Abstract
The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of acute and chronic administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat and the prefrontal cortex (PFC). For this purpose, we used three models of administration. In the first, rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1 mg/kg, intraperitoneally) for 20 consecutive days when rats were euthanized and prepared for in vitro binding and in situ hybridization experiments for the above dopaminergic and GABAergic markers. Thus, the repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and inc ...
The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of acute and chronic administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat and the prefrontal cortex (PFC). For this purpose, we used three models of administration. In the first, rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1 mg/kg, intraperitoneally) for 20 consecutive days when rats were euthanized and prepared for in vitro binding and in situ hybridization experiments for the above dopaminergic and GABAergic markers. Thus, the repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and increased D1 receptor mRNA and binding in nucleus accumbens. Furthermore, both dopamine receptor and transporter binding and mRNA levels were decreased in substantia nigra. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and substantia nigra.In the second model of administration, we used rats which chronically (20 days) received 1 mg/kg of WIN55,212-2 and then abstained from the agonist for 7 days. The last day of abstinence rats were euthanized and prepared for in vitro binding and in situ hybridization experiments for dopamine receptors and transporter, tyrosine hydroxylase (TH) and CB1 receptor in the regions mentioned above. Our results showed a significant increase in D1 and D2 receptor binding in frontal cortex of the rats. A statistically significant decrease was observed in SNpc and VTA for DAT binding sites in all groups and its mRNA expression following WIN55,212-2 administration but significantly increased following a period of abstinence. The same effect was also observed for TH mRNA expression in the regions mentioned above. Decrease was also shown in mRNA levels for D2S isoform of D2 receptor in SNpc and VTA, while the mRNA expression for D2L isoform was not altered. The mRNA expression for CB1 receptor in striatum and nucleus accumbens (NAc) was significantly reduced after WIN55,212-2 exposure and the abstinence period. In the last model of administration, rats were divided into three groups. In the first group they were administrated a single dose of WIN55,212-2 (1mg/kg), the second group received a vehicle injection, while the last one received an injection of the CB1 receptor antagonist AM251 before the WIN55,212-2 administration. All rats were euthanized 2h after the last injection. In vitro binding and in situ hybridization used in order to estimate binding sites and mRNA levels of dopaminergic markers and CB1 receptors. The acute administration of the cannabinoid receptor agonist decreased binding sites and mRNA levels of DAT, and mRNA levels of TH and D2S isoform in SNpc and the VTA, while remained unchanged in the group which was first administrated with AM251. Specific binding for D1 receptors in striatum and NAc was not affected after cannabinoid administration. CB1 receptor mRNA levels were significantly decreased in rat striatum following WIN55,212-2 administration but increased in the regions of NAc and PFC. The present findings support significant alterations in dopaminergic and GABAergic systems in the rat brain after chronic and acute WIN55,212-2 exposure, which may underlie possible neuroadaptive changes induced in these neurotransmitter systems in a region-, dose-, and neurotransmitter-selective manner.
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