INVOLVEMENT OF CAMP-DEPENDENT PROTEIN-KINASE IN THE NUCLEUS-ACCUMBENSIN COCAINE SELF-ADMINISTRATION AND RELAPSE OF COCAINE-SEEKING BEHAVIOR

cAMP-dependent protein kinase (PKA) in the nucleus accumbens (NAc) has been implicated in cocaine addiction because (1) cocaine reinforcemen t is mediated by dopamine receptors that modulate cAMP formation, and (2) repeated exposure to cocaine upregulates the cAMP system in NAc ne urons. This study tested PKA involvement in cocaine self-administratio n and relapse of cocaine-seeking behavior by infusing cAMP analogs tha t activate or inhibit PKA into the NAc of rats. Bilateral intra-NAc in fusions of the PKA inhibitor R-p-cAMPS reduced baseline cocaine self-a dministration, shifted the dose-response curve for cocaine self-admini stration to the left, and induced relapse of cocaine-seeking behavior after extinction from cocaine self-administration, consistent with an enhancement of cocaine effects in each paradigm. In contrast, pretreat ment with intra-NAc infusions of a PKA activator, S-p-cAMPS or dibutyr yl cAMP, increased baseline cocaine self-administration during the sec ond hour of testing and shifted the dose-response curve to the right, consistent with an antagonist-like action. After extinction from cocai ne self-administration, similar infusions of Sp-cAMPS induced generali zed responding at both drug-paired and inactive levers. As an index of PKA activity in vivo, NAc infusions of Rp-cAMPS reduced basal levels of dopamine-regulated phosphoprotein-32 phosphorylation and blocked am phetamine-induced increases in cAMP response element-binding protein ( CREB) phosphorylation. Conversely, NAc infusions of S-p-cAMPS increase d phosphorylation of CREB. Together, these results suggest that sustai ned upregulation of the cAMP system in the NAc after repeated cocaine exposure could underlie tolerance to cocaine reinforcement, whereas ac ute inhibition of this system may contribute to drug craving and relap se in addicted subjects.