CRH neurons in a dose-dependent manner, showing differential sensit ivity and efficacy with respect to region. CNA CRH neurons were most r esponsive and were maximally stimulated by the low dose of nicotine (6 2% of CRH neurons were cFos+, compared to 10-27% of the CRH population in other regions, including the PVN). Although the BNST also was acti vated by the low dose, only the non-CRH+ neurons were involved; in con trast, 41% of the BNST CRH neurons responded to the higher dose. Nicot inic activation of DR neurons was dose-dependent, with 22% of the CRH neurons activated by the high dose. Few BN neurons were activated by t he low dose of nicotine, but 26% of the CRH population responded to th e higher dose. these results indicate that the effect(s) of nicotine o n the brain may be mediated, in part, by the selective activation of s pecific extrahypothalamic regions containing CRH neurons that also are involved in autonomic and behavioral responses to stress. The large f raction of CRH neurons responding to the low dose of nicotine in the C NA suggests that this limbic region may be particularly important in m ediating these CNS effects of nicotine.