Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a powerful stimulant and reinforcer. Importantly, besides its unconditional effects, nicotin also has conditional stimulus effects that may contribute to the tenacity of the smoking habit. Investigation of learning processes involving nicotine as a conditioned stimulus (CS) is an understudied area relevant to nicotine dependence. Understanding these associative processes with the interoceptive effects of nicotine is of importance if a goal is to develop a comprehensive theory of addiction and, hence, develop better prevention and treatment strategies. A preliminary study assessing neurobiological loci involved in nicotine-evoked CR found that activation (as revealed through elevation of c-Fos) of dmCPu was dependent on learning history with nicotine. The proposed research builds on this finding and is designed to elucidate functional involvement of dmCPu in the conditioning processes with nicotine as a CS. Because anatomical connections within anterior-posterior axis of the rat's dorsal striatum are not homogeneous and can differ in their control of conditioning processes, both anterior (a-dmCPu) and posterior (p-dmCPu) portions of dmCPu will be tested for their involvement in acquisition and expression of the nicotine-evoked CR. The current study will examine the effect of permanent neurotoxin lesions of either a- or p-dmCPu on acquisition of nicotine evoked CR, and the effect of transient lesions of either a- or p-dmCPu on the expression of the nicotine-evoked CR. In the first experiment, rats will receive lesions (NMDA) or sham lesions (vehicle) of either a-dmCPu or p-dmCPu before nicotine CS training. During nicotine CS training (32 total daily sessions), nicotine injections (0.4 mg/kg;SC) will be paired 100% of a time with intermittent (36 per session) sucrose deliveries;sucrose will not be available on alternative saline days. Using this protocol, the nicotine CS readily acquires control of a goal-tracking CR (anticipatory food-seeking response). Deficits in acquiring this nicotine- evoked CR (using this standard protocol) will indicate a region's involvement in acquisition of the CR to the nicotine CS. In the second experiment, rats will first undergo nicotine CS training (identical to Experiment 1) and then receive implantation of intracranial cannulae (a- or p-dmCPu). Rats will be bilaterally infused with either lidocaine or saline before testing for the nicotine-evoked CR. Attenuated CR during testing will indicate critical involvement of implicated area in the expression of the CR. Knowledge gained from these experiments will fill a gap in understanding regional neurobiological processes potentially contributing to the tenacity of tobacco dependence.
Our recent preliminary finding implicating dorsomedial caudate-putamen in the conditioning processes with the nicotine stimulus is the first to investigate the potential neurobiological substrates of this effect. A better understanding of neurobiological mechanisms involved in excitatory conditioning with nicotine can be used to design more effective behavioral and pharmacological treatments for individuals seeking to discontinue the debilitating habit of tobacco use. The current project will do that by examining involvement of anterior and posterior dorsomedial caudate-putamen in acquisition and expression of nicotine-evoked conditioned response.
