5-HT2A receptor activation induces CB₁-dependent presynaptic inhibitory long-term depression in the nucleus accumbens core.
5 affiliations
- 1Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- 2Departamento de Ciencias Biomédicas, Facultad de Ciencias de la Vida, Universidad Viña del Mar, Viña del Mar, Chile.
- 3Millennium Nucleus of Neuroepigenetics and Plasticity (EpiNeuro), Universidad de Valparaiso, Santiago, Chile.
- 4Centro Interdisciplinario de Neurociencia de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
- 5Facultad de Ciencias, Instituto de Fisiología, Universidad de Valparaíso, Valparaíso, Chile.
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.
Related
- Presynaptic CAST Deficiency Disrupts Neural Regulation and Promotes Restlessness and Depression-Like Behaviors
- LIF and let die: Generation, mechanistical and structural characterization of bispecific antibodies triggering leukemia inhibitory factor (LIF) receptor activation independent of the cytokine LIF
- NK Cell Activation as an Immune Mechanism in Depression: Insights from Single-Cell Multi-Omics
- Distinct Patterns of Reward-Related Neural Activation and Dopamine Neurophysiology in Adolescent Depression with and without Mixed Manic Features
- Periodontal pathogen Tannerella forsythia promotes liver fibrosis via ICAM-1⁺ neutrophil–dependent hepatic stellate cell activation
BibTeX
@article{estayolmos20265ht2a,
title = {{5-HT2A receptor activation induces CB₁-dependent presynaptic inhibitory long-term depression in the nucleus accumbens core.}},
author = {Camila Estay-Olmos and Koyam Morales-Weil and Juan Ahumada and Ramón Sotomayor-Zárate and Marco Fuenzalida},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1916522},
url = {https://europepmc.org/article/MED/42908661},
note = {CC BY},
}
RIS
TY - JOUR
TI - 5-HT2A receptor activation induces CB₁-dependent presynaptic inhibitory long-term depression in the nucleus accumbens core.
AU - Camila Estay-Olmos
AU - Koyam Morales-Weil
AU - Juan Ahumada
AU - Ramón Sotomayor-Zárate
AU - Marco Fuenzalida
PY - 2026
DA - 2026/10/07
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1916522
UR - https://europepmc.org/article/MED/42908661
AB - 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.
SN - 1663-9812
ER -