Effects of acamprosate on alprazolam-induced conditioned place preference in male rats: The role of GABA and NMDA receptor subunits

Abstract

Alprazolam, a commonly prescribed benzodiazepine (BZD), poses a risk for abuse and has been linked to conditioned place preference (CPP). Research indicates that effective long-term treatments for alprazolam misuse are lacking. The mechanisms of tolerance and dependence for BZDs are similar to those seen with alcohol, involving gamma-aminobutyric acid (GABA) and glutamate neurotransmitter systems. Additionally, managing withdrawal symptoms and reducing relapse rates may be identical for both substances. Acamprosate's ability to reduce alcohol cravings and relapse has led this study to explore its potential as a treatment for the extinction and reinstatement of alprazolam-induced CPP. Accordingly, we evaluated the effects of different doses of acamprosate on the extinction period and reinstatement of alprazolam-induced CPP in male rats. We also assessed hippocampal gene expression of GABA_A receptor (α1, α5, γ2) subunits and N-methyl-D-aspartate (NMDA) receptor (NR1, NR2A, NR2B) subunits after reinstatement, given alprazolam's action on these receptors. Alprazolam (1.5 mg/kg) could induce CPP in a 14-day paradigm. Acamprosate (20, 50, and 100 mg/kg) attenuated alprazolam-induced extinction period and reinstatement (P < 0.01). At the molecular level, acamprosate reduced the gene expression of α1 (P < 0.05) while increased α5 and γ2 subunits of GABA_A receptors (p < 0.01). Besides, the gene expression of NR1, NR2A, and NR2B subunits of NMDA receptors were significantly enhanced by acamprosate (P < 0.001). These findings suggest that acamprosate is able to reduce the duration of extinction and reinstatement of alprazolam-induced CPP in male rats.