During cannabinoid withdrawal, the mesolimbic reward system shows reduced function, which may drive aversive states leading to relapse. The lateral habenula (LHb) exerts negative control over the ventral tegmental area (VTA) via the rostromedial tegmental nucleus (RMTg), suggesting a convergence point for opponent processes. In adult male rats treated with THC (15 mg/kg, i.p.) twice daily for 6.5–7 days, rimonabant-precipitated withdrawal reduced VTA dopamine neuron firing and burst activity, prolonged RMTg-evoked inhibition, and depressed spontaneous activity in both RMTg and LHb neurons. The authors propose that functional changes in the habenulo–mesencephalic circuit contribute to substance use disorders.
Methoxetamine (MXE), a novel ketamine-like drug increasingly linked to emergency cases, was tested in male rats trained to self-administer ketamine. Low doses of MXE (0.125 and 0.25 mg/kg) substituted for ketamine self-administration, while the highest dose (0.5 mg/kg) did not. MXE dose-dependently increased the firing rate and burst firing of dopamine neurons in the ventral tegmental area projecting to the nucleus accumbens shell. It also raised dopamine levels in that brain region, with a 0.5 mg/kg dose having a faster onset (40 minutes) than 0.25 mg/kg (100 minutes). These findings indicate MXE has reinforcing and addiction-related properties.