PHARMACOLOGICAL CHARACTERISTICS OF 5-HYDROXYTRYPTAMINE AUTORECEPTORS IN RAT-BRAIN SLICES INCORPORATING THE DORSAL RAPHE OR THE SUPRACHIASMATIC NUCLEUS

1 Changes in extracellular concentrations of 5-hydroxytryptamine elicited by electrical stimulation in rat brain slices containing the dorsal raphe nucleus and the suprachiasmatic nucleus were monitored with fast cyclic voltammetry. 2 Using pseudo single pulse stimulation (5 pulses applied at 100 Hz) we have shown that the release of 5-hydroxytryptamine in the dorsal raphe and the suprachiasmatic nucleus can be regulated by autoreceptors in both brain regions. 3 In the suprachiasmatic nucleus, 5-carboxamidotryptamine, RU24969, 1-(m-trifluoromethylphenyl) piperazine and sumatriptan caused a concentration-dependent inhibition of stimulated 5-hydroxytryptamine overflow in the range 1 x 10(-9) M to 3 x 10(-6) M. The actions of 5-carboxamidotryptamine and RU24969 were reversed competitively by methiothepin (10(-8) M to 10(-6) M); Schild plots revealed pK(B) values of 7.9 and 8.1. By contrast, ipsaparone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) are not effective 5-hydroxytryptamine autoreceptor agonists in the suprachiasmatic nucleus. 4 Isamoltane (10(-6) M), the putative 5-HT1B receptor antagonist, blocked the responses to RU24969 (10(-6) M) and 1-(m-trifluoromethylphenyl)piperazine (10(-6) M) in the suprachiasmatic nucleus. 5 In the dorsal raphe nucleus, 8-OH-DPAT, ipsapirone, RU24969, 5-carboxamidotryptamine, and sumatriptan (all 1 x 10(-8) M to 3 x 10(-6) M) produced a concentration-dependent reduction in the stimulated release of 5-hydroxytryptamine. The maximum effect observed was less than that seen in the suprachiasmatic nucleus. 6 Methiothepin (1 x 10(-7) M) blocked the effect of 5-carboxyamidotryptamine (10(-8) M to 10(-6) M) in the dorsal raphe nucleus while propranolol (10(-6) M) and NAN-190 (10(-6) M) but not isamoltane (10(-6) M) were found to block significantly the effect of ipsapirone (10(-6) M). 7 We conclude, that drugs with 5-HT1A binding activity act as agonists in the dorsal raphe nucleus while drugs showing some activity for 5-HT1B and 5-HT1D binding sites, act as agonists in the suprachiasmatic nucleus. Our results confirm predictions from binding studies, that functional 5-HT autoreceptors regulating release of endogenous 5-HT have different drug specificity in the dorsal raphe and suprachiasmatic nucleus.