Transient viral-mediated overexpression of calcium/calmodulin-dependent protein kinase II & behavioral responding to amphetamine

CaMKII is known to contribute to the expression of psychostimulant sensitization by regulating dopamine (DA) overflow from DA neuron terminals in the nucleus accumbens (NAcc). The present experiments explored the contribution of CaMKII in NAcc neurons postsynaptic to these terminals where it is known to participate in a number of signaling pathways that regulate responding to psychostimulant drugs. Exposure to amphetamine transiently increased alphaCaMKII levels in the shell but not the core of the NAcc. Thus, herpes simplex viral (HSV) vectors were used to transiently overexpress alphaCaMKII in NAcc neurons in drug naive rats and behavioral responding to amphetamine was assessed. Transiently overexpressing alphaCaMKII in the NAcc shell led to long-lasting enhancement of amphetamine-induced locomotion and self-administration manifested when alphaCaMKII levels were elevated and persisting long after they had returned to baseline. Enhanced locomotion was not observed following infection in NAcc core or sites adjacent to the NAcc. Transient elevation of NAcc shell alphaCaMKII levels also enhanced locomotor responding to NAcc AMPA and increased phosphorylation levels of GluR1 (ser831), a CaMKII site, both soon and long after infection. Similar increases in pGluR1 (ser831) were observed both soon and long after exposure to amphetamine. These results indicate that the transient increase in alphaCaMKII observed in neurons of the NAcc shell following viral-mediated gene transfer and likely exposure to amphetamine leads to neuroadaptations in AMPA receptor signaling in this site that may contribute to the long-lasting maintenance of behavioral and incentive sensitization by psychostimulant drugs like amphetamine.;To also assess the role that NAcc CaMKII activity plays in the expression of established sensitization observed weeks after exposure to the drug, the effect of CaMKII inhibition on the expression of behavioral sensitization was assessed. Pharmacologically inhibiting CaMKII in the NAcc shell but not core attenuated the enhanced amphetamine self-administration normally observed in sensitized rats. To more directly assess the role of postsynaptic NAcc CaMKII in the expression of sensitization, HSV vectors were used to overexpress an inactive form of alphaCaMKII (K42M) that effectively blocks endogenous CaMKII activity. Overexpressing alphaCaMKII K42M in NAcc shell neurons prevented the expression of amphetamine-induced locomotion after several weeks of withdrawal from the drug. Taken together, these findings directly link changes in NAcc shell alphaCaMKII protein levels to enhanced behavioral responding to amphetamine and identify a role for alphaCaMKII in NAcc neurons in the expression of behavioral sensitization. These findings also identify alphaCaMKII as a potential target for therapeutic intervention in the treatment of stimulant abuse and addiction.