Serotonin activates presynaptic and postsynaptic receptors in rat globus pallidus

Although recent histological, behavioral, and clinical studies suggest that serotonin (5-HT) plays significant roles in the control of pallidal activity, only little is known about the physiological action of 5-HT in the pallidum. Our recent unit recording study in monkeys suggested that 5-HT provides both presynaptic and postsynaptic modulations of pallidal neurons. The present study using rat brain slice preparations further explored these presynaptic and postsynaptic actions of 5-HT. Bath application of 5-HT or the 5-HT(1A/1B/1D/5/7) receptor (R) agonist 5-carboxamidotryptamine maleate (5-CT) depolarized some and hyperpolarized other pallidal neurons. Pretreatments of slices with blockers of the hyperpolarization-cyclic nucleotide-activated current or with the 5-HT(2/7)R-selective antagonist mesulergine occluded 5-CT-induced depolarization. The 5-HT(1A)R-selective blocker N-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohex-anecarboxamide maleate occluded the 5-CT-induced hyperpolarization. These results suggested involvement of 5-HT(7)R and 5-HT(1A)R in the postsynaptic depolarization and hyperpolarization, respectively. 5-CT presynaptically suppressed both internal capsule stimulation-induced excitatory postsynaptic currents (EPSCs) and striatal stimulation-induced inhibitory postsynaptic currents (IPSCs). The potencies of 5-CT on the presynaptic effects were 20- to 25-fold higher than on postsynaptic effects, suggesting that 5-HT mainly modulates presynaptic sites in the globus pallidus. Experiments with several antagonists suggested involvement of 5-HT(1B/D)R in the presynaptic suppression of EPSCs. However, the receptor type involved in the presynaptic suppression of IPSCs was inconclusive. The present results provided evidence that 5-HT exerts significant control over the synaptic inputs and the autonomous activity of pallidal neurons.