Role of striatal pathways in learning with nicotine stimulus

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Project Summary Nicotine is a mild stimulant when compared to other stimulants like cocaine or methamphetamine. Indeed, responding for nicotine in preclinical self-administration studies is only marginally higher than responding for saline and is often insensitive to variation in nicotine dose. The fact that nicotine is a weak primary reinforcer is somewhat incongruent with the fact that it is one of the most abused substances. The wide use of nicotine products has been attributed to the complex nature of nicotine reward that involves genetic, biological, learning, and pharmacological dimensions, to name a few. The pharmacological effects of nicotine can serve as an interoceptive stimulus (CS) that can come into association with other reinforcing events in the environment (US; e.g., food, alcohol, work breaks, peer interaction) and through associative processes can acquire additional properties that likely contribute to perpetuation of nicotine use. Previous studies show that dorsomedial caudate-putamen (dmCPu) is functionally involved in learning with nicotine stimulus. We also know that anterior (a-) and posterior (p-) dmCPu are differentially involved in various stages of that learning. Both a- and p-dmCPu receive excitatory input from the prefrontal cortex and provide inhibitory output to substantia nigra pars reticulata/globus pallidus internus complex (SNr/GPi) via direct (D1 driven) or indirect (D2 driven) pathways. What we do not know is how these afferent and efferent connections to dmCPu contribute to learning with nicotine stimulus. Thus, the overall objective of this application is to investigate the functional involvement of afferent and efferent connections to dmCPu in learning with nicotine stimulus using pathways- specific chemogenetic approach. The experiments proposed in this application will be the first to identify immediate circuitry involved in associative learning with any drug state. A better understanding of neurobiological mechanisms involved in associative learning with nicotine stimulus may open new avenues in preclinical or clinical research investigating the neural underpinnings of nicotine dependence.