Naringenin prevents ethanol-induced reward behavior in adolescent rats through inhibition of TRPM3-dependent inflammation in the pVTA.

Ethanol intake activates the posterior ventral tegmental area (pVTA), enhancing dopamine synthesis in the nucleus accumbens shell (AcbSh) and contributing to Alcohol Use Disorder (AUD). Chronic adolescent ethanol exposure promotes neuroinflammation and disrupts reward pathways, increasing susceptibility to addiction. Although transient receptor potential melastatin 3 (TRPM3) activation promotes inflammation and contributes to psychiatric disorders, its role in reward mechanisms remains unclear. Current AUD treatments reduce cravings and promote alcohol aversion but are often limited by adverse effects, highlighting the need for safer, natural alternatives. Naringenin, a citrus flavonoid, exhibits anti-inflammatory and neuroprotective properties. This study investigates the involvement of TRPM3 in reward processing and whether naringenin modulates its activity to reduce ethanol-induced neuroinflammation and craving. The effect of intraperitoneal (i.p.) naringenin (50 mg/kg) was tested by administering it daily prior to ethanol (2 g/kg, 20% w/v, i.p.) in adolescent male Sprague-Dawley rats for 2 weeks. Reward behavior was assessed using the conditioned place preference and open field tests. The pVTA was examined for TRPM3 expression, biochemical and synaptic changes, while dopamine levels in the AcbSh. Ethanol increases preference scores (0.46±0.01), locomotion (84.4±2.13), TRPM3 expression (48.77±2.58%) and co-expression with tyrosine hydroxylase (27.70±1.29%), TNF-α (298.29±10.48 pg/mg protein) and IL-6 (198.29±9.31 pg/mg protein), dendritic length in the pVTA (887.31±21.07 µm), and dopamine contents in the AcbSh (387,126.1±10,390.04 AUC). Naringenin reversed these effects, suggesting its potential anti-addictive properties and supporting TRPM3 as a promising therapeutic target for AUD.