Influence of sigma-1 receptor modulators on ethanol-induced conditioned place preference in the extinction–reinstatement model

Abstract

Sigma-1 receptor agonists are reported to augment and antagonists block the rewarding effects of drugs of abuse. However, their effect on reinstatement of ethanol-induced conditioned place preference (CPP) has not yet been explored. Therefore, we investigated the ability of 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate (PRE-084), a sigma-1 receptor agonist, and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD-1047), a sigma-1 receptor antagonist, on the acquisition, expression, and reinstatement of ethanol-induced CPP using adult male Swiss mice. BD-1047 (0.1-10 μg/mouse, intracerebroventricularly) dose-dependently blocked the development, expression, and reinstatement of ethanol-induced CPP, and PRE-084 (0.01-10 μg/mouse, intracerebroventricularly) dose-dependently reinstated the extinguished response. These effects of PRE-084 and BD-1047 alone or in combination with ethanol did not influence the motor activity. Therefore, it is concluded that sigma-1 receptor ligands can modulate the acquisition, expression, and reinstatement of conditioned reinforcing effects of ethanol with no reinforcing or aversive influence of their own. The results add to the growing literature on sigma-1 receptor modulation in the pharmacotherapy of ethanol addiction.

Sigma receptors [σRs]: biology in normal and diseased states

“…σR antagonists and antisense oligonucleotides ameliorate cocaine-induced convulsions, lethality and locomotor activity ( 49 , 50 ), as well as sensitization, and conditioned place-preference in rodents ( 51 ). They also reduce alcohol consumption in alcohol-drinking rats ( 52 , 53 ) and Swiss mice ( 54 ). Interestingly, the interaction of fluvoxamine [Luvox], a selective serotonin reuptake inhibitor [SSRI], and the σRs may account for its potential amelioration of psychotic depression ( 55 , 40 ), where increased glutamate [Glu] release occurs through activation of serotonin [5-HT 3 ] mediated by σ 1 Rs ( 56 ), and in patients with schizophrenia ( 57 , 40 ).…”

Modeling Relapse in Animals

“…CPP reactivation procedures have been successfully applied in conjunction with abstinence manipulations following which drug injections or stress reactivate CPP. (e.g., Buthada et al 2011a,b; Itzhak and Martin 2002; Kuzmin et al 2003; Mueller and Stewart 2000; Romieu et al 2004; Szumlinski et al 2002; Thanos et al 2009; for review see Aguilar et al 2009; Tzschentke 2007) .…”

Role of Sigma Receptors in Alcohol Addiction

“…The systemic administration of the selective Sig-1R agonist PRE-084 prior to ethanol enhances ethanol-induced CPP (Maurice et al, 2003). Studies using intracerebroventricular administration of the same agonist also showed a facilitation of the acquisition of ethanol-induced CPP (Bhutada et al, 2012). Moreover, pretreatment with the Sig-1R antagonist BD-1047, administered during conditioning, blocks the acquisition of ethanol-induced CPP (Maurice et al, 2003), while its intracerebroventricular administration has been shown to reduce both acquisition and expression (Bhutada et al, 2012).…”

“…Studies using intracerebroventricular administration of the same agonist also showed a facilitation of the acquisition of ethanol-induced CPP (Bhutada et al, 2012). Moreover, pretreatment with the Sig-1R antagonist BD-1047, administered during conditioning, blocks the acquisition of ethanol-induced CPP (Maurice et al, 2003), while its intracerebroventricular administration has been shown to reduce both acquisition and expression (Bhutada et al, 2012). Lastly, neither Sig-1R agonists nor antagonists affect place preference when administered alone (Romieu et al, 2000; Maurice et al, 2003).…”

“…Another procedure is the priming-induced alcohol-seeking method, which mimics the human condition known as “one drink, one drunk,” initially described by Jellinek and later validated by Hodgson and colleagues (Jellinek, 1952; Hodgson et al, 1979). In the context of reinstatement of ethanol-induced CPP, the administration of the selective Sig-1R agonist PRE-084 intracerebroventricularly was shown to be sufficient to induce reinstatement (Bhutada et al, 2012). Furthermore, pretreatment with the Sig-1R antagonist BD-1047 dose-dependently blocks both ethanol-induced and PRE-084-induced reinstatement, thus confirming that Sig-1R activation is required for priming-induced reinstatement (Bhutada et al, 2012).…”