REPEATED HALOPERIDOL INCREASES BOTH CALMODULIN AND A CALMODULIN-BINDING PROTEIN IN RAT STRIATUM

Repeated treatment with the antipsychotic drug, haloperidol, leads to an increased behavioral sensitivity to dopamine agonists exhibited upo n withdrawal from the drug. An increase in the particulate content of the endogenous Ca2+-binding protein, calmodulin, has been demonstrated after repeated treatment of rats with haloperidol. In this study, the anatomical specificity of the effect of repeated haloperidol treatmen t on the content and subcellular localization of calmodulin was invest igated. Responsivity of calmodulin localization to dopaminergic input following drug treatment was assessed by determining the subcellular l ocalization of calmodulin following an in vivo amphetamine challenge b efore sacrifice. Male, Sprague-Dawley rats were treated with 0.5 mg/kg haloperidol (s.c.) for 3 weeks and withdrawn from the drug for 4 days . Repeated haloperidol increased calmodulin content only in the striat um but altered the subcellular distribution of calmodulin in rat limbi c forebrain and frontal cortex. In the latter areas, the soluble calmo dulin was increased while the particulate calmodulin was decreased, Th ere was no change in calmodulin in either hippocampus or cerebellum in response to drug treatment. Challenge with the dopamine mimetic, amph etamine, before sacrifice was effective in redistributing calmodulin o nly in striatum from rats that had been treated repeatedly with halope ridol, demonstrating an increased sensitivity of the translocation pro cess. In order to determine whether a change in a calmodulin-binding p rotein would accompany the drug-induced increase in calmodulin,;striat al calmodulin-binding proteins were examined using a biotinylated calm odulin overlay technique. Repeated haloperidol treatment enhanced calm odulin binding to a 150 kDa protein in striatal membranes. The 150 kDa protein exhibited the same gel mobility and subcellular distribution as myosin light chain kinase immunoreactivity. There was an increase i n myosin light chain kinase immunoreactivity in striatal membranes aft er repeated haloperidol that was apparent in animals withdrawn either 4 or 10 days from haloperidol treatment. Therefore, repeated haloperid ol could increase the rat striatal content of calmodulin and potential ly that of the calmodulin-binding protein, myosin light chain kinase. Increases in striatal calmodulin and myosin light chain kinase may sig nal a greatly enhanced sensitivity of-actin-myosin interactions after repeated haloperidol that could contribute to haloperidol-induced neur ochemical or morphological changes involved in drug-induced synaptic p lasticity.