Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference Possible Dependence on Dopamine Uptake Blockade

Abstract

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 ...

Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

“…The following experiments were performed; 1) the effects of (+)-morphine, (−)-morphine and (+)-pentazocine injected subcutaneously on the tail-flick inhibition produced by (−)-morphine given subcutaneously; 2) the effect of (+)-naloxone given subcutaneously on the attenuation of the (−)-morphine-produced tail-flick inhibition induced by (+)-morphine, (−)-morphine or (+)-pentazocine given subcutaneously; 3) the effect of the sigma receptor antagonist BD1047 given subcutaneously (Romieu et al, 2000(Romieu et al, , 2002Maurice et al, 2003) on the attenuation of the (−)-morphine-produced tail-flick inhibition induced by (+)-morphine, (−)-morphine or (+)-pentazocine given subcutaneously.…”

σ1 Receptor Ligands and Related Neuroactive Steroids Interfere with the Cocaine-Induced State of Memory

“…Cocaine self-administration and relapse are also mediated by glutamate neurotransmission in the nucleus accumbens (Cornish et al, 1999;Park et al, 2002). In addition, cocaine interacts with the s 1 receptor at a similar dose range as observed for the dopamine transporter (Sharkey et al, 1988), and the s 1 receptor is implicated in several of cocaine's effects such as locomotor stimulation, sensitization, acquisition and reactivation of conditioned place preference, convulsions, and lethality (Reith et al, 1986;Menkel et al, 1991;Ujike et al, 1992;Ritz and George, 1993;Romieu et al, 2000Romieu et al, , 2002Romieu et al, , 2003Romieu et al, , 2004; for a review, see Maurice et al, 2002). This intracellular protein sharing some characteristics of neuromodulatory receptors is also a target for several neuroactive steroids, including pregnenolone, dehydroepiandrosterone (3b-hydroxy-5a-androsten-17-one (DHEA)), their sulfate esters, or progesterone, but not pregnanolone or allopregnanolone (Su et al, 1988;Monnet et al, 1995;Bergeron et al, 1996;Maurice et al, 1999).…”

Differential Effects of σ1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward

“…Behaviorally, s 1 receptors have been implicated in cognitive function, anxiety, depression, and regulation of stress responses (eg Maurice et al, 2001;Urani et al, 2001). Additionally, s 1 receptors have been found to modulate several neurobehavioral effects of cocaine, including the drug's subjective (Katz et al, 2003), psychomotor stimulant (Menkel et al, 1991;Ujike et al, 1996), rewarding (Romieu et al, 2000), and toxic (Matsumoto et al, 2001) actions. Of interest with regard to a s 1 receptor role in cocaine addiction is that pharmacological blockade of this receptor attenuates expression of cocaine-conditioned place preference (CPP) (Romieu et al, 2000, suggesting that s 1 receptors participate in mediating the conditioned incentive effects of cocaine-related environmental stimuli.…”

“…Additionally, s 1 receptors have been found to modulate several neurobehavioral effects of cocaine, including the drug's subjective (Katz et al, 2003), psychomotor stimulant (Menkel et al, 1991;Ujike et al, 1996), rewarding (Romieu et al, 2000), and toxic (Matsumoto et al, 2001) actions. Of interest with regard to a s 1 receptor role in cocaine addiction is that pharmacological blockade of this receptor attenuates expression of cocaine-conditioned place preference (CPP) (Romieu et al, 2000, suggesting that s 1 receptors participate in mediating the conditioned incentive effects of cocaine-related environmental stimuli. It is well established that such stimuli can evoke craving or lead to relapse in abstinent individuals (eg O'Brien et al, 1998) and, in animals, consistently elicit reinstatement of extinguished cocaineseeking (See, 2002;Shaham et al, 2003;Weiss, 2005).…”

“…To establish whether BD1047 preferentially modifies drug-directed behavior or exerts general suppressant effects on motivated behavior, BD1047 effects were tested also on responding induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Because s 1 receptors have been implicated not only in the expression but also acquisition (Romieu et al, 2000 of cocaine CPP (ie a process linked to the acute reinforcing actions of cocaine), tests of BD1047 effects on self-administration of cocaine and SCM were conducted as well.…”