Somatodendritic 5-HT1A Autoreceptors Mediate the Anti-Aggressive Actions of 5-HT1A Receptor Agonists in Rats An Ethopharmacological Study with S-15535, Alnespirone, and WAY-100635

Abstract

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...

Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats

“…Both S-15535 and 8-OHDPAT were found to enhance cocaine's psychomotor effects in SERT +/+ and SERT −/− rats. While the effects of 0.25 mg/kg 8-OHDPAT are most likely to be mediated by postsynaptic receptors, as reported by others (Müller et al 2007), the effects of S-15535 may be more difficult to interpret because of its pharmacological profile (Millan et al 1993a;Newman-Tancredi et al 1999;de Boer et al 2000). In contrast to 8-OHDPAT, S-15535 by itself had no effect on activity, which suggests at least that S-15535 did not act as postsynaptic 5-HT 1A receptor agonist.…”

“…However, combined with our observation that 8-OHDPAT-induced activity and 5-HT syndrome, which are postsynaptically mediated (Yamada et al 1988), were reduced in SERT −/− rats relative to SERT +/+ rats in the locomotor tests, the 8-OHDPATinduced hypothermia findings imply that predominantly postsynaptic 5-HT 1A receptors are involved. This view is further supported by the lack of a hypothermic effect of S-15535 (Millan et al 1993a;de Boer et al 2000). Previous studies have convincingly demonstrated that this compound is a full somatodendritic 5-HT 1A receptor agonist and has only weak partial agonistic or even antagonistic properties at postsynaptic 5-HT 1A receptor (Millan et al 1993a;Newman-Tancredi et al 1999;de Boer et al 2000).…”

“…This view is further supported by the lack of a hypothermic effect of S-15535 (Millan et al 1993a;de Boer et al 2000). Previous studies have convincingly demonstrated that this compound is a full somatodendritic 5-HT 1A receptor agonist and has only weak partial agonistic or even antagonistic properties at postsynaptic 5-HT 1A receptor (Millan et al 1993a;Newman-Tancredi et al 1999;de Boer et al 2000).…”

Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

“…Both agonists reduce aggression in different experimental procedures but cause impairment of motor activity or stimulation (7,9,12). However, several recently developed 5-HT 1A receptor agonists like alnespirone and S-15535 have more specific anti-aggressive effects in male rats (16). The 5-HT 1B receptor agonists, such as CP-94,253, anpirtoline and zolmitriptan, have shown anti-aggressive effects in male mice when administered systemically (17).…”

The Effect of male-male competition and its Underlying Regulatory Mechanisms on the Electric Signal of the Gymnotiform fish <em>Brachyhypopomus gauderio</em>

“…Therefore, it is possible for B. gauderio 5HT 1A R's transcription to be regulated by GCs. Thus GCs could exert negative feedback on 5HT 1A R expression by downregulating transcription, thereby suppressing aggression through action at 5HT 1A autoreceptors (de Boer et al, 2000), and reducing electric signal magnitude through action at 5HT 1A post-synaptic receptors . I currently do not know whether 5HT 1A R is found as an autoreceptor and postsynaptic receptor in the hypothalamus of B. gauderio.…”