| Sensitization is a progressive and enduring augmentation of locomotor-activating and stereotyped behaviors in rats that results from repeated intermittent administration of psychostimulant drugs. Sensitization may reflect the neurochemical and cellular plasticity or changes within the brain reward circuitry induced by exposure to psychomotor stimulants. Ionotropic glutamate receptors, L-type calcium channels, and calcium-mediated second messengers may play critical roles in the initiation of behavioral sensitization to cocaine, a process that takes place in the ventral tegmental area (VTA). The experiments presented here examined the effect of administration of an alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor antagonist, N-methyl-D-aspartic acid (NMDA) receptor antagonist, L-type calcium channel blocker, or inhibitor of calcium/calmodulin-dependent protein kinase II (CaM-KII) directly into the VTA prior to each of four daily systemic cocaine injections in order to assess their influence on the initiation phase of behavioral sensitization. Each of thefour pretreatments impaired the initiation of cocaine-induced behavioral sensitization in rats. Consistent with this finding, behavioral sensitization was attenuated in homozygous alpha-CaM-KII knockout mice. Western blotting analysis indicated that while there is no change in total CaM-KII protein levels in either the VTA or nucleus accumbens (NA) of rats 2 hr after a sensitizing regimen of cocaine injections, there is an increase in CaM-KII in the VTA at 24 hrs, but still no change in the NA. Collectively, these results suggest that increased calcium influx through AMPA receptors, NMDA receptors, and L-type calcium channels on dopamine neurons in the VTA contributes significantly to the initiation of behavioral sensitization by amplifying calcium signaling through CaM-KII. Tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is one of the numerous intracellular targets of CaM-KII. The findings suggest that cocaine-induced increases in CaM-KII might result in enhanced dopamine synthesis. However, repeated cocaine administration had no effect on tyrosine hydroxylase activity in the nucleus accumbens core or shell, which receive dopaminergic projections from the VTA. These data indicate that CaM-KII contributes to the cocaine-induced plasticity associated with the initiation of behavioral sensitization. They suggest that therapeutics that influence the activity of this enzyme may be useful in treating addiction. |
