Cocaine treatment causes early and long-lasting changes in muscarinic and dopaminergic receptors.

1. The study of changes that persist after drug discontinuation could be fundamental to understand the mechanisms involved in craving and relapse. 2. In this work the changes occurring in muscarinic, D1- and D2-like receptors after 30 min (immediate), 1 day (early), 5 and 30 days (late) withdrawal periods were studied, in the striatum of rats treated once a day for 7 days with cocaine 20 and 30 mg/kg, i.p. 3. Binding assays were performed in 10% homogenates and ligands used were [3H]-N-methylscopolamine, [3H]-SCH 23390, and [3H]-spiroperidol for muscarinic (M1 + M2-like), D1-, and D2-like receptors, respectively. 4. Muscarinic receptors presented a downregulation at all doses and discontinuation times, while the dissociation constant (Kd) for this receptor decreased after 30 min, 5 and 30 days abstinence times. In relation to D1-like receptors we found an antagonistic effect with 100% increase in receptor number 30 min after the last cocaine injection, but after 1-day withdrawal a downregulation was observed with both doses that persisted up to 30 days, only with the higher dose. The dissociation constant value (Kd) for this receptor showed a decrease only with 5 and 30 days withdrawal. An increase occurred with D2-like receptors at all doses and withdrawal periods studied, while Kd increased in 30-min, 5, and 30 days withdrawal. 5. In this work we found that the subchronic cocaine treatment produces early and long-lasting modifications in cholinergic muscarinic as well in dopaminergic receptors that persist up to 30 days of cocaine withdrawal.

Muscarinic cholinergic receptor blockade impairs free fatty acid mobilization during fasting in pigeons (Columba livia).

The effects of intracerebroventricular pretreatment with muscarinic (scopolamine or methylscopolamine; 2.7 nmol or 5.4 nmol) or nicotinic (mecamylamine, 2.7 nmol or 5.4 nmol) cholinergic receptor antagonists on plasma free fatty acid increases induced by intracerebroventricular injections of carbachol in conscious resting pigeons (Columba livia) were examined. Plasma glucose levels were also measured throughout the experiments. Pretreatment with methylscopolamine suppressed the lipolytic effect of carbachol injections, while mecamylamine left this response unchanged. Neither carbachol treatment alone, nor the pretreatments with cholinergic agents affected glucose levels. Subsequently, the effects of intracerebroventricular injections of methylscopolamine were investigated in 24-h food-deprived pigeons. The increase in free fatty acid levels after fasting was of a magnitude similar to that observed after carbachol treatment; intracerebroventricular injections of methylscopolamine (5.4 nmol) transiently but powerfully decreased plasma free fatty acids in 24-h food-deprived pigeons to levels comparable to those of free-feeding animals. The fasting-induced decrease in glucose levels was not affected by this treatment. These data indicate that the lipolytic response induced by carbachol may be mediated by central muscarinic cholinergic receptors and that this central cholinergic mechanism partially contributes to plasma free fatty acid increases observed during fasting. Furthermore, the absence of effects on glucose levels suggests that these cholinergic mechanisms participate selectively in the lipolytic component of the metabolic response to fasting.