Pharmacological mechanisms involved in nicotine‐induced orexin neurons activation

Orexin (hypocretin) neurons are important for sleep/wakefulness cycle and metabolic regulation. These neurons are activated (shown by Fos) by variety of psychostimulants, including —as we have recently shown— nicotine. However, the mechanisms regulating nicotine‐elicited activation of orexin neurons and the target projections of the psychostimulant activated orexin neurons subpopulation are unknown. Here, we treated rats with acute (‐)‐nicotine hydrogen tartrate (0, 0.4 or 2.0 mg/kg) and used immunohistochemistry to measure Fos expression in orexin neurons. As previously reported, nicotine dose‐dependently increased Fos expression in orexin neurons, with a preferential effect in the medial part of the LH/PFA. Nicotine administration in a subset of animals which had received basal forebrain deposits of FluoroGold indicate that many of these nicotine‐responsive orexin neurons project to forebrain regions containing magnocellular basal forebrain cholinergic neurons. Nicotine‐elicited Fos expression in orexin neurons was attenuated by pretreatment with the non‐selective nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (1.0 mg/kg) or di‐hydro‐β‐ erythroidine (2.0 mg/kg), suggesting a predominantly α 4 β 2 ‐nAChR‐mediated effect. In addition, because the LH/PFA is rich in glutamatergic and cholinergic inputs, in vivo microdialysis was used to determine the effect of systemic nicotine on release of glutamate and acetylcholine in this region of the hypothalamus. These data provide suggest that the cholinergic basal forebrain is a prominent target of orexin neurons activated by psychostimulants. Orexin‐acetylcholine interactions are likely to contribute to nicotine effects on arousal and attention.