Setola, V. | bioRxiv Science

bioRxiv2026

No evidence for direct physical interaction of 5-HT2A-mGluR2 receptors in vitro or in vivo

Activation of mGluR2 (metabotropic glutamate receptor 2), the primary presynaptic autoreceptor for glutamate in the brain, is well established to attenuate the psychedelics-mediated behavioral and electrophysiological effects. However, the mechanisms responsible for these actions are controversial. The two competing mechanistic hypotheses have been proposed to explain this phenomenon are: (1) direct actions mediated by mGluR2/5-HT2A heterodimers, and (2) inhibition of 5-HT2A-mediated excitation of pyramidal neurons via presynaptic inhibition of glutamate release by mGluR2 receptors. Consistent with prior reports, we show that mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice engineered to express mGluR2-mCherry and 5-HT2A-eGFP-CT tagged receptors. We next employed multiple orthogonal in vivo and in vitro approaches to explore the potential for direct physical interactions between mGluR2 and 5-HT2A receptors. Across all approaches, we found no evidence for receptor colocalization or oligomerization under basal or 5-HT2A agonist-exposed conditions in vitro or in vivo. Radioligand binding and kinetic analyses revealed no evidence for mGluR2-mediated modulation of 5-HT2A ligand binding in vitro or in vivo. Collectively, our findings support models in which mGluR2 signaling modulates the activity of Gq-coupled 5-HT2A receptors in layer V pyramidal neurons, rather than models positing the requirement of mGluR2/5-HT2A multimers.

neuroscience↗

bioRxiv2024

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPePV) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPePV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNrGABA), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTADA) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPePV cells is the indirect pathway of the dorsomedial striatum (DMSD2), which receives DAergic innervation from collaterals of VTADA[->]NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMSD2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPePV cells, closing the loop. Interestingly, the level of GPePV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPePV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPePV cells following a single cocaine exposure, contributing to the elevation in GPePV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPePV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

neuroscience↗