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...
