Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study

Abstract

Ras‐related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma‐1 receptors (σ‐1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ‐1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine‐seeking behavior in a rat model of self‐administration. The opipramol effect was shown in two phases. It decreased cocaine‐seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine‐primed reinstatement in 75% of the opipramol‐treated group (termed ‘responders’). All opipramol‐treated rats showed a decrease in σ‐1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non‐responder rats. Hence, Rac1 differentiated responders from non‐responders. Rac1 correlated positively with σ‐1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ‐1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.

Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder—An Animal Model and a Human Study

“…In our previous study using the same model, we demonstrated that there is no order effect in the reinstatement tests ( Bareli et al, 2021 ).…”

“…In addition, we found that those rats which responded to opipramol (Responders = Rs) exhibited significantly less Ras-related C3 botulinum toxin substrate 1 (Rac1) mRNA expression in the nucleus accumbens (NAc), compared with opipramol non-responder (NR) rats. Hence, we concluded that Rac1 differentiated Rs from NRs ( Bareli et al, 2021 ). A study by Tsai et al (2012) demonstrated that σ-1 receptor knock-down in the hippocampus is associated with a parallel downregulation of gamma-aminobutyric acid B receptor 1 (GABA B ,Gabbr1) and Rac1.…”

“…Opipramol was administered 15 min before entering the operant chamber and baclofen 30 min before entering it. The difference in administration time was due to differences in pharmacokinetic properties ( Di Ciano and Everitt, 2003 ; Bareli et al, 2021 ). An opipramol dose of 12.5 mg/kg was chosen since it was the optimal dose still having an impact but not affecting the locomotion behavior ( Bareli et al, 2021 ).…”

“…The difference in administration time was due to differences in pharmacokinetic properties ( Di Ciano and Everitt, 2003 ; Bareli et al, 2021 ). An opipramol dose of 12.5 mg/kg was chosen since it was the optimal dose still having an impact but not affecting the locomotion behavior ( Bareli et al, 2021 ). After preliminary experiments with two doses of baclofen (3.2 or 0.1 mg/kg) the lower dose of 0.1 mg/kg was chosen since it was shown to be without sedative side effects (data presented in the first part of Results).…”

“…This receptor is defined as a chaperone and can modulate the activity of several ion channels thus affecting neuronal excitability and synaptic activity ( Su et al, 2016 ; Yang et al, 2019 ) and may be involved in cocaine addiction ( Ferris et al, 1991 ; Katz et al, 2016 ). Recently, we showed significant reduction of cocaine-primed reinstatement in 75% of the opipramol-treated group as well as demonstrating the involvement of σ-1 receptor in a rat model of cocaine self-administration (SA) ( Bareli et al, 2021 ). In addition, we found that those rats which responded to opipramol (Responders = Rs) exhibited significantly less Ras-related C3 botulinum toxin substrate 1 (Rac1) mRNA expression in the nucleus accumbens (NAc), compared with opipramol non-responder (NR) rats.…”