Differential regulation of calmodulin content and calmodulin messenger RNA levels by acute and repeated, intermittent amphetamine in dopaminergic terminal and midbrain areas

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Repeated doses of psychoactive drugs often produce adaptive responses that differ from the initial drug application and additional adaptive processes occur following cessation of the drug. The relationship between alterations in calmodulin protein and messenger RNA produced by an initial versus a repeated dose of amphetamine was examined, as well as changes following drug cessation. Calmodulin protein and messenger RNA of the three individual calmodulin genes were measured in rat dopaminergic cell body and terminal areas following acute or repeated amphetamine. Rats were either injected once with 2.5 mg/kg amphetamine or saline and decapitated after 3 h, or given 10 injections of amphetamine three to four days apart and decapitated 3 h after the final injection. Calmodulin messenger RNA and protein were also measured three and seven days after ceasing drug treatment. Acute amphetamine increased calmodulin 1.7-fold in the striatum and threefold in the ventral mesencephalon, with corresponding elevations in calmodulin messenger RNAs. In response to the 10th dose of amphetamine, however, the degree of increase in calmodulin was diminished in the striatum and ablated in the ventral mesencephalon. Correspondingly, select species of calmodulin messenger RNA were decreased from control levels. In the frontal cortex or nucleus accumbens, calmodulin levels were basically unaltered by the first or 10th doses of amphetamine, but both calmodulin and its messenger RNA were altered with time upon cessation of the drug. Three days later, both calmodulin protein and messenger RNA were decreased in select brain areas. By seven days after the 10th injection, calmodulin content was altered compared to saline controls in all areas, but the change in messenger RNA no longer paralleled the change in protein. Our findings demonstrate that both calmodulin protein and select species of calmodulin messenger RNA are altered by acute amphetamine, but this effect is attenuated after repeated, intermittent amphetamine. There are further time-dependent changes after cessation of repeated amphetamine, which may reflect compensatory neuronal responses. The alterations in calmodulin content and synthesis could contribute to changes in patterns or duration of behaviors that occur upon cessation of repeated amphetamine.