Characterization of 8‐OH‐DPAT‐induced hypothermia in mice as a 5‐HT_1A autoreceptor response and its evaluation as a model to selectively identify antidepressants

Abstract

1 8-Hydroxy-2-(di-n-propylamino)tetralin dose-dependently induced hypothermia in mice.2 The 5-HTIA receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 6 Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-', s.c.), (± )-pindolol (10mg kg-', i.p.) and ketanserin (0.5 mg kg-', i.p.).7 In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HTIA autoreceptors. They also indicate that the response involves D2 receptors. The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

“…Mice homozygous for the corresponding mouse Tph2 allele 1449A showed an 80% reduction of 5-HT synthesis and a strong decrease in total and extracellular 5-HT concentrations. In addition, frontal 5-HT 2A receptor function was upregulated and the 5-HT 1A -receptor agonist-induced hypothermia was blunted (Jacobsen et al, 2011), indicating 5-HT 1A autoreceptor desensitization or downregulation in serotonergic neurons of the raphe nuclei (Gross et al, 2002;Martin et al, 1992). Despite these findings and in contrast to our results, Jacobsen et al (2011) did not find altered 5-HT 1A G-protein coupling in the dorsal raphe.…”

Hormonal and temperature responses to the 5-HT 1A receptor agonist flesinoxan in normal volunteers

“…In fact, the nature of neuronal mechanisms involved in the hypothermic effect remains a subject of controversy. In the rat, both pre-and postsynaptic receptors have been implicated (Bill et al 1991;Millan et al 1993;McAllister-Williams et al 2001), and in the mouse hypothermic response is mediated via cell body 5-HT 1A receptors (Goodwin et al 1987;Martin et al 1992). However, overall, temperature response to flesinoxan could be used as a relatively direct, simple and robust measure of 5-HT 1A receptor sensitivity (Cryan et al 1999).…”

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.…”