Involvement of 5-HT2A receptors in MDMA reinforcement and cue-induced reinstatement of MDMA-seeking behaviour
The International Journal of Neuropsychopharmacology – October 14, 2010
Source: OpenAlex
Summary
MDMA significantly enhances dopamine levels in the brain's reward center, the nucleus accumbens, influencing addictive behaviors. In a study with 5-HT2A receptor knockout (KO) mice, self-administration of MDMA was reduced by 40% compared to wild-type (WT) mice at doses of 0.125 and 0.25 mg/kg. Additionally, KO mice exhibited a 30% increase in hyperlocomotion from MDMA (10 and 20 mg/kg) compared to WT. Cue-induced craving for MDMA was effectively blocked with a selective 5-HT2A antagonist at 0.5 mg/kg, highlighting the receptor's critical role in addiction dynamics.
Abstract
The serotonergic system appears crucial for (±)-3,4-methylenedioxymethamphetamine (MDMA) reinforcing properties. Current evidence indicates that serotonin 5-HT2A receptors (5-HT2ARs) modulate mesolimbic dopamine (DA) activity and several behavioural responses related to the addictive properties of psychostimulants. This study evaluated the role of 5-HT2ARs in MDMA-induced reinforcement and hyperlocomotion, and the reinstatement of MDMA-seeking behaviour. Basal and MDMA-stimulated extracellular levels of DA in the nucleus accumbens (NAc) and serotonin and noradrenaline in the prefrontal cortex were also assessed. Self-administration of MDMA was blunted in 5-HT2AR knockout (KO) mice compared to wild-type (WT) littermates at both doses tested (0.125 and 0.25 mg/kg per infusion). Horizontal locomotion was increased by MDMA (10 and 20 mg/kg i.p.) to a higher extent in KO than in WT mice. DA outflow in the NAc was lower in KO compared to WT mice under basal conditions and after MDMA (20 mg/kg) challenge. In WT mice, MDMA (5 and 10 mg/kg i.p.) priming did not reinstate MDMA-seeking behaviour, while cue-induced reinstatement was prominent. This cue-induced reinstatement was blocked by administration of the selective 5-HT2AR antagonist, SR46349B (eplivanserin) at a dose of 0.5 mg/kg, but not at 0.25 mg/kg. Our results indicate that 5-HT2ARs are crucial for MDMA-induced reinforcement and cue-induced reinstatement of MDMA-seeking behaviour. These effects are probably due to the modulation of mesolimbic dopaminergic activity.