The serotonin 2A receptor (5-HT2A) is a Gq/11-coupled receptor implicated in reward processing, neuropsychiatric disorders, and the actions of serotonergic psychedelics. Although 5-HT2A activation has been shown to engage endocannabinoid (eCB) signaling in several brain regions, its role in inhibitory synaptic plasticity within the nucleus accumbens (NAc) remains poorly understood. Here, we investigated whether 5-HT2A activation modulates GABAergic synaptic transmission onto medium spiny neurons (MSNs) in the mouse NAc core. Using whole-cell patch-clamp recordings, we found that activation of 5-HT2A receptors with the selective agonist TCB-2 induced a robust inhibitory long-term depression (iLTD) of evoked GABAergic synaptic transmission. This depression was accompanied by reduced spontaneous and miniature IPSC frequency, increased paired-pulse ratio, and changes in coefficient of variation analysis consistent with a presynaptic reduction in GABA release probability. Mechanistically, iLTD was occluded by the CB1 receptor agonist WIN55,212-2 and blocked by the CB1 receptor antagonist AM251, supporting a critical role for endocannabinoid signaling. Furthermore, iLTD induction required postsynaptic G-protein signaling, phospholipase Cβ (PLCβ) activity, and synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Together, these findings demonstrate that 5-HT2A activation induces a CB1-dependent presynaptic iLTD through a postsynaptic PLCβ/2-AG signaling cascade. These results demonstrate that 5-HT2A receptor activation engages endocannabinoid signaling to regulate inhibitory synaptic transmission in the NAc, highlighting a mechanism through which 5-HT2A signaling may modulate mesolimbic circuit function.
