The k-opioid receptor agonist U-69593 prevents cocaine-induced DARPP-32 phosphorylation at Thr34 in the rat brain

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) is a potent endogenous inhibitor of protein phosphatase-1, which plays an important role in dopaminergic transmission. A large body of evidence supports the key role of DARPP-32-dependent signalling in mediating the actions of multiple drugs of abuse, including cocaine, which, when acutely administered, increases the Thr34 phosphorylation of DARPP-32 in the striatal and cortical areas. In this study, we have examined the contribution of the kappa-opioid system to the regulation of DARPP-32 phosphorylation at Thr34, following acute cocaine administration, in selected rat brain areas. Results showed that a single injection of cocaine induces a significant increase in DARPP-32 phosphorylation at Thr34 in the hippocampus, caudate putamen and prefrontal cortex. In addition, pretreatment with the kappa opioid receptor agonist U-69593 prevented cocaine effects in all the investigated areas. These data could be considered consistent with the ability of kappa opioid agonists to attenuate many behavioural effects of cocaine, and support the hypothesis of the potential usefulness of these drugs as functional antagonists of cocaine.