The long range goal of this research is to understand the interaction(s) between stress-responsive systems within the brain and nicotine, since tobacco is often linked with stress. Thus, the principle aim of this proposal is to further recent observations about the neuroanatomical and neurochemical mechanism(s) that account for activation of the brainstem-hypothalamicACTH axis by nicotine. Nicotine stimulates noradrenergic/adrenergic circuits at their brainstem sites of origin, leading to secretion of ACTH which rapidly desensitizes. In vivo microdialysis studies show that nicotine stimulates norepinephrine secretion in the hypothalamic paraventricular nucleus (PVN); this undergoes rapid, though partial desensitization. Nicotine stimulates ACTH when selectively infused into catecholaminergic brainstem regions, and i.v. nicotine induces cfos protein expression, an indicator of acute neuronal activation, in the same brainstem areas. The role of PVN neuropeptides, such as CRF, oxytocin and vasopressin, in nicotine-stimulated ACTH secretion will be defined using cfos/neuropeptide colocalization to identify activated parvocellular PVN neurons. Additional approaches to identify the neuropeptides involved include (i) the peripheral delivery of specific peptide receptor antagonists and antisera to inhibit ACTH responses to nicotine, and (ii) measurement of CRF depletion from the median eminence in colchicine pretreated animals as an index of CRF secretion. Whether nicotine-induced norepinephrine release uniformly mediates the activation of these PVN peptidergic neurons will be determined by administering specific adrenergic receptor antagonists prior to nicotine. Effects of nicotine on PVN epinephrine secretion also will be assessed indirectly and desensitization of this response will be evaluated. Finally, desensitization of the ACTH response to norepinephrine or epinephrine, administered into the third ventricle, will be evaluated to determine whether this contributes to the desensitization of the ACTH response to nicotine.
The second aim of the proposal is to compare the brainstem-PVN-neuroendocrine effects of nicotine to another nicotine-responsive region, the hippocampal complex, which is potentially involved in the effects of nicotine on memory. Nicotine also stimulates norepinephrine secretion and cfos expression in the hippocampus, although the dose-response characteristics are distinctively different and desensitization of the norepinephrine response is not observed, in comparison to the PVN. These differences can be explored in pharmacological studies using nicotinic cholinergic agonists and antagonists which distinguish different subtypes of neuronal nicotinic receptors to determine whether different receptors mediate PVN vs hippocampal norepinephrine secretion. Whether brainstem catecholaminergic systems mediate these PVN vs hippocampal responses will be evaluated by injecting nicotine into brainstem regions and measuring norepinephrine secretion and the expression of cfos protein. cFos expression will also be used to determine whether 'cross-talk' occurs between brainstem catecholaminergic regions in response to local nicotine. Thus, comparison of the PVN and the hippocampus will provide new insights into mechanisms underlying the differential effects of nicotine on brain function.
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