Effects of oxycodone on tonic levels and phasic release of serotonin in the rat nucleus accumbens core

Despite widespread oxycodone misuse, the role of serotonin in opioid addiction remains understudied compared to dopamine. This study investigated the acute effects of oxycodone (2.5 mg/kg, i.v.) on serotonergic neurotransmission in the rat nucleus accumbens core using high-resolution electrochemical methods. We employed fast-scan cyclic voltammetry (FSCV) to monitor medial forebrain bundle stimulation-evoked phasic release and N-shaped multiple cyclic square wave voltammetry (N-MCSWV) to measure tonic concentrations in urethane-anesthetized rats. Results demonstrated a distinct dissociation between tonic and phasic dynamics. Tonic serotonin levels increased significantly (+23.4 nM) from baseline 1-h post-administration. Conversely, stimulation-evoked phasic release initially increased (+24%) but subsequently declined below baseline. Kinetic analysis revealed that serotonin production and maximum reuptake rates followed a similar pattern of initial increase followed by a decrease. In conclusion, oxycodone acutely modulates serotonergic signaling in the nucleus accumbens core by differentially affecting phasic and tonic neurotransmission. These findings demonstrate oxycodone induces temporal dynamics in phasic versus tonic serotonergic signaling in the nucleus accumbens core, highlighting the value of multimodal electrochemical approaches for dissecting opioid neurochemical effects.