Amphetamine has complex behavioral actions in the rat that depend upon the release of dopamine in striatal and mesolimbic brain regions. To explore a possible role of the dopamine-sensitive CAMP second-messenger system in mediating these effects, we examined the effects of in viva amphetamine treatments on the Dl receptor-coupled adenylate cyclase system in membranes from striatal and mesolimbic rat brain regions. The results show that amphetamine produces a regional, dose-and time-dependent down-regulation of adenylate cyclase activity. Intermediate and high doses of amphetamine (2.5 and 7.5 mg/kg, respectively), but not a low dose (1.0 mg/kg), resulted in a decrease in the apparent Vmx and/or an increase in the apparent K. for the selective Dl partial agonist, SKF38393, in striatal membranes 30 min after amphetamine treatment. Treatment of rats with 7.5 mg/kg amphetamine for 30 and 60 min, but not 10 min, similarly resulted in a down-regulation of Dl-mediated adenylate cyclase activity in striatal membranes. In contrast, in mesolimbit tissues, no amphetamine treatment at any time resulted in an alteration of SKF38393-stimulated adenylate cyclase activity relative to saline controls. The results of behavioral analyses also showed that animals exhibiting intense stereotypies had significantly lower striatal apparent V,, values than did those animals engaged in moderate or no behavioral activity at the time of decapitation. These findings demonstrate that amphetamine treatments result in a down-regulation of striatal, but not mesolimbic, dopamine-sensitive adenylate cyclase activity that parallels the intense, stereotyped behaviors characteristic of dopaminergic activation in the striatum.Amphetamine (AMPH), a phenylethylamine derivative, is a potent CNS stimulant with a multiplicity of behavioral and physiological effects (see Tepper, 1983, andSchuckit, 1983, for reviews). At lower doses of AMPH (1 .O mg/kg), rats exhibit enhanced locomotor activity and exploratory behaviors. As the dose is increased (e.g., 2.5 mg/kg), rats begin to show episodic bouts of repetitive head and limb movements (stereotypies). After a high dose of AMPH (5-7.5 mg/ kg), a similar sequence of behaviors may be observed as a function of time after AMPH administration. Shortly after the drug injection (ca. 10 min), rats show a marked increase in rearing and sniffing, or locomotor activity, followed (ca. 30 min) by stereotyped head and limb movements. By 60 min after AMPH administration, most animals are engaged in intense, continuous stereotypy, head oriented down toward the cage floor, often accompanied by oral stereotypies such as licking or gnawing. These multiphasic time-and dose-dependent behavioral effects

Adenylate cyclase activity in bovine retina is highly responsive to Ca2+ and the endogenous Ca2+-binding protein, calmodulin (CaM). CaM stimulated adenylate cyclase activity in washed particulate fractions of bovine retina by 6.6-fold in a Ca2+-dependent manner. Activation of adenylate cyclase activity by CaM was maximal at 0.12 microM free Ca2+. The apparent Ka for calmodulin stimulation of adenylate cyclase was 67 nM and the apparent Vmax was 116 pmol/min/mg of protein above basal activity. Adenylate cyclase activity in bovine retina was stimulated approximately 50% by guanosine 5'-triphosphate (GTP), but the nonhydrolyzable GTP analogue, guanosine-5'-(beta, gamma-imido)triphosphate (Gpp(NH)p), was able to activate the enzyme nearly 5-fold. CaM and Gpp(NH)p appeared to be partially competitive activators of adenylate cyclase in the retina particulate fraction. Dopamine stimulated adenylate cyclase activity in the presence of GTP with an apparent Ka of 1.0 microM and an apparent Vmax of 66 pmol/min/mg of protein. Ca2+ and CaM increased the apparent Vmax of the dopamine-stimulated adenylate cyclase activity more than 2-fold to a level of 146 pmol/min/mg of protein but did not alter the apparent Ka. This suggests that CaM is an endogenous modulator of dopamine-stimulated adenylate cyclase activity in the retina. CaM-stimulated adenylate cyclase activity may be a common component to retina since we found this activity in retinas from rabbit, rat, and goldfish as well as cow.