THE EFFECT OF THE SELECTIVE 5-HT1A AGONISTS ALNESPIRONE (S-20499) AND8-OH-DPAT ON EXTRACELLULAR 5-HYDROXYTRYPTAMINE IN DIFFERENT REGIONS OF RAT-BRAIN

1 We have examined the effects of the systemic administration of the s elective 5-HT1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryp tamine (5-HT) release in the dorsal raphe nucleus, the median raphe nu cleus and four forebrain areas innervated differentially by both (dors al striatum, frontal cortex, ventral hippocampus and dorsal hippocampu s). 2 Alnespirone (0.1-3 mg kg(-1), s.c.) dose-dependently reduced ext racellular 5-HT in the six areas examined. In forebrain, the maximal r eductions occurred in striatum and frontal cortex (maximal reduction t o 23 and 29% of baseline, respectively). Those in dorsal and ventral h ippocampus were more moderate (to ca 65% of baseline). In contrast, th e decrease in 5-HT elicited in the median raphe nucleus was more marke d than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT1A antagonist WAY-100635 (0.5 mg kg( -1), s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg(-1), s.c.) in frontal cortex. 3 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg(-1), s.c.) also reduced extracellular 5-HT in a regionally-selecti ve manner (e.g., to 32% of baseline in striatum and to 69% in dorsal h ippocampus at 0.1 mg kg(-1) s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nu cleus at all doses examined. 4 Doses of both compounds close to their respective ED50 values (0.3 mg kg(-1) alnespirone, 0.025 mg kg(-1) 8-O H-DPAT) reduced 5-HT to a comparable extent in all regions examined. H owever, the reductions attained at higher doses were more pronounced f or 8-OH-DPAT. 5 These data show that the reduction of 5-HT release eli cited by alnespirone and 8-OH-DPAT is more important in forebrain area s innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe n ucleus. This regional selectivity seems unlikely to be accounted for b y differences in the sensitivity of 5H-T-1A autoreceptors controlling 5-HT release, given the dissimilar effects of these two 5-HT1A agonist s in regions rich in cell bodies and nerve terminals. This suggests th e presence of complex mechanisms of control of 5-HT release by 5-HT1A receptors.