Amphetamine produces enhanced behavioral responding in sensitized male rats: Parallel changes in AMPA receptor...

Repeated intermittent exposure to drugs like amphetamine and cocaine leads to long-lasting sensitization of their behavioral and neurochemical effects. Several lines of evidence suggest that dopamine (DA) and glutamate in the forebrain nucleus accumbens (NAcc) contribute to these effects and that AMPA receptors in this site play an essential role. Here, in experiments conducted in outbred male rats, we again show that, unlike cocaine, prior sensitizing exposure to amphetamine does not lead to an increase in basal cell surface expression of AMPA receptors. However, 30-min after an amphetamine challenge, when the drug's enhanced behavioral effects are evident, both saline and amphetamine exposed rats show an increase in NAcc AMPA receptor surface expression that is significantly enhanced in sensitized rats. As overflow of both DA and glutamate is enhanced following a drug challenge in stimulant sensitized rats, we examined the contribution of two DA and glutamate receptor initiated signaling pathways in the NAcc to the expression of amphetamine sensitization: one using protein kinase A (PKA) and one using protein kinase C (PKC). We found that an amphetamine challenge increases NAcc PKC but not PKA activity in amphetamine sensitized rats, suggesting that the former but not the latter is required for the expression of amphetamine sensitization. To further assess this possibility, we used serine to alanine mutants to prevent phosphorylation by these kinases of residues on the AMPA receptor GluA1 subunit known to contribute to AMPA receptor trafficking and function: GluA1(S845A) for PKA and GluA1(S816A-S818A) for PKC. Consistent with the above findings, preventing phosphorylation of NAcc GluA1 by PKC, but not by PKA, blocked expression of the sensitized locomotor response to NAcc amphetamine as well as the enhanced self-administration of IV amphetamine normally observed in sensitized rats. Together, these results support the need for PKC but not PKA phosphorylation of NAcc GluA1 in the expression of behavioral sensitization by amphetamine and highlight the importance of NAcc AMPA receptor regulation by PKC in generation of the sensitized response.