Serotonin‐mediated inhibitory postsynaptic potential in guinea‐pig prepositus hypoglossi and feedback inhibition by serotonin.

1. Intracellular recordings were made from neurones of the nucleus prepositus hypoglossi (PH) in slices of guinea‐pig brain. Focal stimulation evoked an inhibitory postsynaptic potential (IPSP) that was typically 10‐25 mV in amplitude and 1 s in duration. The IPSP reversal potential showed a Nernstian dependence on the external potassium concentration ([K+]o). 2. Spiperone blocked the IPSP with an IC50 of 40 nM, while ketanserin and (‐)sulpiride had no effect. Cocaine (1 microM) prolonged the IPSP half‐duration by 157%, and increased the amplitude by 28%. 3. 5‐Hydroxytryptamine (5‐HT, serotonin) hyperpolarized PH cells with an EC50 of 8.5 microM in control, and 135 nM in cocaine (10 microM). 8‐Hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT) also hyperpolarized PH cells with an EC50 of 16 nM, although the maximal effect was only 81% of the maximum 5‐HT hyperpolarization. Spiperone produced a parallel, right shift of the 5‐HT concentration‐response curve; Schild analysis gave a Kd of 10 nM. Application of 5‐HT to neurones voltage‐clamped near their resting potential (about ‐55 mV) caused an outward current and an increase in membrane conductance. 4. The amplitude of the IPSP was reversibly decreased by non‐hyperpolarizing concentrations of 5‐HT and by the 5‐HT1 receptor agonists 1‐(m‐trifluoromethylphenyl)piperazine (TFMPP) and 1‐(3‐chlorophenyl)piperazine (mCPP). The IC50 values for the latter two compounds were 50 nM and 1.5 microM, respectively; the maximal effect was a 90% inhibition. Neither compound affected the membrane potential nor changed the hyperpolarization induced by 5‐HT. Quipizine competitively antagonized TFMPP with an estimated Kd of 165 nM. 5. When trains of stimuli were applied, an inhibition of the IPSP was observed following the first stimulus. At a frequency of 1 Hz, the inhibition was approximately 75%. This frequency‐dependent ‘run‐down’ of the IPSP was markedly attenuated by pre‐treatment with TFMPP (1 microM). 6. It is concluded that the IPSP in PH cells is caused by 5‐HT acting on 5‐HT1A receptors to activate a potassium conductance. The release of 5‐HT can be inhibited by activation of a presynaptic 5‐HT1D receptor. This presynaptic receptor appears to be at least partly responsible for the run‐down phenomenon, and may be involved in the physiological regulation of 5‐HT synaptic transmission.