Research Project
10430774
Title: Targeting Neurokinin Receptors to Regulate of Nicotine Reward Abstract Current FDA approved treatments are not sufficient to promote nicotine cessation in all individuals, highlighting the need for novel drug targets. Several studies have highlighted the role of ?5-containing (?5*) nicotinic acetylcholine receptors (nAChRs) in the modulation of both nicotine intake and the emergence of nicotine withdrawal-associated behaviors. To date there are no ?5 nAChR selective drugs available for human use. Another approach to probe the potential therapeutic effects of ?5* nAChRs is to target other neurotransmitter systems that directly interacts with ?5 nAChR signaling pathways in the brain. One such system is the neurokinin signaling pathway. Previous research conducted by my colleagues and I have demonstrated a direct interaction between ?5* nAChRs and neurokinin 1 receptors (NK1Rs) in modulating the neuronal response to nicotine and the emergence of physical signs of nicotine withdrawal. The goal of this proposal is to gather preliminary data to characterize the role that NKRs play on nicotine-induced behaviors and their interaction with ?5* nAChRs. Aim 1 of the proposal will address the hypothesis that selective antagonism of NK1Rs will alter the rewarding effects of nicotine in wild type mice. We will use behavioral tests such as conditioned place preference and operant self-administration of nicotine vapor to measure the influence that NK1Rs have on nicotine-induced rewarding effects. We will also use in vivo microdialysis to measure nicotine-induced dopamine release in the nucleus accumbens. Specific aim 2 will address the hypothesis that NKRs interact with ?5* nAChRs to mediate nicotine reward associated behaviors. ?5 null mice have altered nicotine reward behaviors such as enhanced nicotine consumption and altered nicotine-induced dopamine release. Given our previous data suggesting a direct interaction between these two receptor systems, we predict that direct stimulation of NK1Rs will normalized dopamine release within the nucleus accumbens. Moreover this aim will collect preliminary data to test whether antagonism of NK1Rs will normalize nicotine consumption in ?5 null mice. This proposal will allow for the collection of preliminary data to be used in the preparation of a SURE-First R16 Award. We have evidence that both NK1Rs modulate nicotine activity via interaction with ?5* nAChRs, therefore; we do expect to see significant changes in nicotine-induced rewarding behaviors. Future studies will on understanding the specific mechanism in which NKRs and ?5* nAChRs modulate drug-induced behaviors.
