P.2.a.011 In vivo electrophysiological characterisation of the acute effects of brexpiprazole administration on monoamine systems

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and overdose potential. One strategy to increase the utility of opioids is to balance the activity of known partial or full mu opioid agonists with a pharmacologically active mu opioid antagonist. It is hypothesized that such a combination would modulate the pharmacodynamic effects of the agonist molecule so as to minimize its potential for abuse and overdose while preserving therapeutic efficacy. Previously, it has been demonstrated that co-administration of buprenorphine with samidorphan dose-dependently attenuated buprenorphine-induced elevations of extracellular dopamine and its metabolites in the nucleus accumbens and medial prefrontal cortex in rats (Deaver, et al., ACNP 2013). Corticosterone-induced decreases in saccharin consumption and the forced swim test are models commonly used to study the antidepressant-like effects of drugs. In the first model, rats were induced into a depressive-like state with chronic exposure to corticosterone, as indicated by a decrease in saccharin consumption. In the forced swim test, Wistar-Kyoto rats were used because they are a spontaneously hypertensive strain that demonstrate endogenous hormonal and behavioral abnormalities often used in nonclinical models of behavioral despair. Antidepressant drugs reverse corticosterone-induced decreases in saccharin consumption and reduce immobility time in the forced swim test. Here, two doses of samidorphan (0.3mg/kg and 3.0mg/kg) were administered with a fixed dose of buprenorphine (0.1mg/kg) and data were analyzed using one-way analysis of variances. Buprenorphine, combined with 0.3mg/kg samidorphan, reversed corticosterone-induced decreases in saccharin consumption and decreased immobility in the forced swim test. However, when buprenorphine was combined with the higher dose of samidorphan (3.0mg/kg), the positive effects observed with the lower dose were reversed in both the saccharin consumption test and forced swim test. Thus, balanced modulation of opioid pharmacology may unlock the potential therapeutic value of known opioids by improving their safety. Together, the current data suggest that modulation of mu receptor activity plays an important role in the observed effects in these rat models of depression-like behavior.