Rapid desensitization of 5-HT(1A) receptors in Fawn-Hooded rats after chronic fluoxetine treatment.
Anxiety, platelet serotonin (5-HT) content and functions of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were measured in Sprague--Dawley (SD) and Fawn-Hooded (FH) rats, a strain with genetically impaired 5-HT storage and reuptake system and a putative model of depression and anxiety. In addition, the effects of 7 and 16 days treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine on 8-OH-DPAT-induced responses were studied. FH rats showed significantly higher anxiety in the social interaction test, and much lower platelet 5-HT content compared to SD rats. The efficacy of 8-OH-DPAT (15-120 microg/kg, i.v.) to induce lower lip retraction (an effect mediated by median raphe receptors) was increased in FH rats. In most FH but only a few SD rats a special neurological syndrome, clonic movement of the masseters and in-and-out movement of the eyeballs, was induced by 8-OH-DPAT, and this behaviour like other effects of 8-OH-DPAT, was completely blocked by pretreatment with the 5-HT(1A) receptor antagonist WAY-100635. In SD rats fluoxetine (10 mg/kg/day, i.p.) caused a moderate inhibition of 8-OH-DPAT-induced hypothermia, an effect mediated most likely by hypothalamic 5-HT(1A) receptors, (-19% and -40% after 7 and 16 days of fluoxetine, 24 h after the last injection, respectively). In FH rats fluoxetine caused a rapid and complete reduction in the 8-OH-DPAT-induced hypothermia (-65% and -91% after 7 and 16 days of fluoxetine, respectively). Fluoxetine caused no change in lower lip retraction but a reduction in the masseter-eyeball syndrome in both SD and FH rats. Our data provide evidence that in FH rats, median raphe 5-HT(1A) receptors are hypersensitive, and the hypothalamic 5-HT(1A) receptor desensitization, caused by SSRI antidepressants, is faster and more complete. These data support the notion that chronic treatment with SSRIs induces a desensitization of some 5-HT(1A) receptor populations, and impaired 5-HT storage and reuptake may accelerate this process.
Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Huvosvolgyi ut 116, H-1021 Budapest, Hungary.
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Kantor
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Graf
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Anheuer
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Bagdy
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000097:blood; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000503:physiopathology; D001831:Body Temperature / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005473:Fluoxetine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors