Work

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

Year: 2024

Type: article

Abstract: 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. • Atorvastatin reduces the maintenance of morphine CPP and prevent reinstatement. • Acute atorvastatin before priming prevents morphine-primed relapse. • Atorvastatin induces region-dependent changes in BDNF expression. • Atorvastatin reverses the reduction in Oprm1 mRNA following morphine priming in PFC, Hipp and NAc. • The excitability of PFC neurons increases following atorvastatin treatment.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2024.117639

Authors: Shiva Hashemizadeh, Elham Alaee, Niloofar Aghajani, Hossein Azizi, Saeed Semnanian

Institutions: Tarbiat Modares University, Institute for Research in Fundamental Sciences

Language: English

Topic: Neurotransmitter Receptor Influence on Behavior

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,420