Serotonin 5-HT1A receptor-mediated hypothermia in mice: absence of spare receptors and rapid induction of tolerance.
The mixed 5-hydroxytryptamine1A (5-HT1A) receptor agonist/antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4.5]- decane-7,9-dione (BMY 7378) (5 mg/kg) did not significantly depress body temperature, but pretreatment with BMY 7378 blocked hypothermia induced by the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In contrast, another partial 5-HT1A agonist, pindolol (10 mg/kg), slightly but significantly depressed body temperature by itself but did not attenuate hypothermia elicited by 8-OH-DPAT. Attempts to identify the synaptic locus of the receptor were unsuccessful because depletion of central serotonin (5-HT) by treatment with para-chlorophenylalanine (PCPA; 3 x 150 mg/kg) did not alter the hypothermic response to 8-OH-DPAT. Partial, irreversible 5-HT1A receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (1 mg/kg) reduced the maximal hypothermic effect of 8-OH-DPAT (to 53% of control) without altering its ED50 (0.96 mg/kg). Analysis of the data indicated a linear relationship between 5-HT1A receptor occupancy and hypothermic response, that is, absence of receptor reserve. When groups of mice were treated with each of five different doses of 8-OH-DPAT (0.04, 0.16, 0.63, 2.5, and 10 mg/kg) 48 h apart, there was a significant reduction in hypothermic response after the second injection, but only at the three highest doses. The results demonstrate that 8-OH-DPAT-induced hypothermia in mice is mediated by a 5-HT1A receptor whose synaptic localization is uncertain but that has no receptor reserve. In addition, tolerance is observed after only a single agonist treatment.
Millhauser Laboratories, Department of Psychiatry, New York University Medical Center, NY 10016.
E
E
Meller
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M
Chalfin
K
K
Bohmaker
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D004361:Drug Tolerance; D010134:Fenclonine / Q000494:pharmacology; D007035:Hypothermia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D010869:Pindolol / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism
D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011804:Quinolines; D011985:Receptors, Serotonin; D005576:Colforsin; D012701:Serotonin; C000470:EEDQ; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010869:Pindolol; C053428:BMY 7378; D010134:Fenclonine