5-HT2A receptor activation induces CB1-dependent presynaptic inhibitory long-term depression in the nucleus accumbens core.
Camila Estay-Olmos, Koyam Morales-Weil, Juan Ahumada, Ramon Sotomayor-Zárate, Marco Fuenzalida
Frontiers in Pharmacology 2026 DOI: 10.3389/fphar.2026.1916522 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic science study (ex vivo electrophysiology in mouse brain slices) Peer reviewed |
|---|---|
| Population | Medium spiny neurons in the nucleus accumbens core of mice |
| Interventions | TCB-2 WIN55 212-2 AM251 |
| Measures | whole-cell patch-clamp recordings, evoked IPSCs, spontaneous IPSCs, miniature IPSCs, paired-pulse ratio, coefficient of variation analysis |
| Topics | Serotonin Depression |
| Keywords | Cb1 receptor Gabaa receptor Iltd Nucleus accumbens |
| Key points | Activation of 5-HT2A receptors by TCB-2 induced a robust inhibitory long-term depression of evoked GABAergic transmission onto mouse nucleus accumbens medium spiny neurons, with evidence of reduced presynaptic GABA release probability. The effect was occluded by the CB1 agonist WIN55,212-2 and blocked by the CB1 antagonist AM251, and required postsynaptic G-protein signaling, phospholipase Cβ, and 2-AG synthesis, indicating a CB1-dependent presynaptic iLTD driven by a postsynaptic PLCβ/2-AG cascade. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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- Ketamine administration during adolescence impairs synaptic integration and inhibitory synaptic transmission in the adult dentate gyrus. Progress in Neurobiology March 1, 2025
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and 2 more in the library