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We have previously demonstrated that nicotine withdrawal produces depression-like behavior and that serotonin (5- HT)2A/2C receptor ligands modulate that mood-like state. In the present study we aimed to identify the mechanisms (changes in radioligand binding, transcription or RNA-editing) related to such a behavioral outcome. Rats received vehicle or nicotine (0.4 mg/kg, s.c.) for 5 days in home cages. Brain 5- HT2A/2C receptors were analyzed on day 3 of nicotine withdrawal. Nicotine withdrawal increased [3H]ketanserin binding to 5- HT2A receptors in the ventral tegmental area and ventral dentate gyrus, yet decreased binding in the nucleus accumbens shell. Reduction in [3H]mesulergine binding to 5- HT2C receptors was seen in the ventral dentate gyrus. Profound decrease in the 5- HT2A receptor transcript level was noted in the hippocampus and ventral tegmental area. Out of five 5- HT2C receptor mRNA editing sites, deep sequencing data showed a reduction in editing at the E site and a trend toward reduction at the C site in the hippocampus. In the ventral tegmental area, a reduction for the frequency of CD 5- HT2C receptor transcript was seen. These results show that the reduction in the 5- HT2A receptor transcript level may be an auto-regulatory response to the increased receptor density in the hippocampus and ventral tegmental area during nicotine withdrawal, while decreased 5- HT2C receptor mRNA editing may explain the reduction in receptor labeling in the hippocampus. [ABSTRACT FROM AUTHOR]

Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D2 receptors (D2Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D2-likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D2-likeR binding characteristics and Gαi/o-protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D2-likeR agonist quinpirole (10 μM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPγS to striatal D2-likeRs, whereas the D2-likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPγS binding to D2-likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Gαi/o-protein coupling of D2Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects. [ABSTRACT FROM AUTHOR]

We verified the hypothesis that serotonin (5-HT)2 receptors control the locomotor effects of nicotine (0.4 mg kg−1) in rats by using the 5-HT2A receptor antagonist M100907, the preferential 5-HT2A receptor agonist DOI, the 5-HT2C receptor antagonist SB 242084, and the 5-HT2C receptor agonists Ro 60-0175 and WAY 163909. Repeated pairings of a test environment with nicotine for 5 days, on Day 10 significantly augmented the locomotor activity following nicotine administration. Of the investigated 5-HT2 receptor ligands, M100907 (2 mg kg−1) or DOI (1 mg kg−1) administered during the first 5 days in combination with nicotine attenuated or enhanced, respectively, the development of nicotine sensitization. Given acutely on Day 10, M100907 (2 mg kg−1), Ro 60-0175 (1 mg kg−1), and WAY 163909 (1.5 mg kg−1) decreased the expression of nicotine sensitization. In another set of experiments, where the nicotine challenge test was performed on Day 15 in animals treated repeatedly (Days: 1-5, 10) with nicotine, none of 5-HT2 receptor ligands administered during the second withdrawal period (Days: 11-14) to nicotine-treated rats altered the sensitizing effect of nicotine given on Day 15. Our data indicate that 5-HT2A receptors (but not 5-HT2C receptors) play a permissive role in the sensitizing effects of nicotine, while stimulation of 5-HT2A receptors enhances the development of nicotine sensitization and activation of 5-HT2C receptors is essential for the expression of nicotine sensitization. Repeated treatment with the 5-HT2 receptor ligands within the second nicotine withdrawal does not inhibit previously established sensitization. Synapse 64:511-519, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]