Further evidence for negative feedback control of serotonin release in the central nervous system

Summary

In the presence of the serotonin (5-HT) uptake inhibitor citalopram (2×10⁻⁵ M), 5-HT, added to the superfusion medium, diminished the electrically induced ³H-overflow from rat cortex slices prelabelled with ³H-5-HT. A 50% decrease of the ³H-overflow was obtained with 6×10⁻⁷ M 5-HT. Of the 5-HT antagonists tested (methysergide, methergoline, methiothepin, cyproheptadine, cinanserin, mianserin, pizotifen), methiothepin (50% at 4.5×10⁻⁷ M), methergoline (31% at 10⁻⁶ M) and cinanserin (30% at 10⁻⁶ M) increased the stimulation-induced ³H-overflow. In some experiments the overflow of endogenous 5-HT was measured simultancously with ³H-overflow. The results were qualitatively and quantitatively very similar, indicating that ³H-overflow can be taken as a reliable measure of 5-HT release. The existence of a functional negative feedback control of 5-HT release mediated by presynaptic autoreceptors was confirmed by analysis of the ³H-overflow per pulse at stimulation frequencies between 0.1 and 50 pulses per second (pps). The ³H-overflow per pulse decreased with increasing stimulus frequency, reaching a low level at 1.6 pps corresponding to 30% of the initial value at 0.1 pps. Methiothepin did not increase the stimulation-induced ³H-overflow at 0.1 pps. The stimulation-induced ⁵H-overflow at 0.1 pps in the absence of methiothepin was equivalent to that at 1.6 pps in the presence of methiothepin. These results suggest that, under the given experimental conditions, at a stimulation frequency of 0.1 pps the 5-HT concentration in the synaptic cleft drops to very low levels, barely sufficient to induce negative feedback. Among a variety of drugs tested, LSD, dimethyltryptamine, m-chlorophenylpiperazine and clonidine decreased the stimulation-induced ³H-overflow, whereas salbutamol, propranolol, oxprenolol, spiroperidol and haloperidol had no effect. Quipazine, known as a 5-HT agonist, unexpectedly augmented the stimulation-induced ³H-overflow. This effect might be attributable partly to its 5-HT uptake inhibiting component, and also to blockade of presynaptic 5-HT receptors.