Serotonin 1A Receptor Activation and Hypothermia in Humans Lack of Evidence for a Presynaptic Mediation

Abstract

The hypothermia produced by 5-HT 1A 1A receptors are located both on the cell body of 5-HT neurons and on postsynaptic neurons throughout the central nervous system. On 5-HT neurons, 5-HT 1A receptors mediate a negative feedback influence on firing activity. When overactivated by an excess amount of 5-HT, or by an exogenous agonist, they slow down the pacemaker activity leading to a decreased firing rate of 5-HT neurons (Aghajanian and Lakoski 1984;Blier and de Montigny 1987). As 5-HT release is proportional to firing rate, the excess activation of these 5-HT 1A autoreceptors generally results in a decrease of 5-HT release in projecting structures (see Rueter et al. Gainesville, FL 32610, Tel.: 352-392-3681, Fax : 352-392-2579, E-mail : blier@psych.med.ufl.edu Received May 11, 2001 revised January 16, 2002; accepted February 20, 2002. Online publication: 2/27/02 at www.acnp.org/citations/ Npp022702253. 302 P. Blier et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 2 1997). The postsynaptic 5-HT 1A receptors, particularly abundant in the limbic system, commonly exert an inhibitory function on neuronal activity as well. Therefore, the net effect of the systemic administration of a 5-HT 1A receptor agonist on 5-HT 1A signal transfer in postsynaptic areas represents a composite of decreased 5-HT release, resulting from 5-HT 1A autoreceptor activation, and direct occupation of the postsynaptic 5-HT 1A receptors.Although it is well established that neuroendocrine responses, such as growth hormone and adenocorticotropic hormone release, produced by systemic administration of 5-HT 1A agonists are mediated by postsynaptic 5-HT 1A receptors (Van de Kar et al. 1985;Gilbert et al. 1988;Pan and Gilbert 1992), there has been controversy with respect to the hypothermia resulting from this pharmacological challenge. The very first study examining the pre-versus postsynaptic mediation of the hypothermia clearly indicated that this response was produced by postsynaptic 5-HT 1A receptors (Hjörth 1985). Indeed, this initial study clearly showed that the hypothermic response to the prototypical 5-HT 1A agonist 8-OH-DPAT was not attenuated, but even enhanced in rats pretreated daily for 3 days with the 5-HT synthesis inhibitor parachlorophenylalanine (PCPA). Subsequently, identical results were obtained by another group of investigators using 2-day injections of a higher dose of PCPA (Goodwin et al. 1987). When their PCPA treatment was prolonged, however, for 14 days, despite producing its maximal effect on 5-HT levels after the first 3 days, the 8-OH-DPATinduced hypothermia was dampened and the conclusion of a presynaptic mediation of this phenomenon was made. From then on, several studies carried out in laboratory animals and humans used the 5-HT 1A -induced hypothermia to assess the responsiveness of the 5-HT 1A autoreceptor in different disease states and following administration of various types of psychotropic drugs. Although the majority of studies (Hutson et al. 1987;O'Connell et al. 1992;Hillegaart 1991;Mill...

Buspirone Raises Blood Pressure through Activation of Sympathetic Nervous System and by Direct Activation of α1-Adrenergic Receptors after Severe Hemorrhage

“…In subsequent work, we found that systemic 8-OH-DPAT rapidly reversed the sympatholytic response to hypotensive hemorrhage when administered after establishment of hypotensive hemorrhage (Scrogin, 2003). In addition, 5-HT1A receptor agonists reduce core body temperature and stimulate the release of endogenous adrenocorticotropin hormone, both of which have been found to have beneficial effects in suppressing reperfusion injury after resuscitation from hypovolemic shock (Guarini et al, 1990;Vicentic et al, 1998;Blier et al, 2002;Takasu et al, 2002). Together, these stud- jpet.aspetjournals.org ies suggest that lipophilic 5-HT1A receptor agonists have potential as adjuncts to volume resuscitation in the treatment of hypovolemic shock.…”

“…5-HT1A receptor agonists have additional effects that may provide an advantage over hypertonic saline use during volume resuscitation. For instance, systemically administered 5-HT1A receptor agonists can readily cross the blood-brain barrier and act on thermoregulatory centers to reduce body temperature (Blier et al, 2002). Recent work indicates that mild hypothermia reduces reperfusion injury after resuscitation from hypovolemic shock (Takasu et al, 2002;Takasu et al, 2003).…”

Central circuitries for body temperature regulation and fever

“…7D) or intravenous injection of leptin (92,107), as well as shivering evoked by cooling or PGE 2 injection into the POA (18,106). These sympathoinhibitory effects of 5-HT 1A receptor agonists through their action in the rMR might be a major pharmacological cause of severe hypothermia observed following systemic administration of such drugs in rats (52), mice (43), and humans (11). Activation of 5-HT 1A receptors is considered to inhibit neuronal functions through their negative coupling to adenylate cyclase via G i proteins (6), and these receptors are located in spinal projecting neurons in the medullary raphe region (50).…”

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

“…In rats (e.g., Millan et al 1993b;Bill et al 1991;Goodwin et al 1987) and humans (Blier et al 2002), 5-HT 1A receptor-induced hypothermia is thought to be mediated by postsynaptic 5-HT 1A receptors, while in mice, the somatodendritic 5-HT 1A receptors seem to be involved (Goodwin et al 1985;Martin et al 1992), although some controversies regarding the pre-and postsynaptic modulation of 5-HT 1A receptor-mediated hypothermia in rat exist (Higgins et al 1988;Hillegaart 1991). 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.…”