Modulation of the Dopamine- and Calmodulin-Sensitive Second Messenger System in Rat Forebrain By Amphetamine Administration.

Molecular events regulating the dopamine- and calcium/calmodulin-sensitive adenylate cyclase system were investigated in mesolimbic and striatal regions of the rat forebrain following in vivo treatments with behaviorally potent doses of the indirect dopamine agonist, d-amphetamine sulfate. Chronic treatment of rats with 2.5 mg/kg amphetamine resulted in a significant elevation of total calmodulin levels in the striatum from 563 to 914 ng/mg wet weight. On the other h and , acute treatment of rats with amphetamine did result in a rapid dose- and time-dependent desensitization of striatal adenylate cylase activity for the D1 dopamine receptor-selective agonist, SKF38393. This desensitization was characterized by a decrease in the apparent V$\\sb{\\rm max}$ from 153 to 110, and from 199 to 157 pmol of cyclic AMP/minute/mg protein after 2.5 and 7.5 mg/kg amphetamine, respectively, as well as an increase in the apparent K$\\sb{\\rm a}$ from 0.05 to 0.08 $\\mu$ M SKF38393 after 7.5 mg/kg amphetamine. No effects on adenylate cyclase activity were observed after 1.0 mg/kg amphetamine. Treatment of rats with 7.5 mg/kg amphetamine for 30 or 60, but not 10 minutes, similarly resulted in a desensitization of D1-mediated adenylate cyclase activity in striatal membranes. This effect was characterized by a decrease in the apparent V$\\sb{\\rm max}$ from 128 to 97 pmol-minute/mg, and an increase in the apparent ${\\rm K\\sb{a}}$ from 0.04 to 0.08 $\\mu{\\rm M}$ SKF38393 60 minutes after 7.5 mg/kg amphetamine. The results of behavioral analyses also showed that animals exhibiting intense stereotypies had significantly lower striatal ${\\rm V\\sb{max}}$ values than did those animals engaged in moderate or no behavioral activity at the time of decapitation. In contrast, the mesolimbic brain region showed no alterations in adenylate cyclase activity after any amphetamine treatment. The studies described in this dissertation demonstrate alterations in forebrain calmodulin and adenylate cyclase activity that are linked to pharmacological manipulations of dopaminergic activity. These intracellular neurochemical changes paralleled the alterations in behavior which are characteristic of acute or repeated administration of amphetamine to rats. The studies presented here thus provide a new avenue for exploring the cellular biology of dopaminergic systems in relation to their role in normal and pathological behavior.PhDPsychobiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/161452/1/8712197.pd