A single dose of 8-OH-DPAT reduces raphe binding of [3H]8-OH-DPAT and increases the effect of raphe stimulation on 5-HT metabolism.
8-Hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) has antidepressant-like effects in rats and selectively reduces presynaptic 5-HT1A function a day after administration. In the present study, the effect of 8-OH-DPAT (1 mg/kg s.c.) pretreatment on presynaptic (raphe nuclei) and postsynaptic (frontal cortex and hippocampus) [3H]8-OH-DPAT binding was studied. Bmax values were markedly reduced in the raphe, but not in the hippocampus and frontal cortex. Kd values were unchanged. Electrical stimulation of the dorsal raphe (300 microA, 1 ms, 20 Hz, 30 min) significantly increased 5-hydroxyindoleacetic acid in the frontal cortex, but not in the amygdala or the nucleus accumbens and caused smaller increases in the rest of the brain. The increase in the frontal cortex was significantly potentiated one day after giving 8-OH-DPAT. These results confirm the ability of 8-OH-DPAT to desensitise presynaptic 5-HT1A receptors and suggest that this may lead to a loss of feedback control so that, on neuronal stimulation, the increase of 5-HT function is enhanced. This effect may underlie the antidepressant-like action of 8-OH-DPAT pretreatment, i.e. its ability to oppose restraint-induced defects in locomotion on placement in an open field one day later. A requirement of presynaptic 5-HT for this behavioural effect is consistent with its prevention by the 5-HT synthesis inhibitor parachlorophenylalanine.
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
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Beer
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Kennett
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Curzon
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism
D001679:Biogenic Amines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D014364:Tryptophan