The frequency of cocaine administration impacts cocaine-induced receptor alterations.

The present study investigated the impact of dosing schedule on cocaine-induced receptor alterations. Rats were injected with 30 mg/kg per day of cocaine given either as a single injection or in two equally divided doses for 14 days. The effects of these two dosing regimens were compared with our previous findings following administration of cocaine three times daily at 1-h intervals. Using receptor autoradiography, twice daily injections of cocaine produced an upregulation of mu opioid receptors in the rostral nucleus accumbens, rostral caudate putamen, and layer I of the rostral cingulate cortex, whereas single daily injections resulted in a significant increase in the nucleus accumbens only. Only small insignificant increases in kappa opioid receptor densities were found following either once or twice daily cocaine injections, whereas three daily injections produced an increase in kappa receptor density in the cingulate cortex, nucleus accumbens, and caudate putamen. Increased dopamine D1 receptor binding was found in the nucleus accumbens and olfactory tubercle following twice daily cocaine injections, but not after single daily injections of the same total daily dose. These results demonstrate that the same total daily dose of cocaine administered in multiple small injections produces a greater effect on receptor regulation than a single larger injection. This suggests that the interval between cocaine injections is an important variable when studying the effects of cocaine on neurochemistry.

Dopamine-opioid interactions in the rat striatum: a modulatory role for dopamine D1 receptors in delta opioid receptor-mediated signal transduction.

Dopaminergic and opioidergic systems interact in the striatum to modulate locomotor and motivated behaviors. The present study investigated the molecular interactions of these two systems by determining the role of dopamine D1 and D2 receptors in the modulation of opioid receptor-mediated signal transduction. Male Fischer rats were injected daily for 10 days with either saline, the D1 receptor agonist SKF 82958, the D2 receptor agonist quinpirole, or both SKF 82958 and quinpirole. Administration of SKF 82958 alone or together with quinpirole attenuated the ability of the delta receptor agonist D-Pen2,D-Pen5-enkephalin (DPDPE) to inhibit adenylyl cyclase activity in the caudate putamen and nucleus accumbens. Quinpirole administration alone had no effect. The efficacy and potency of the mu opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin (DAMGO) to inhibit adenylyl cyclase activity was unaltered following administration of either dopamine receptor agonist. Administration of SKF 82958 had no affect on delta receptor binding, forskolin-stimulated adenylyl cyclase activity, or G protein/adenylyl cyclase coupling. However, the ability of DPDPE to stimulate binding of [35S]GTPgammaS to inhibitory G proteins was attenuated in animals that received SKF 82958. These results suggest that repeated activation of D1 receptors attenuates the functional coupling of delta opioid receptors with adenylyl cyclase due to decreased coupling between delta receptors and G proteins.

Sympathetic nerve responses elicited by cocaine in anesthetized and conscious rats.

Recent evidence suggests that cocaine decreases rather than increases sympathetic nerve discharge (SND). The purpose of the present study was to provide the first complete characterization of the dose-response relationships of cocaine (0.005-3 mg/kg, IV) for arterial pressure, heart rate, and lumbar, splanchnic, or renal SND in pentobarbital-anesthetized rats. Cocaine was also tested in conscious rats. In pentobarbital-anesthetized rats cocaine elicited prolonged (lasting up to 56 min), dose-dependent decreases in SND on all three nerves. The splanchnic nerve was significantly more sensitive to the inhibitory actions of cocaine than was the lumbar nerve. Cocaine increased arterial pressure and elicited bradycardia at doses above 0.5 mg/kg. Comparison of the dose-response curves of cocaine for splanchnic SND in sham-operated and sinoaortically deafferentated (SAD) rats showed that the baroreceptor reflex made only a minor contribution to the magnitude of sympathoinhibitory response. However, the duration of the sympathoinhibitory response was significantly shorter in SAD than in sham animals. In conscious rats, cocaine (0.1 and 1.0 mg/kg) elicited a pattern of neural and cardiovascular responses similar to that seen in anesthetized rats, except that the prolonged sympathoinhibitory responses were preceded by a brief (lasting < 10 s) increase in SND. From these data we conclude that cocaine produces prolonged decreases in SND in conscious and anesthetized rats. These sympathoinhibitory responses do not appear to result from baroreceptor reflex activation and may involve a central mechanism of action.