Preferential modulatory action of 5-HT 2A receptors on the dynamic regulation of basal ganglia circuits.

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-HT 2A 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-HT 2A 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-HT 2A 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-HT 2A 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-HT 2A 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-HT 2A 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 5HT 2A 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-HT 2A receptor-mediated effects that require mobilisation of the endogenous 5-HT system. These findings provide evidence about the specific signature of 5-HT 2A receptors on the dynamic regulation of BG circuits.