Quetiapine attenuates the acquisition of morphine-induced conditioned place preference and reduces ERK phosphorylation in the hippocampus and cerebral cortex.

Background: Quetiapine is an atypical antipsychotic that antagonizes dopamine and serotonin receptors. It has been suggested that quetiapine can be used to treat substance use disorders, including opioid use disorder. Opioids modulate dopaminergic functions associated with conditioned reinforcement and these effects can be measured via the conditioned place preference (CPP) paradigm. Opioids' unconditioned effects are regulated by several proteins, including extracellular signal-regulated kinase (ERK) and cAMP-responsive element-binding (CREB).Objective: To assess the effect of quetiapine on morphine-induced CPP and motor activity levels, and on the levels of ERK and CREB proteins in the hippocampus and cerebral cortex.Methods: 42 male rats were exposed to a CPP protocol, in which they underwent a conditioning paradigm with saline, quetiapine (40 mg/kg), morphine (10 mg/kg), morphine plus quetiapine (10, 20, or 40 mg/kg), or morphine plus memantine (7.5 mg/kg, a positive control drug) (n = 6 per group). The rats were tested for CPP and exploratory activity. Levels of ERK and CREB proteins in the hippocampus and cerebral cortex were also measured.Results: Quetiapine co-administered with morphine inhibited morphine-induced CPP [F (6, 70) = 11.67, p < .001] and morphine's effects on motor activity (p < .001). Morphine enhanced ERK phosphorylation in the hippocampus (p < .001) and cerebral cortex (p < .001), an effect inhibited by quetiapine.Conclusion: Quetiapine attenuates morphine-induced CPP and locomotion and these effects are associated with a reduction of ERK phosphorylation in the hippocampus and cerebral cortex. These results suggest that quetiapine should be further explored as a potential treatment for opioid use disorder.

Effect of Topiramate on Morphine-induced Conditioned Place Preference (CPP) in Rats: Role of ERK and CREB Proteins in Hippocampus and Cerebral Cortex.

In this study, the effect of topiramate, as an antiepileptic drug, was evaluated on morphine craving in rats. The conditioned place preference (CPP) test was used for this purpose. Repeated administration of morphine (10 mg/kg, i.p. for 4 days) induced significant CPP. Administration of topiramate (50 and 100 mg/kg, i.p. for 4 days) with each morphine administration decreased the acquisition of morphine-induced CPP. At the next step, the levels of extracellular signal-regulated kinase (ERK), p-ERK, cAMP responsive element binding (CREB), and p-CREB proteins were evaluated in hippocampus and cerebral cortex using western blot analysis. Following the repeated administration of morphine, the level of p-ERK protein markedly enhanced in both tissues, while topiramate could significantly reduce the phosphorylation of ERK in these brain regions. Additionally, the level of CREB and p-CREB proteins did not change in different groups. Memantine as a positive control reduced the acquisition of morphine-induced CPP. Also, memantine significantly decreased the level of p-ERK protein in hippocampus and cerebral cortex. These results demonstrated that topiramate can attenuate the acquisition of morphine-induced CPP in rats. This effect in part can be mediated through down regulation of p-ERK protein in hippocampus and cerebral cortex.