Comparison of relative potencies of i.v. and i.c.v. administered 8-OH-DPAT gives evidence of different sites of action for hypothermia, lower lip retraction and tail flicks.
8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced temperature reduction, lower lip retraction and tail flick responses are widely used models of 5-HT1A receptor function. To obtain information about the sites of receptors mediating these effects we measured these responses, parallel over wide dose ranges after intracerebroventricular (i.c.v., 0.6-67 micrograms/kg) and intravenous (i.v., 3-500 micrograms/kg) administration. Analysis of the dose-response curves provided evidence for a 9.8-fold ratio of the potency of 8-OH-DPAT following i.c.v. compared to i.v. administration on body temperature reduction (ED50 values are 5.1 and 50 micrograms/kg, after i.c.v and i.v. administration, respectively) and a 2.9-fold ratio in potency for lower lip retraction (ED50 values are 29 and 86 micrograms/kg, after i.c.v. and i.v. administration, respectively). 8-OH-DPAT was less potent in the induction of tail flicks than of the other responses and had a lower potency after i.c.v. than after i.v. administration (ED50 values, the first one extrapolated, are 526 and 246 micrograms/kg, after i.c.v. and i.v. administration, respectively). In addition, the i.c.v. ED50 for temperature reduction was significantly lower than those for lower lip retraction or tail flick responses. The relative potency, that is, the ratio of i.v. and i.c.v. ED50, was significantly higher for temperature reduction than for lower lip retraction or tail flick responses (ED50 i.v./ED50 i.c.v. values are 9.8, 2.9, and 0.47, respectively). These data provide evidence that distinct sites of action are involved in these models. Temperature reduction is mediated mainly by postsynaptic receptors in the close vicinity of the lateral ventricle. Receptors that mediate lower lip retraction are located more distantly in the brain, supporting previous evidence that they are somatodendritic autoreceptors, and receptors in the spinal cord are probably responsible for tail flick responses.
Bagdy
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Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Budapest, Hungary.
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007035:Hypothermia / Q000139:chemically induced*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007928:Lethal Dose 50; D008046:Lip / Q000187:drug effects; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000633:toxicity*; D013623:Tail / Q000187:drug effects
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin