Behavioral and neurochemical changes in the dopaminergic system after repeated cocaine administration.

In order to determine whether repeated cocaine administration produced persistent changes in dopamine (DA) receptor binding and release consistent with behavioral sensitization, rats were treated with either cocaine (25 mg/kg ip) or saline twice daily for 14 consecutive days followed by a 3-d withdrawal period. The DA transporter site was assayed using [3H]GBR 12935, whereas D1 and D2 sites were assayed using [3H]SCH 23390 and [3H]spiperone, respectively. The density (Bmax) of the DA transporter binding sites in the ST of the cocaine-treated group increased significantly (p < 0.05) over controls 3 d after the last injection, whereas the density of striatal D1 and D2 binding sites remained unchanged. The DA transporter in the nucleus accumbens (NA) was also studied with [3H]GBR 12935 and was unchanged following drug treatment. D1 and D2 binding parameters for the NA were not determined in this study. Furthermore, cocaine administration did not affect the affinities (Kd) of the radioligands used to label the transporter, D1, or D2 sites in any of the studies performed. In addition, striatal DA release was measured using in vivo microdialysis in anesthetized rats. Linear regression analysis on maximal decreases in DA release after apomorphine (0.02, 0.2, and 2.0 mg/kg sc) injection showed no difference in the functional capacity of the ST to modulate DA transmission between control and treated groups. Moreover, animals pretreated with cocaine showed a significant (p < 0.01) decrease in locomotor activity (LA) after a presynaptic, autoregulating dose of apomorphine (0.03 mg/kg sc) was given. These results suggests that the effects seen after repeated exposure to cocaine may be regulated, in part, by changes in striatal DA transporter binding site densities and not necessarily by DA-releasing mechanisms or D1 and D2 receptor modification.

Effect of acute cocaine administration on the cholinergic enzyme levels of specific brain regions in the rat.

Adult male Sprague-Dawley rats weighing between 170 and 204 g and maintained under controlled lighting and temperature conditions were used in this experiment. One group of animals was treated with 30 mg/kg of cocaine hydrochloride and the other group with saline. Rats were decapitated 20 min after cocaine injection and their brains were removed and the different regions including the medulla, pons, midbrain, cerebellum, hypothalamus, thalamus, hippocampus, and the cortex were dissected. All brain regions were assayed for choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities. The results obtained indicated that the administration of cocaine was associated with significant increases (p less than 0.01) in AChE activity in the medulla, pons, midbrain, hypothalamus, thalamus, and also in the hippocampus (p less than 0.05). A significant decrease in ChAT activity was found in the pons (p less than 0.01), hypothalamus, and thalamus (p less than 0.05), while a significant increase in ChAT activity was found in the cortex (p less than 0.05). The results suggest that the changes in general activity followed by stereotypic behavior may be related to the changes in the levels of cholinergic enzymes in specific brain regions.

Both dynorphin A(1-17) and [Des-Tyr1]dynorphin A(2-17) inhibit adenylyl cyclase activity in rat caudate putamen.

In this study, the ability of a series of dynorphin peptides to inhibit adenylyl cyclase (AC) activity was determined. The endogenous ligand of the kappa opioid receptor, dynorphin A(l-17) (Dyn A(l-17)), produced a significant concentration-dependent inhibition of AC activity in membranes prepared from the caudate putamen (CPu) of naive Fischer 344 rats. The opioid receptor antagonist, naloxone (10(-5)M), which is predominantly mu opioid receptor directed, but with modest kappa and delta receptor activity, partially blocked this inhibition. Nor-Binaltorphimine (10(-5)M), the selective kappa receptor antagonist, also blocked the effect of Dyn A(l-17), but to a lesser degree. [Des-Tyr1]Dyn A(2-17), a major nonopioid biotransformation product of Dyn A(l-17) with known biological activities, also inhibited AC in rat CPu membranes. Dyn A(l-13) inhibited AC, as did its major opioid biotransformation product, Dyn A(l-12). One of the major nonopioid biotransformation products of Dyn A(l-13), Dyn A(4-12), showed no activity. Dyn A(2-12), another nonopioid product of Dyn A(l-13), showed limited activity. Dyn A(l-6), a minor biotransformation product of both Dyn A(l-17) and Dyn A(l-13), also inhibited AC activity. These findings suggest that, in rat CPu membranes, the inhibition of AC activity by Dyn A(l-17) is mediated in part by kappa and mu opioid receptors. In addition, Dyn A(2-17), and to a lesser extent Dyn A(2-12), may bind to a yet unidentified site that is also coupled to the AC enzyme in rat CPU.