Thalamic 5-HT2A receptor activation reduces GABA uptake, increases tonic GABAA inhibition and induces absence seizures in Wistar rats.
Vincenzo Crunelli, Tatiana P Morais, William M Connelly, Giulia Salamanca, Sandra H Vaz, Ana M. Sebastião, Cristiano Bombardi, Giuseppe Di Giovanni
Neuropharmacology June 11, 2026 DOI: 10.1016/j.neuropharm.2026.111073 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Wistar rats |
| Intervention | ethosuximide |
| Topics | Serotonin |
| Keywords | Absence epilepsy Nucleus reticularis thalami Selective serotonin ligands Tonic gabaa current Ventrobasal thalamus |
| Key findings | Activation of thalamic 5-HT2ARs enhances tonic GABAA currents and induces absence seizure-like activity in rats. |
Abstract
Renewed interest in psychedelic therapeutics has brought serotonin 5-HT2A receptors (5-HT2ARs) back into focus. Given the role of the thalamus in sensory integration and network synchronization, we examined the expression, developmental regulation, and functional impact of thalamic 5-HT2ARs, with particular emphasis on their interaction with extrasynaptic GABAA receptors and the generation of aberrant thalamocortical rhythms in Wistar rats. Immunofluorescence revealed a developmental increase of 5-HT2AR expression in both the reticular thalamic nucleus (NRT) and ventrobasal (VB) thalamus, that is accompanied by a shift in VB expression from GABAergic interneurons in juveniles to thalamocortical (TC) neurons in adults. Astrocyte density increased in both regions, more prominently in the NRT than in the VB, with approximately half of astrocytes expressing 5-HT2ARs regardless of age or region. Activation of 5-HT2ARs with the potent agonist TCB-2 reduced thalamic GABA uptake, an effect that was occluded in the presence of GAT1 inhibitor NO711. Patch-clamp recordings showed that TCB-2 enhanced tonic GABAA currents in VB TC neurons. This effect was absent in δ-subunit KO mice and was unaffected by blockade of postsynaptic G-protein signaling or phospholipase C pathways in TC neurons, suggesting that it is not dependent on postsynaptic signaling mechanisms. EEG recordings in freely moving rats showed that bilateral microinjection of TCB-2 into the VB induced spike-and-wave discharges accompanied by behavioral arrest that were blocked by ethosuximide, indicating that they were absence seizures. In summary, these findings support a mechanism, through which serotonergic signaling via 5-HT2ARs can shape thalamocortical network dynamics and increase susceptibility to aberrant rhythmic activity, which could potentially occur under conditions of altered serotonergic tone.
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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and 9 more in the library