Haloperidol and MK-801 block increases in striatal calmodulin resulting from repeated amphetamine treatment

Repeated, intermittent treatment with amphetamine leads to a behavioral sensitization characterized in rats by an increase in locomotor activity and a more rapid onset of stereotyped behaviors. Induction of amphetamine sensitization is blocked by dopamine and N-methyl-D-aspartate (NMDA) antagonists. We have reported an increase in the content of the Ca2(+)-binding protein, calmodulin, in striatum and limbic forebrains from rats given repeated, intermittent amphetamine. To determine whether the increase was related to development of amphetamine sensitization, 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 haloperidol s.c., 0.1 mg/kg MK-801 i.p. or saline. Twice weekly amphetamine treatment increased calmodulin in the cytosol fraction of striatum and limbic forebrain and the increase was blocked by pretreatment with either haloperidol or MK-801. Neither antagonist alone affected cytosolic calmodulin. Haloperidol pretreatment, but not amphetamine or MK-801, increased calmodulin in striatal but not limbic forebrain membranes. Calmodulin-binding proteins were examined by biotinylated calmodulin blotting to determine if repeated, intermittent amphetamine altered the content of calmodulin-binding proteins in striatal cytosol or membranes. A band of 73 kDa was increased in striatal membranes. Immunoblotting with antisera to caldesmon, a cytoskeletal calmodulin-binding protein of 77 kDa, demonstrated increases in immunoreactivity in striatal membranes and cytosol. These data suggest that dopaminergic and glutamatergic components are required for the increases in striatal and limbic forebrain calmodulin and that the rise in calmodulin is related to the development of amphetamine sensitization. In addition, the content of select calmodulin-binding proteins can be coordinately regulated with increases in calmodulin.