M. El Mansari

Electrophysiological effects of the co-administration of escitalopram and bupropion on rat serotonin and norepinephrine neurons

Clinical studies indicate that addition of bupropion to selective serotonin (5-HT) reuptake inhibitors (SSRIs) provides incremental benefit over SSRI monotherapy in depression. This study was designed to investigate the effects of co-administration of bupropion with escitalopram on the firing rate of 5-HT and norepinephrine (NE) neurons in anesthetized rats. Escitalopram (10 mg/kg/day × 2 days), given via subcutaneously (s.c.) implanted minipumps, decreased the firing of 5-HT and NE neurons by 70% and 55%, respectively. The firing of 5-HT neurons, unlike that of NE neurons, recovered after the 14-day escitalopram regimen. Bupropion, injected once daily (30 mg/kg/day, s.c. × 2 days), did not increase 5-HT firing but decreased that of NE by 55%. After 14 days of repeated bupropion administration, 5-HT firing was increased by 50%, and NE firing was back to baseline. Co-administration of escitalopram and bupropion doubled 5-HT firing after 2 and 14 days, whereas NE neurons were inhibited by 60% after 2 days, but partially recovered after 14 days. The responsiveness of 5-HT1A autoreceptors was significantly attenuated in the combination-treated rats after 2 days, indicating an early desensitization. These results provide support for contributions from 5-HT and NE mechanisms for enhanced effectiveness of combination of SSRI and bupropion treatment.

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

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.

P.1.c.059 Electrophysiological properties of the triple reuptake inhibitor SEP 225289 on monoaminergic neurons

SEP 225289 reduced the firing rate of NE, DA and 5-HT neurons through the activation of 2, D2 and 5-HT1A autoreceptors, respectively. The predominant inhibitory effect of SEP 225289 was detected in the LC while it produces only a partial decrease in VTA DA and DRN 5-HT neuronal activities. The unexpected moderate inhibitory effect of SEP 225289 in the DRN is not due to a lesser degree of reuptake blockade of 5-HT than for NE because it is similarly effective in prolonging the recovery of firing of pyramidal neurons following 5-HT and NE applications. It is thus possible that noradrenergic and/or dopaminergic inputs innervating the DRN produce excitatory influence on 5-HT neurons thereby limiting the inhibitory effect of SEP 225289 in the DRN. The observation that SEP 225289 activates the firing of 5-HT neurons in the presence of the 5-HT1A receptor antagonist WAY 100635 is consistent with this hypothesis. Supported by funding from SEPRACOR Inc.