Differential Actions of Serotonin, Mediated by 5-HT_1Band 5-HT_2CReceptors, on GABA-Mediated Synaptic Input to Rat Substantia Nigra Pars Reticulata NeuronsIn 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 approximately 60% by serotonin, which also caused an inward current with reversal potential of -25 mV. This inward current was blocked by the 5-HT2 receptor antagonist ritanserin, whereas the IPSC depression was blocked by the 5-HT1B 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-HT1B 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-HT2C receptor activation, but it is depressed by GABA(B) receptor activation. Thus, serotonin can both depolarize and disinhibit SNr neurons via 5-HT2C and 5-HT1B receptors, respectively, but excitation may be limited by GABA released from axon collaterals.

Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration

“…This action is likely indirect since stimulation of 5-HT 2C receptors induces membrane depolarization and neuronal excitation (Di Giovanni et al, 2001;Sheldon and Aghajanian, 1991;Stanford and Lacey, 1996). Examination of the patterns of expression of 5-HT 2C receptor mRNA indicates that 5-HT 2C receptors are localized to GABA-ergic, and not dopaminergic neurons, in the VTA (Eberle Wang et al, 1997).…”

Effects of the 5-HT2C/2B Antagonist SB 206553 on Hyperactivity Induced by Cocaine

“…For example, systemic and microiontophoretic administration of the 5-HT 2C/1B agonist meta-chlorophenylpiperazine (mCPP) decreased the firing rate of VTA DA neurons; the systemic actions of mCPP were antagonized by the 5-HT 2/1A antagonist mesulergine, which alone increased firing rates of a subpopulation of these cells (Prisco et al 1994;Prisco and Esposito 1995). Although 5-HT 2C/2B/1B ligands failed to alter the firing characteristics of DA neurons in the substantia nigra (Kelland et al 1990; but see Stanford and Lacey 1996), the activity of VTA DA neurons is reported to increase following administration of the 5-HT 2C/2B antagonists SB 200646A (Ashby and Minabe 1996) or SB 206553 (Lejeune et al 1997). These results suggest that 5-HT 2C/2B receptors may tonically inhibit cell firing of DA neurons in the VTA.…”

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

“…The agonists that mimicked that effect were only of the 5-HT 1B class (CP 93129 and TFMPP). Neither the 5-HT 2 antagonist ritanserin nor the GABA A antagonist bicuculline were able to block that inhibition, suggesting that, in addition to an indirect action (Stanford and Lacey, 1996), some SNr neurons may be directly inhibited by 5-HT.…”

“…The inhibition of SNr neurons by 5-HT is supported by the finding that unilateral injection of 5-HT, 5-HT 1D agonist and selective serotonin reuptake inhibitors (SSRIs) into the SNr of freely moving rats elicited a contraversive circling behaviour (James and Starr, 1980;Blackburn et al, 1981;Oberlander et al, 1981;Higgins et al, 1991;Bata-Garcia et al, 2002) as muscimol does (Oberlander et al, 1981). In spite of this evidence, Lacey and co-workers have shown, by using in vitro electrophysiological methods, that 5-HT not only directly excites SNr neurons but also disinhibits them by reducing GABA release from striatonigral terminals, acting on presynaptic 5-HT 1B receptors (Rick et al, 1995;Stanford and Lacey, 1996). On the other hand, a subsequent electrophysiological in vitro study demonstrated also a direct inhibitory action of 5-HT on SNr neurons (Gongora-Alfaro et al, 1997).…”