A Novel Role of Dexmedetomidine in the Modulation of Morphine Reward Memory via γ-Aminobutyric Acid Transporter-1.

backgroundOpioid use disorder (OUD) remains a major public health challenge with limited effective treatments. Opioid-induced reward memory, driven primarily by increased dopamine release in the nucleus accumbens (NAc), contributes to the development and relapse of OUD. Dexmedetomidine (Dex) has been reported to reduce dopamine release in the NAc, but its ability in OUD intervention remains unclear. This study aimed to determine whether Dex promotes extinction of morphine-induced reward memory.

methodsAdult male and female C57BL/6J mice were subjected to morphine-induced conditioned place preference (CPP) to evaluate reward memory. CPP scores were measured after systemic Dex administration or microinjection into the ventral tegmental area (VTA). Calcium imaging and whole cell patch clamp recordings were used to evaluate the excitability of dopaminergic and γ-aminobutyric acid-mediated (GABAergic) neurons in the VTA and D1-type medium spiny neurons (D1-MSNs) in the NAc. Extracellular γ-aminobutyric acid (GABA) and dopamine in the VTA and NAc were quantified using fiber photometry. Molecular docking and microscale thermophoresis were performed to validate the binding of Dex to GABA transporter-1 (GAT1).

resultsSystemic and intra-VTA Dex administration facilitated the extinction of morphine-induced CPP and suppressed increased dopamine release with resultant hyperactivity of D1-MSNs in the NAc. In the VTA, Dex attenuated hyperexcitability of dopaminergic neurons by increasing extracellular GABA without affecting GABAergic neuron activity or GABA synthesis. Molecular and functional assays demonstrated that Dex competitively inhibits GAT1, reducing GABA reuptake. Intra-VTA bicuculline-but not idazoxan-blocked Dex's proextinction effect, indicating a GABA receptor but not an α 2 -dependent mechanism.

conclusionsDex facilitates the extinction of morphine-associated reward memory by competitively inhibiting GAT1, enhancing VTA GABAergic inhibition, and rescuing NAc D1-MSN activity. These findings reveal a novel GAT1-dependent, α 2 -independent mechanism by which Dex modulates opioid reward circuitry, highlighting its potential as a therapeutic agent for OUD.