Atorvastatin facilitates extinction and prevents reinstatement of morphine-induced conditioned place preference in rats

Opioid addiction is known as a chronic relapsing disorder associated with long-lasting molecular and cellular neuroadaptations that lead to compulsive behavior. Current pharmacotherapies target the modulation of mu-opioid receptors (MOR); however, the relapse rate remains high. In this study, we evaluated the potential effect of atorvastatin, a blood-brain barrier-permeable statin, on preventing morphine relapse through both extinction-reinstatement and abstinence-reinstatement models using conditioned place preference (CPP). Adult male Wistar rats were used to establish morphine-induced CPP (5 mg/kg), followed by extinction training and subsequent priming injection of morphine (2 mg/kg, i.p.) to induce relapse-like behavior. Extinguished rats significantly reinstated their morphine-seeking behavior. In contrast, rats that received different doses of atorvastatin (0.1, 0.5, 1 mg/kg) 1 hour before each extinction training session did not show a preference for the morphine-paired chamber. Moreover, acute atorvastatin injection (1 mg/kg, i.p.) 1 h before the reinstatement test significantly prevented reinstated morphine-seeking behavior. We found that atorvastatin 1 mg/kg attenuated morphine-seeking behaviors, and this attenuation of reinstatement was partly mediated by the upregulation of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (Hipp). Furthermore, atorvastatin reversed Oprm1 upregulation (mu-opioid receptor gene) induced by relapse in the nucleus accumbens and Hipp. Moreover, treatment with atorvastatin during the extinction period alters the electrophysiological properties of the mPFC neurons following morphine priming and enhances neuronal excitability. We conclude that atorvastatin was effective in decreasing reinstatement.