EXCITATION OF RAT SUBSTANTIA-NIGRA PARS RETICULATA NEURONS BY 5-HYDROXYTRYPTAMINE IN-VITRO - EVIDENCE FOR A DIRECT ACTION MEDIATED BY 5-HYDROXYTRYPTAMINE(2C) RECEPTORS

Single-unit extracellular and whole-cell patch clamp recording were us ed 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 ce lls (254/334) recorded extracellularly were excited by 5-hydroxytrypta mine (EC(50) = 9.56 mu M); in the remainder, inhibitions (13.5%), biph asic responses (4.2%) or lack of response (6.3%) were observed. Using whole-cell patch recording, 5-hydroxytryptamine (10 mu M) caused eithe r an inward current (9/9 cells) or a depolarization (3/3 cells) at mem brane potentials in the range -50 to -90 mV, which was resistant to te trodotoxin (4/4 cells), indicating that the predominant, excitatory ac tion of 5-hydroxytryptamine was due to a direct action on substantia n igra pars reticulata neurons. The 5-hydroxytryptamine excitation (reco rded extracellularly) was reduced to 24 +/- 6% of control values by me thysergide (0.1 mu M) and to 17 +/- 5% of control by ketanserin (1O mu M), but was unaffected by the 5-hydroxytryptamine antagonists spipero ne (0.1 mu M), yohimbine (O.l mu M), pindolol (1 mu M), GR113808A (1 m u M) or ICS 205930 (10 mu M). In addition, the 5-hydroxytryptamine exc itation was mimicked by the 5-hydroxytryptamine(2C) receptor-preferrin g agonist oc-methyl 5-hydroxytryptamine (10 mu M), but the agonists CP 93,129 (0.1-1 mu M) and(+/-)-2-dipropylamino-8-hydroxy-1 ,2,3,4-tetrah ydronaphthalene hydrobromide (0.1-1 mu M) were without effect. Taken t ogether, this pharmacology indicated involvement of the 5-hydroxytrypt amine(2C) receptor in the 5-hydroxytryptamine excitation, while other candidate receptors known to be present in rat substantia nigra pars r eticulata (5-hydroxytryptamine(1B), 5-hydroxytryptamine(2A) and 5-hydr oxytryptamine(4)) could be excluded from consideration. While in accor d with current information on the location of 5-hydroxytryptamine rece ptor subtypes in substantia nigra pars reticulata, and the consequence of activation of neuronal 5-hydroxytryptamine(2C) receptors, these re sults contrast with data from in vivo experiments which suggest that t he net effect of 5-hydroxytryptamine is to inhibit substantia nigra pa rs reticulata neurons. The reason for this apparent discrepancy may li e in detailed consideration of the microcircuitry of the substantia ni gra pars reticulata. This may lead to a re-evaluation of the influence of 5-hydroxytryptamine on this basal ganglia output relay nucleus, an d its role in motor control and the gating of generalized seizure acti vity.