Differential Actions of Serotonin, Mediated by 5-HT _1Band 5-HT _2C Receptors, on GABA-Mediated Synaptic Input to Rat Substantia Nigra Pars Reticulata Neurons In Vitro

Abstract

The ability of serotonin to modulate GABA-mediated synaptic input to substantia nigra pars reticulata (SNr) neurons was investigated with the use of whole-cell patch-clamp recording from slices of rat midbrain. Fast evoked GABA _A receptor-mediated synaptic currents (IPSCs) were attenuated reversibly ∼60% by serotonin, which also caused an inward current with reversal potential of −25 mV. This inward current was blocked by the 5-HT ₂ receptor antagonist ritanserin, whereas the IPSC depression was blocked by the 5-HT _1B receptor antagonist pindolol. The amplitude ratio of IPSC pairs (50 msec interpulse interval) was enhanced by serotonin (in ritanserin) and also by the GABA _B receptor agonist baclofen (which also depressed the IPSC), consistent with a presynaptic site of action in both cases. In contrast, spontaneous tetrodotoxin-sensitive GABA _A synaptic currents (sIPSCs) were increased in frequency by serotonin (an action that was sensitive to ritanserin, but not pindolol) but reduced in frequency by baclofen. SNr neurons therefore receive inhibitory synaptic input mediated by GABA _A receptors from at least two distinct sources. One, probably originating from the striatum, may be depressed via presynaptic 5-HT _1B and GABA _B receptors. The second is likely to arise from axon collaterals of SNr neurons themselves and is facilitated by an increase in firing via postsynaptic, somatodendritic 5-HT _2C receptor activation, but it is depressed by GABA _B receptor activation. Thus, serotonin can both depolarize and disinhibit SNr neurons via 5-HT _2C and 5-HT _1B receptors, respectively, but excitation may be limited by GABA released from axon collaterals.