HALOPERIDOL AND MK-801 BLOCK INCREASES IN STRIATAL CALMODULIN RESULTING FROM REPEATED AMPHETAMINE TREATMENT

Repeated, intermittent treatment with amphetamine leads to a behaviora l sensitization characterized in rats by an increase in locomotor acti vity and a more rapid onset of stereotyped behaviors. Induction of amp hetamine sensitization is blocked by dopamine and N-methyl-D-aspartate (NMDA) antagonists. We have reported an increase in the content of th e Ca2+-binding protein, calmodulin, in striatum and limbic forebrains from rats given repeated, intermittent amphetamine. To determine wheth er the increase was related to development of amphetamine sensitizatio n, we examined whether the increase in calmodulin would be blocked by the dopamine antagonist, haloperidol, or the NMDA antagonist, MK-801. Rats were given amphetamine or saline twice weekly for 5 weeks. Thirty min prior to the amphetamine, rats were pretreated with 0.25 mg/kg ha loperidol s.c., 0.1 mg/kg MK-801 i.p. or saline. Twice weekly amphetam ine treatment increased calmodulin in the cytosol fraction of striatum and limbic forebrain and the increase was blocked by pretreatment wit h either haloperidol or MK-801. Neither antagonist alone affected cyto solic calmodulin. Haloperidol pretreatment, but not amphetamine or MK- 801, increased calmodulin in striatal but not limbic forebrain membran es. Calmodulin-binding proteins were examined by biotinylated calmodul in blotting to determine if repeated, intermittent amphetamine altered the content of calmodulin-binding proteins in striatal cytosol or mem branes. A band of 73 kDa was increased in striatal membranes. Immunobl otting with antisera to caldesmon, a cytoskeletal calmodulin-binding p rotein of 77 kDa, demonstrated increases in immunoreactivity in striat al membranes and cytosol. These data suggest that dopaminergic and glu tamatergic components are required for the increase in striatal and li mbic forebrain calmodulin and that the rise in calmodulin is related t o the development of amphetamine sensitization. In addition, the conte nt of select calmodulin-binding proteins can be coordinately regulated with increases in calmodulin.