1 We have examined the e ects of the systemic administration of the selective 5-HT 1A agonist alnespirone (S-20499) on in vivo 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus, the median raphe nucleus and four forebrain areas innervated di erentially by both (dorsal striatum, frontal cortex, ventral hippocampus and dorsal hippocampus). 2 Alnespirone (0.1 ± 3 mg kg 71 , s.c.) dose-dependently reduced extracellular 5-HT in the six areas examined. In forebrain, the maximal reductions occurred in striatum and frontal cortex (maximal reduction to 23 and 29% of baseline, respectively). Those in dorsal and ventral hippocampus were more moderate (to ca 65% of baseline). In contrast, the decrease in 5-HT elicited in the median raphe nucleus was more marked than that in the dorsal raphe nucleus (to ca 30 and 60% of baseline, respectively). The selective 5-HT 1A antagonist WAY-100635 (0.5 mg kg 71 , s.c.) prevented the decrease in 5-HT induced by alnespirone (0.3 mg kg 71 , s.c.) in frontal cortex. 3 8-OH-DPAT (0.025, 0.1 and 0.3 mg kg 71 , s.c.) also reduced extracellular 5-HT in a regionallyselective manner (e.g., to 32% of baseline in striatum and to 69% in dorsal hippocampus at 0.1 mg kg 71 , s.c.). In midbrain, 8-OH-DPAT reduced the dialysate 5-HT slightly more in the median than in the dorsal raphe nucleus at all doses examined. 4 Doses of both compounds close to their respective ED 50 values (0.3 mg kg 71 alnespirone, 0.025 mg kg 71 8-OH-DPAT) reduced 5-HT to a comparable extent in all regions examined. However, the reductions attained at higher doses were more pronounced for 8-OH-DPAT. 5 These data show that the reduction of 5-HT release elicited by alnespirone and 8-OH-DPAT is more important in forebrain areas innervated by 5-hydroxytryptaminergic neurones of the dorsal raphe nucleus. This regional selectivity seems unlikely to be accounted for by di erences in the sensitivity of 5-HT 1A autoreceptors controlling 5-HT release, given the dissimilar e ects of these two 5-HT 1A agonists in regions rich in cell bodies and nerve terminals. This suggests the presence of complex mechanisms of control of 5-HT release by 5-HT 1A receptors.

Serotonin; Hypothermia; Rat A dysregulation of brain serotoninergic (5-HT) transmission, particularly at 5-HT 1A receptors, is implicated in the pathophysiology of anxiety, depression, and impulsive states like violent aggression (i.e., Coplan et al. 1995;Maes and Meltzer 1995;Berman et al. 1997). CorFrom the Department of Animal Physiology (SFB, JMK), University of Groningen, The Netherlands; and the Institut de Recherches Internationales Servier (ML, EM), Courbevoie Cedex, France.Address correspondence to: Dr. Sietse F. de Boer, Department of Animal Physiology, University of Groningen, PO Box 14, 9750 AA Haren, The Netherlands.Received January 13, 1999; revised August 5, 1999; accepted January 4, 2000. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 1 Somatodendritic 5-HT 1A Autoreceptors and Aggression 21 respondingly, various 5-HT 1A receptor agonists exert potent anxiolytic, antidepressant, and anti-aggressive properties in experimental models (see for reviews, De Vry 1995;Broekkamp et al. 1995;Miczek et al. 1995;Olivier et al. 1995) and in man (Stahl 1994;Mann 1995;Ratey et al. 1991).Brain 5-HT 1A receptors are located postsynaptically, on various neurons in the limbic system and cortex, and presynaptically, as somatodendritic autoreceptors on the perikarya of serotoninergic neurons in the dorsal and median raphé (Palacios et al. 1987(Palacios et al. , 1990. Actions at both pre-and postsynaptic 5-HT 1A receptors appears to play a role in the therapeutic properties of 5-HT 1A receptor ligands, although their relative contribution remains to be clarified more precisely. To date, the anxiolytic-like effects of 5-HT 1A receptor agonists are generally ascribed to a selective stimulation of somatodendritic 5-HT 1A autoreceptors, thereby inhibiting the firing activity of 5-HT neurons consequently leading to a transient decrease in (anxiety-enhanced) 5-HT neurotransmission in limbic brain areas (Kidd et al. 1993;Schreiber and De Vry 1993;Millan et al. 1997). On the other hand, the rapid (i.e., immediately after drug administration) antidepressant-like effects of the same drugs mainly involve the acute stimulation of certain forebrain populations of postsynaptic 5-HT 1A receptors (Martin et al. 1990). Whereas a net increase in the tonic activation of these postsynaptic receptors is thought to underlie the therapeutic effects of several classes of antidepressants for long-term treatment Haddjeri et al. 1998).Concerning the potent anti-aggressive properties of 5-HT 1A receptor agonists, evidence on whether this occurs via a pre-or postsynaptic receptor mechanisms is conflicting. (e.g., McMillen et al. 1988;Sijbesma et al. 1991;Mos et al. 1993;Millan et al. 1997;De Almeida and Lucion 1997;Sanchez and Hyttel 1994). However, all these studies investigating the role of pre-and/or postsynaptic receptors in the anti-aggressive actions of 5-HT 1A receptor agonists have relied on 5-HT lesion/depletion or intracranial microinjection techniques, and it must be realized that both experimental approaches have limitati...

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