Drugs of Abuse

Substantial evidence indicates that the mesolimbic pathway, particularly the dopaminergic system innervating accumbal areas, is implicated in the reward value of both natural and drug reinforcers, such as sexual behavior or psychostimulants, respectively (Koob 1992; Di Chiara and Imperato 1988; Salamone et al. 2007; Spanagel and Weiss 1999). The fact that drugs of abuse act through different cellular mechanisms leads to the possibility that their effects on DA release could be modulated differentially by each of the 5-HT2 receptor subtypes. As an example, it has been reported that the increased locomotor activity, as well as the accumbal DA release, elicited by phencyclidine is further enhanced by the blockade of 5-HT2C receptors (Gobert and Millan 1999), while antagonism at 5-HT2A receptors has opposite effects (Maurel-Remy et al. 1995). A similar picture emerges when considering the influence of these receptors on MDMA (aka ecstasy)-induced effects on DA neuron activity. Thus, the selective 5-HT2A antagonist MDL 100,907 significantly reduced the hyper-locomotion and stimulated DA release produced by MDMA, while the selective 5-HT2C antagonists SB 242084 and SB 206553 potentiated it (Schmidt et al. 1992; Kehne et al. 1996; Bankson and Cunningham 2002; Fletcher et al. 2002a).

It was recently found that SB 206553 administration potentiates both the enhancement of DA release in the nucleus accumbens and striatum and the increased DA neuron firing rate induced by morphine in both the VTA and the SNc (Porras et al. 2002). Consistent with these findings, stimulation of central 5-HT2C receptors has been shown to inhibit morphine-induced increase in DA release in the nucleus accumbens of freely moving rats (Willins and Meltzer 1998). A series of studies showed that blockade of 5-HT2A or 5-HT2C receptors had opposite effects on cocaine-induced locomotor activity. Thus, 5-HT2A-receptor blockade with M100,907 attenuated cocaine-induced locomotion, whereas 5-HT2C blockade with SB 242084 or SB 206553 enhanced cocaine-induced activity (McCreary and Cunningham 1999; McMahon and Cunningham 2001; O'Neill et al. 1999; Fletcher et al. 2002b). Consistent with these data obtained in rats, 5-HT2C receptor null mutant mice showed enhanced cocaine-induced elevations of DA levels in the nucleus accumbens and marked increase in locomotor response to cocaine as compared with wild-type mice, suggesting that selective 5-HT2C receptor agonist treatments may represent a promising novel approach for treating cocaine abuse and dependence (Rocha et al. 2002). In line with this hypothesis, it was found that RO 60-0175 reduced cocaine-reinforced behavior by stimulating 5-HT2C receptors (Grottick et al. 2000) and that intra-VTA injection of the same 5-HT2C receptor agonist reduced the enhancement of DA outflow in the nucleus accumbens induced by a systemic injection of cocaine, while intra-VTA administration of SB 242084 had no effect (Alex et al. 2005). Moreover, it was also shown that RO 60-0175 reduced ethanol- and nicotine-induced self-administration and hyperactivity (Grottick et al. 2000; Tomkins et al. 2002).

Consistent with this evidence, we showed that the selective activation of 5-HT2C receptors by RO 60-0175 blocks the stimulatory action of nicotine on SNc DA

neuronal activity and DA release in the corpus striatum (Di Matteo et al. 2004; Pierucci et al. 2004). The mesolimbic DA system appeared to be less sensitive to the inhibitory effect of 5-HT2C receptors activation on nicotine-induced stimulation; indeed a higher dose of RO 60-0175 was necessary to prevent the enhancement of VTA DA neuronal firing elicited by acute nicotine. Furthermore, pretreatment with the 5-HT2C agonist did not affect nicotine-induced DA release in the nucleus accumbens (Di Matteo et al. 2004; Pierucci et al. 2004). Interestingly, in animals treated repeatedly with nicotine, pretreatment with RO 60-0175 reproduced the same pattern of effects on the enhancement in DA neuronal firing caused by challenge with nicotine, resulting effective only at a higher dose in preventing nicotine excitation in the VTA compared with the SNc. Furthermore, the 5-HT2C receptors agonist counteracted nicotine-induced DA release both in the striatum and in the nucleus accumbens in rats chronically treated with this alkaloid, even if this effect was observed only with the highest dose of RO 60-0175 (Di Matteo et al. 2004; Pierucci et al. 2004). Therefore, we hypothesized that after repeated nicotine exposure an upregulation of 5-HT2C receptors occurs only in the DA mesolimbic system and the blocking of its hyperfunction by 5-HT2C receptor activation might be a useful approach in reducing nicotine reward and eventually helping in smoking cessation. Further, it was also found that nicotine-induced increase in VTA DA neuronal activity can be prevented by 5-HT2C agonism and that 5-HT2C receptor agonist effects can be induced intracellularly using the protein peptide Tat-3L4F, which prevents 5-HT2C receptor dephosphorilation induced by the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) (Ji et al. 2006; Müller and Carey 2006). Thus, systemic administration of Tat-3L4F or the 5-HT2C receptor agonist RO 60-0175 suppressed the increased firing rate of VTA dopaminergic neurons induced by tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana (Ji et al. 2006; Müller and Carey 2006). Using behavioral tests, it was found that Tat-3L4F or RO 60-0175 blocks conditioned place preference of THC or nicotine and that RO 60-0175 but not Tat-3L4F produces anxiogenic effects, thus providing a preclinical basis for treating drug addiction with the Tat-3L4F peptide (Ji et al. 2006; Müller and Carey 2006; Maillet et al. 2008). Thus, these and other preclinical studies indicate that 5-HT2A receptor antagonists and/or 5-HT2C receptor agonists may effectively reduce craving and/or relapse and, likewise, enhance abstinence from several drugs of abuse and that 5-HT2C receptor agonists may also effectively reduce cocaine intake in active cocaine users.

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