RT Journal Article SR Electronic T1 Preferential modulatory action of 5-HT2A receptors on the dynamic regulation of basal ganglia circuits JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP JN-RM-1181-22 DO 10.1523/JNEUROSCI.1181-22.2022 A1 Guilhemsang, Lise A1 Gutierrez-Ceballos, Amaia A1 Antonazzo, Mario A1 Mallet, Nicolas A1 Ugedo, Luisa A1 Morera-Herreras, Teresa YR 2022 UL http://www.jneurosci.org/content/early/2022/11/09/JNEUROSCI.1181-22.2022.abstract AB In rodents, cortical information is transferred to the substantia nigra pars reticulata (SNr) through motor and medial prefrontal (mPF) basal ganglia (BG) circuits implicated in motor and cognitive/motivational behaviours, respectively. The serotonergic 5-HT2A receptors are located in both of these neuronal networks, displaying topographical differences with a high expression in the associative/limbic territories, and a very low expression in the subthalamic nucleus (STN).This study investigated if the stimulation of 5-HT2A receptors could have a specific signature on the dynamic regulation of BG circuits, preferentially modulating the mPF information processing through trans-striatal pathways. We performed in vivo single-unit extracellular recordings to assess the effect of the 5-HT2A agonist TCB-2 on the spontaneous and cortically evoked activity of lateral and medial SNr neurons in male rats (involved in motor and mPF circuits, respectively).TCB-2 (50-200 μg/kg, i.v.) increased the basal firing rate and enhanced the cortically evoked inhibitory response of medial SNr neurons (transmission through the direct striato-nigral pathway). A prior administration of the preferential 5-HT2A receptor antagonist MDL11939 (200 μg/kg, i.v.) did not modify any electrophysiological parameter, but occluded TCB-2-induced effects. In animals treated with the 5-HT synthesis inhibitor pCPA, TCB-2 failed to induce abovementioned effects, thus suggesting the contribution of endogenous 5-HT. However, the mobilisation of 5-HT induced by the acute administration of fluoxetine (10 mg/kg, i.p.), did not mimic the effects triggered by TCB-2. Overall, these data suggest that 5-HT2A receptors have a preferential modulatory action on the dynamic regulation of BG circuitry.SIGNIFICANT STATEMENT:Motor and medial prefrontal (mPF) basal ganglia (BG) circuits play an important role in integrative brain functions like movement control or cognitive/motivational behaviour, respectively. Although these neuronal networks express 5-HT2A receptors, the expression is higher in associative/limbic structures than in the motor ones. We show a topographical-dependent dissociation in the effects triggered by the 5HT2A agonist TCB-2, which specifically increases the medial substantia nigra pars reticulata (SNr) neuron activity and has a preferential action on mPF information processing through the striato-nigral direct pathway. These are very likely to be 5-HT2A receptor-mediated effects that require mobilisation of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT2A receptors on the dynamic regulation of BG circuits.