? The transition from drug abuse to the addicted state is characterized by the escalation of drug intake during self-administration, and markedly increased craving in withdrawal. Both drug-taking and drug-seeking behaviors are differentially regulated by D1 and D2 dopamine receptors in the nucleus accumbens (NAc). Drug-induced up-regulation of cAMP/PKA signaling may contribute to escalation and relapse, possibly by differentially altering dopamine receptor-responsiveness in the NAc. To investigate this hypothesis, studies will measure changes in NAc cAMP-dependent protein phosphorylation in vivo produced by chronic cocaine, heroin, and ethanol self-administration. Additionally, studies will measure alterations in sensitivity to D1 and D2 receptor-regulation of cAMP-dependent protein phosphorylation after chronic cocaine self-administration. Changes in cAMP-dependent protein phosphorylation in both core and shell subregions of NAc will be compared to individual propensities for escalating cocaine self-administration and relapse to cocaine seeking in withdrawal. In vivo phosphoprotein measures will include pGluR1 and pNR1 subunits of AMPA and NMDA receptors, pDARPP-32, pCREB, and pD1 receptor using a novel site-specific antibody. These studies are aimed at understanding molecular mechanisms that underlie drug and alcohol addiction, and may identify targets for therapeutic intervention. ? ? ? ?
