Effects of antidepressant drug combinations on cortical 5-HT2 receptors and wet-dog shakes in rats.
Rats pretreated with the monoamine oxidase inhibitor, phenelzine 18 h (46.8 mg/kg) and 90 min (11.7 mg/kg) previously or only 90 min (46.8 mg/kg) previously developed a 5-HT dependent syndrome (including wet-dog shakes, WDS) when given the 5-HT uptake inhibitor, paroxetine (11.6 mg/kg). After 2 h, but only in rats pretreated with 2 injections of phenelzine, there was a gradual reduction in the number of cortical 5-HT2 receptors, determined in vitro with [3H]ketanserin, and this was temporally related to a reduction in the frequency of WDS. Both effects (down-regulation and WDS) were prevented by the 5-HT2 receptor antagonist, pirenperone. A second injection of paroxetine at 3 h evoked additional WDS in rats pretreated with 1 injection of phenelzine but not in rats pretreated with 2 injections, suggesting that spinal 5-HT2 receptors might also have been down-regulated at the same time. Similar results were obtained when rats were pretreated instead with the selective MAO A inhibitor, clorgyline or when given either citalopram or fenfluramine instead of paroxetine. 5-HTP also evoked WDS in phenelzine-treated rats and markedly increased brain 5-HT concentration but only slowly down-regulated 5-HT2 receptors; in carbidopa-treated animals, 5-HTP was without effect on receptor numbers despite production of frequent WDS. It thus appears that drugs which increase synaptic 5-HT (as indicated by production of WDS) by interference with the release or reuptake of 5-HT more readily down-regulate 5-HT2 receptors than 5-HTP which does not directly affect these mechanisms.
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002230:Carbidopa / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D015283:Citalopram; D004347:Drug Interactions; D005277:Fenfluramine / Q000494:pharmacology; D008297:Male; D008732:Methoxydimethyltryptamines / Q000494:pharmacology; D017374:Paroxetine; D010624:Phenelzine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D013997:Time Factors
D000928:Antidepressive Agents; D008732:Methoxydimethyltryptamines; D010880:Piperidines; D011437:Propylamines; D011985:Receptors, Serotonin; D015283:Citalopram; D005277:Fenfluramine; D012701:Serotonin; D017374:Paroxetine; D006916:5-Hydroxytryptophan; D002230:Carbidopa; D010624:Phenelzine