Forced wheel running pre-conditioning diminishes reward learning induced by methamphetamine: Involvement of orexin 1 receptor in the hippocampus

Methamphetamine (METH) is a highly addictive drug that leads to neurobehavioral changes related to the brain's reward circuit. Orexin and orexinergic receptors, found in crucial brain areas involved in reward processing, may play a significant role in reward mechanisms and addiction. Studies have shown that physical exercise can be an effective non-pharmacological approach to controlling drug use but limited research explores its role as pre-conditioning to prevent dependency on narcotics. In this study, 48 male Wistar rats were assigned into six groups: exercise training+saline (EX-SA), exercise training+METH 1mg/kg (EX-METH1), exercise training + METH 2 mg/kg (EX-METH2), control+saline (CON), control+METH 1 mg/kg (CON-METH1), control+METH 2 mg/kg (CON-METH2). The pre-conditioning groups underwent forced wheel-running training (five days a week, at 65 % Vmax) for eight weeks. Following pre-conditioning with exercise training, the METH groups received intraperitoneal (IP) METH injections using the conditioned place preference (CPP) model. After the post-test, the animals were dissected, and hippocampal tissue was collected to measure orexin receptor1 (OXR1) expression levels. The results showed that long-term, moderate-intensity forced exercise pre-conditioning prevented METH-induced CPP. However, CPP was observed only in the EX-METH2 group, receiving a double dose of the drug. Molecular analysis also revealed a significant increase in OXR1 expression in the hippocampus following METH injections, while physical exercise caused suppression in OXR1 increment. Seemingly, prior exercise influences this pathway and effectively prevents conditioning to METH, probably through OXR1, indicating an adaptation in the mesolimbic reward pathway that helps protect against METH addiction.