Role of DARPP-32: Individual Responsiveness to Nicotine

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DESCRIPTION (provided by applicant): Tobacco use is the number one preventable cause of death in the world. Nicotine (NIC), the most abundant alkaloid in tobacco, is the primary reinforcing agent in tobacco smoking. Many factors contribute to susceptibility to NIC. One such factor is the environment. The environment animal model is that rats are raised in one of three different conditions: an enriched condition (EC) containing novel objects and social partners, a social condition (SC) containing social partners only, or an impoverished condition (IC) without objects or partners. This animal model identifies environmental influences that may alter individual vulnerability to drug abuse. Environmental stimuli-induced alterations in the behavioral response to psychostimulants are mediated through differential modulation of dopaminergic neurotransmission. Activation of the dopamine (DA)/D1 receptor/cAMP/protein kinase A (PKA)-regulated signaling pathway leads to phosphorylation of the DA and cAMP-regulated phosphoprotein-32 (DARPP-32). This postsynaptic signaling pathway is known to be essential for cellular plasticity in response to repeated exposures to drugs of abuse (Greengard et al., 1999). Although evidence shows individual differences in the susceptibility to NIC addiction, little is known about the molecular consequences of environmental enrichment on DARPP-32 phosphorylation, and the potential relationship between these molecular changes in DARPP-32 and behavioral responses to NIC compared to environmentally impoverished rats. This proposal will test overall hypothesis that environmental enrichment changes DA receptor-mediated cAMP/PKA signaling, in turn modifying the effects of NIC on DARPP-32, and these changes will contribute to differences in NIC-induced behavioral sensitization observed between EC and IC. The hypothesis that drives this grant attempts to elucidate the underlying neurobiological mechanisms of the environmental influences on NIC addiction. The experiments proposed here are designed to focus on two specific aims: 1) To determine the NIC-induced behavioral sensitization in EC, SC or IC rats following repeated NIC injection, 2) To determine the correlation between environmental enrichment-mediated changes in DARPP-32 phosphorylation and behavioral sensitization following repeated NIC injection in EC, SC or IC rats. An understanding of mechanisms by which environmental enrichment alters DA signaling will have the potential to facilitate the development of therapeutic programs for tobacco dependence, and will contribute to the effectiveness of prevention and treatment intervention strategies in adulthood. These results will elucidate the underlying neurobiological mechanisms of the environmental influences on nicotine addiction. Understanding this mechanism will have the potential to facilitate the development of therapeutic programs for tobacco dependence, and will contribute to the effectiveness of prevention and treatment intervention strategies in adulthood.