The expression of sensitized locomotor activity is known to rely on calcium and calcium/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanisms. However, the exact role CaMKII plays in the expression of sensitization remains unclear. To further characterize its contribution, microinjections of herpes simplex virus (HSV) vectors that cause transient overexpression (at Day 4 post-infection) of wild-type (WT) or constitutively active (T286D) αCaMKII were made into either the nucleus accumbens (NAcc) shell or the ventral tegmental area (VTA) of drug-naïve rats. Locomotor responding to amphetamine (AMPH) was subsequently examined. Rats infected with HSV-WT or -T286D αCaMKII in the NAcc shell but not the VTA showed enhanced locomotor responding to AMPH on day 4 as well as up to 34 days post-infection, long after protein levels had returned to baseline.  Previous studies have shown that CaMKII enhances glutamatergic transmission by increasing α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptor conductance and promoting AMPA receptor trafficking.  In addition, glutamatergic transmission contributes to the expression of stimulant sensitization.  To investigate whether transiently increasing αCaMKII in the NAcc leads to long-term alterations in AMPA receptor function, NAcc microinjections of AMPA were administered 4 and 20 days after injection of HSV-T286D αCaMKII  into the NAcc shell.  HSV-T286D αCaMKII infected rats showed enhanced locomotor responding to AMPA only on day 20 post-infection.   These findings suggest that functional upregulation of AMPA receptors may represent one long-term neuroadaptation that results from transient increases in NAcc αCaMKII levels.  In addition, αCaMKII-dependent alterations in glutamatergic transmission may very well mediate the long-term enhancement in locomotor responding to AMPH observed in NAcc HSV-αCaMKII infected rats. 

Support Contributed By: DA07255 and DA09397 (NIH)

08/08/07