Jonathan Hollander - US grants

[unreadable] DESCRIPTION (provided by applicant): Numerous investigations have shown that orexin-containing neurons that arise within the hypothalamus are critical regulators of sleep and feeding processes. In addition, very recent findings have implicated orexin systems in drug-seeking behaviors. For example, previous studies in our laboratory have shown that the orexin-1 receptor antagonist, SB-334867, blocked stress-induced reinstatement of extinguished cocaine responding in rats. Therefore, the blockade of orexin-1 receptors may be an effective strategy for the treatment of substance abuse disorders. However, the role of orexin-1 receptors in regulating the reinforcing effects of nicotine has not been assessed. Here, the first aim of this application will be to evaluate the effects of SB-334867 on the reinforcing effects of nicotine. To accomplish this task, the PI will utilize intravenous self-administration and intracranial self-stimulation procedures in well-trained rats to determine if SB-334867 decreases nicotine consumption and abolishes the stimulatory effects of nicotine on brain reward systems. The second aim of this proposal will be to identify neuroanatomical substrates of the brain reward system that regulate nicotine reinforcement via orexin-1 receptors. Specifically, the PI will microinfuse SB-334867 into the bed nucleus of the stria terminalis (BNST) or ventral tegmental area (VTA) to determine if blockade of orexin-1 receptors in these areas decreases nicotine intake in rats. While SB- 334867 certainly antagonizes the orexin-1 receptor, it is derived from a class of compounds that has high affinity for other non-orexin receptor classes as well. Indeed, it is presently unclear if SB-334867 acts only at orexin-1 receptors, or has 'off-target' effects at other receptor classes that may confound interpretation of data using this compound. Therefore, the third aim will directly assess the importance of the orexin-1 receptor in nicotine reinforcement by evaluating the acquisition of intravenous nicotine self-administration in orexin-1 receptor knockout mice compared with wildtype littermates. Collectively, these studies will provide important insights into psychobiological mechanisms of nicotine dependence processes, and promise to yield a novel therapeutic strategy for the treatment for human nicotine addiction. The devastating personal, social and economic cost of nicotine addiction has generated much research into understanding how the brain processes drug reward, and has motivated efforts to develop novel treatment strategies for treating the disorder. The experiments presented in this application investigate the role of orexin-1 receptors in nicotine reinforcement in rats and mice. Based on our preliminary research, blockade of orexin receptors may be a viable strategy to aid smokers who wish to quit their habit. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Discovered in the 1990s, orexin (or hypocretin)-containing neurons in the lateral hypothalamus are now receiving considerable attention for their possible role in regulating motivated behavior for drugs of abuse. Indeed, previous studies from our laboratory and others have shown that the orexin-1 receptor antagonist, SB- 334867 (given systemically or directly infused into the insular cortex) decreases intravenous nicotine self- administration in rats. However, the role of orexin-2 (OX2) signaling in mediating nicotine reinforcement is poorly understood. Further, little is known about the effects of abstinence on orexin signaling following repeated nicotine consumption and its precise role in driving relapse. These are critical issues since human smokers often feel 'cravings' and subsequently relapse following intermittent periods of abstinence. Here, the first aim of this proposal is to assess intravenous nicotine self-administration in mice lacking OX1 receptors (OX1-/-), test whether viral-mediated re-expression of OX1 receptors in the insular cortex of OX1-/- mice rescues deficits in nicotine intake, and investigate the role for OX2 receptors in nicotine reinforcement using novel pharmacological agents and OX1-/- mice. Given the susceptibility of addicts to relapse to smoking after periods of cessation, the goal of Aim 2 will be to determine the effectiveness of selective OX1 and OX2 receptor antagonists on nicotine seeking and taking behavior following different periods of drug abstinence (0, 7 or 30 days) in well trained rats. Wit drug-associated cues often elicitors of relapse for smokers, Aim 3 will investigate the effects of nicotine abstinence on the associative properties of orexin cell firing in the lateral hypothalamus This aim will entail electrophysiological recordings in behaving animals to determine if the activity of putative orexin neurons is altered following nicotine-paired cue presentation after extended periods of abstinence. Collectively, these experiments will provide important insight into the psychobiological mechanisms underlying nicotine addiction, and promise to yield a novel therapeutic strategy for treating human smokers. PUBLIC HEALTH RELEVANCE: As the major single cause of cancer-related deaths in the United States, nicotine addiction has devastating personal, economic and social cost. The PI will study the motivational and neural underpinnings of nicotine addiction by investigating the role of orexin signaling in rats and mice. Such investigations could lead to new pharmacotherapies aimed at preventing relapse in smokers who wish to remain drug free.