Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants.
1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 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-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A 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.
Martin
K F
KF
Boots Pharmaceuticals Research Department, Nottingham.
Phillips
I
I
Hearson
M
M
Prow
M R
MR
Heal
D J
DJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007035:Hypothermia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010276:Parasympatholytics / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000928:Antidepressive Agents; D010276:Parasympatholytics; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C039979:gepirone; D002065:Buspirone