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1- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
Abstract:
Background: Opioid use disorder (OUD) is a chronic relapsing condition characterized by high rates of stress-induced relapse even after prolonged abstinence. Converging evidence implicates neuroimmune, glutamatergic transmitters and stress-related mechanisms in relapse vulnerability. Statins exert pleiotropic anti-inflammatory and neuroprotective effects and have recently emerged as potential modulators of relapse-related processes.
Methods: Adult male Wistar rats were trained to self-administer intravenous morphine (0.5 mg/kg/infusion) for 14 days under an FR1 schedule (fixed ratio). Following acquisition, animals underwent 14 days of extinction during which they received daily intraperitoneal injections of saline or atorvastatin (1 mg/kg). Stress-induced reinstatement was triggered by intermittent foot-shock exposure on day 29. Active lever responding served as the primary index of morphine-seeking behavior.
Results: Rats acquired stable morphine self-administration across the acquisition phase. During late extinction, atorvastatin-treated animals exhibited significantly reduced active lever responding compared with saline-treated controls (p = 0.0022). Intermittent foot-shock stress robustly reinstated morphine seeking in saline-treated rats, whereas reinstatement responding was significantly attenuated in the atorvastatin group (p = 0.0022). Quantification of relapse magnitude relative to extinction baseline revealed a significantly smaller increase in active responding in atorvastatin-treated rats (Δ analysis, p = 0.0022). Inactive lever responding remained low across conditions.
Conclusions: Chronic atorvastatin treatment reduced morphine-seeking behavior during extinction and attenuated stress-induced reinstatement in an operant self-administration model. These findings support the potential of statins as adjunctive agents targeting relapse-related neurobiological mechanisms in OUD.
Methods: Adult male Wistar rats were trained to self-administer intravenous morphine (0.5 mg/kg/infusion) for 14 days under an FR1 schedule (fixed ratio). Following acquisition, animals underwent 14 days of extinction during which they received daily intraperitoneal injections of saline or atorvastatin (1 mg/kg). Stress-induced reinstatement was triggered by intermittent foot-shock exposure on day 29. Active lever responding served as the primary index of morphine-seeking behavior.
Results: Rats acquired stable morphine self-administration across the acquisition phase. During late extinction, atorvastatin-treated animals exhibited significantly reduced active lever responding compared with saline-treated controls (p = 0.0022). Intermittent foot-shock stress robustly reinstated morphine seeking in saline-treated rats, whereas reinstatement responding was significantly attenuated in the atorvastatin group (p = 0.0022). Quantification of relapse magnitude relative to extinction baseline revealed a significantly smaller increase in active responding in atorvastatin-treated rats (Δ analysis, p = 0.0022). Inactive lever responding remained low across conditions.
Conclusions: Chronic atorvastatin treatment reduced morphine-seeking behavior during extinction and attenuated stress-induced reinstatement in an operant self-administration model. These findings support the potential of statins as adjunctive agents targeting relapse-related neurobiological mechanisms in OUD.
Type of Study: Original |
Subject:
Behavioral Neuroscience
Received: 2026/04/12 | Accepted: 2026/06/15
Received: 2026/04/12 | Accepted: 2026/06/15
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