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Regulation of gene expression is known to contribute to the long-term adaptations taking place in response to drugs of abuse. Recent studies highlighted the regulation of gene transcription in neurons by chromatin remodeling, a process in which posttranslational modifications of histones play a major role. To test the involvement of epigenetic regulation on drug-reinforcing properties, we submitted rats to the cocaine operant self-administration paradigm. Using the fixed ratio 1 schedule, we found that the histone deacetylase (HDAC) inhibitors trichostatin A and phenylbutyrate dose-dependently reduced cocaine self-administration. Under the progressive ratio schedule, both trichostatin A and depudecin significantly reduced the breaking point, indicating that HDAC inhibition attenuated the motivation of rats for cocaine. Conversely, HDAC inhibition did not decrease self-administration for the natural reinforcer sucrose. This observation was correlated with measurements of HDAC activity in the frontal cortex, which was inhibited in response to cocaine, but not to sucrose self-administration. Control experiments showed that the decrease in the motivation for the drug was not attributable to a general motivational dysfunction because trichostatin A had no adverse effect on locomotion during the habituation session or on cocaine-induced hyperlocomotion. It was not attributable to anhedonia because the inhibitor had no effect on the sucrose preference test. In contrast, trichostatin A completely blocked the cocaine-induced behavioral sensitization. Together, the data show that epigenetic regulation of gene transcription in adult brain is able to influence a motivated behavior and suggest that HDAC inhibition may counteract the neural sensitization leading to drug dependence.

The involvement of the sigma 1 receptor on the rewarding effects of cocaine was examined using the conditioned place preference (CPP) procedure in C57BL/6 mice. Acquisition or expression of cocaine (20 mg/kg i.p.)-induced CPP was significantly decreased by pre-treatment with the selective sigma 1 receptor antagonists N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine (NE-100) or N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047), 1-10 mg/kg, i.p. The sigma 1 receptor agonists igmesine or 2-(4-morpholinoethyl-1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) failed to induce CPP when injected alone. Moreover, the CPP induced by N-[1-(2-benzo(b)Cocaine is a highly addictive substance that is abused by humans worldwide (Warner 1993;Higgins 1997). Cocaine also acts as a potent reinforcer in laboratory animals (Pickens and Thompson 1968;Koob 1992;Stolerman 1992;Woolverton and Johnson 1992). While cocaine inhibits the transport of serotonin (5-HT), norepinephrine and dopamine (DA), it is widely accepted that the ad- NO . 4 Sigma 1 Receptor and Cocaine 445 dictive and reinforcing actions of cocaine are dependent on the drug's ability to block the dopamine transporter (DAT), thereby increasing dopamine (DA) neurotransmission (Kuhar 1992;Ritz et al. 1987;Parsons et al. 1998;Woolverton 1992). Because of the link between cocaine's addictive liability and the DA reward/reinforcement circuitry of the forebrain (Koob 1992), treatment strategies against cocaine abuse have logically targeted the DA system. However, it has been described that cocaine also interacts with the sigma 1 receptor at a similar dose range as observed for the DAT and that the sigma 1 receptor is implicated in some of cocaine's effects such as locomotor activation, sensitization, convulsion and lethality (Koe 1976;Reith et al. 1986;Menkel et al. 1991;Ujike et al. 1992;Ritz and George 1993). Therefore, the diverse pharmacological profile of cocaine may contribute to, or modulate, its behavioral effects through a complex mechanism of action affecting the different monoaminergic transporters as well as other targets. Consistent with this hypothesis is the study by Sora et al. (2000) demonstrating that it is possible to establish cocaineinduced place preference in DA or 5-HT transporter knockout mice, leading to the hypothesis that other targets might be involved in producing the rewarding effects of cocaine. An alternative therapeutic approach to treating cocaine addiction, therefore, would be to target the sigma 1 receptor, which has recently been demonstrated to be involved in cocaine's rewarding effects measured using a conditioned place preference (CPP) paradigm in mice (Romieu et al. 2000). The sigma 1 receptor, localized intracellularly within the neurons, is a 223 amino acid protein, cloned in several animal species and humans (Hanner et al. 1996;Kekuda et al. 1996;Seth et al. 1997Seth et al. , 1998Pan et al. 1998). The receptor appeared devoid of analogy with any other known mammalian protein and its ...

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