Abstract
The Akt - GSK3 signaling pathway has been recently implicated in psychostimulant-induced behavioral and cellular effects. Here, the ability of cocaine to regulate the activity of Akt and GSK3 was investigated by measuring the phosphorylation states of the two kinases. The anatomical specificity of the response was determined, as was the contributions of dopamine and NMDA receptors to the actions of cocaine. As GSK3 activity was found to be increased by cocaine, subsequent experiments investigated the importance of GSK3 activation in cocaine conditioned reward. Adult male CD-1 mice were injected with cocaine or saline, and levels of phosphorylated Akt and GSK3α/β were measured 30 minutes later. Acute administration of cocaine significantly decreased the phosphorylation of Akt-Thr308 (pAkt-Thr308) and GSK3β in the caudate putamen and nucleus accumbens core, without altering pAkt-Ser473 and pGSK3α. To investigate the role of dopamine and NMDA receptors in the regulation of Akt and GSK3 by cocaine, specific receptor antagonists were administered prior to cocaine. Blockade of dopamine D2 receptors with eticlopride prevented the reduction of pAkt-Thr308 produced by cocaine, whereas antagonists at dopamine D1, dopamine D2 or glutamatergic NMDA receptors each blocked cocaine-induced reductions in pGSK3β. The potential importance of GSK3 activity in the rewarding actions of cocaine was determined using a cocaine conditioned place preference procedure. Administration of the selective GSK3 inhibitor, SB 216763, prior to cocaine conditioning sessions blocked the development of cocaine place preference. In contrast, SB 216763 did not alter the acquisition of a contextual fear conditioning response, demonstrating that SB 216763 did not globally inhibit contextual learning processes. The results of this study indicate that phosphorylation of GSK3β is reduced, hence GSK3β activity is increased following acute cocaine, an effect that is contingent upon both dopaminergic and glutamatergic receptors. Further, GSK3 activity is required for the development of cocaine conditioned reward.
Highlights
Cocaine abuse remains one of our society’s major public health problems
These data demonstrate that acute administration of cocaine reduced the activity of Akt by decreasing the phosphorylation of Akt at its Thr308 residue in the caudate putamen
The findings of this study demonstrate that acute cocaine administration reduced the phosphorylation of Akt at the Thr308 regulatory site in the caudate putamen which corresponds to a decrease in Akt activity
Summary
Repeated cocaine exposure increases the likelihood of further drug abuse, leading to the development of addiction. Recent neurobiological research has identified neuroadaptations that occur during drug exposure. These adaptations are thought to produce the states of drug reward, dependence, sensitization, withdrawal, and craving, all of which contribute to continued drug-seeking and drug-taking behaviors that form the basis of addiction. Of direct relevance to drug addiction, Akt and its downstream kinase, GSK3, have been shown to mediate dopaminergic neurotransmission and regulate behaviors including those produced by psychostimulants [1,2,3,4], as well as modulating behavioral and cellular responses to opiates [5]
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