Pharmacological characteristics of 5-hydroxytryptamine autoreceptors in rat brain slices incorporating the dorsal raphe or the suprachiasmatic nucleus.

Abstract

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 pKB 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 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-HTIA binding activity act as agonists in the dorsal raphe nucleus while drugs showing some activity for 5-HTIB and 5-HTID 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.