Excitation of rat substantia nigra pars reticulata neurons by 5-hydroxytryptaminein vitro: Evidence for a direct action mediated by 5-hydroxytryptamine2C receptors

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Single-unit extracellular and whole-cell patch clamp recording were used to study the actions of exogenously applied 5-hydroxytryptamine on substantia nigra pars reticulata neurons in parasaggital slices of rat midbrain. Seventy-six per cent of substantia nigra pars reticulata cells (254/334) recorded extracellularly were excited by 5-hydroxytryptamine (EC50 = 9.56 microM); in the remainder, inhibitions (13.5%), biphasic responses (4.2%) or lack of response (6.3%) were observed. Using whole-cell patch recording, 5-hydroxytryptamine (10 microM) caused either an inward current (9/9 cells) or a depolarization (3/3 cells) at membrane potentials in the range -50 to -90 mV, which was resistant to tetrodotoxin (4/4 cells), indicating that the predominant, excitatory action of 5-hydroxytryptamine was due to a direct action on substantia nigra pars reticulata neurons. The 5-hydroxytryptamine excitation (recorded extracellularly) was reduced to 24 +/- 6% of control values by methysergide (0.1 microM) and to 17 +/- 5% of control by ketanserin (10 microM), but was unaffected by the 5-hydroxytryptamine antagonists spiperone (0.1 microM), yohimbine (0.1 microM), pindolol (1 microM), GR113808A (1 microM) or ICS 205930 (10 microM). In addition, the 5-hydroxytryptamine excitation was mimicked by the 5-hydroxytryptamine2C receptor--preferring agonist alpha-methyl 5-hydroxytryptamine (10 microM), but the agonists CP93, 129 (0.1-1 microM) and (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (0.1-1 microM) were without effect. Taken together, this pharmacology indicated involvement of the 5-hydroxytryptamine2C receptor in the 5-hydroxytryptamine excitation, while other candidate receptors known to be present in rat substantia nigra pars reticulata (5-hydroxytryptamine1B, 5-hydroxytryptamine2A and 5-hydroxytryptamine4) could be excluded from consideration. While in accord with current information on the location of 5-hydroxytryptamine receptor subtypes in substantia nigra pars reticulata, and the consequence of activation of neuronal 5-hydroxytryptamine2C receptors, these results contrast with data from in vivo experiments which suggest that the net effect of 5-hydroxytryptamine is to inhibit substantia nigra pars reticulata neurons. The reason for this apparent discrepancy may lie in detailed consideration of the microcircuitry of the substantia nigra pars reticulata. This may lead to a re-evaluation of the influence of 5-hydroxytryptamine on this basal ganglia output relay nucleus, and its role in motor control and the gating of generalized seizure activity.