Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635.
The possible role of 5-HT1A and 5-HT2C receptors in the anxiety induced by fear, acute treatment with SSRI antidepressants or the 5-HT receptor agonist m-CPP were tested in the social interaction anxiety test in male Sprague-Dawley rats. Fluoxetine (2.5-10 mg/kg, i.p.), sertraline (15 mg/kg, i.p.) and m-CPP (0.5-2.0 mg/kg, i.p.) all had an anxiogenic-like profile (decrease in time of total social interaction and increase in self-grooming compared to vehicle) under low-light, familiar arena test conditions. All these effects were reversed by pretreatment with the highly subtype-selective 5-HT2C receptor antagonist, SB-242084 at doses of either 0.05 or 0.2 mg/kg, i.p. In contrast, the selective 5-HT1A receptor antagonist WAY-100635 (0.05 and 0.2 mg/kg, s.c.) failed to reverse SSRI-induced decrease in time of total social interaction, further, it augmented self-grooming response. SB-242084 (0.2 mg/kg) and WAY-100635 (0.05 and 0.2 mg/kg) reversed hypolocomotion caused by the SSRI antidepressants. SB-242084, tested alone against vehicle under high-light, unfamiliar arena test conditions associated with fear, caused significant anxiolysis at 0.2 mg/kg and higher doses. These results suggest that increased anxiety in rodents, and possibly, also in humans (e.g. agitation or jitteriness after SSRIs and panic after m-CPP), caused by acute administration of SSRI antidepressants or m-CPP, are mediated by activation of 5-HT2C receptors. Blockade of 5-HT1A autoreceptors may exacerbate certain acute adverse effects of SSRI antidepressants. Both 5-HT1A and 5-HT2C receptors are involved in the SSRI-induced decrease in locomotor activity. In addition, our studies confirm data that subtype-selective 5-HT2C receptor antagonists have strong anxiolytic actions.
Bagdy
G
G
Department of Neurology, Semmelweis University, Hungary. bag13638@helka.iif.hu
Graf
M
M
Anheuer
Z E
ZE
Modos
E A
EA
Kantor
S
S
D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D001007:Anxiety / Q000139:chemically induced* / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects; D005473:Fluoxetine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006120:Grooming / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use*; D007398:Interpersonal Relations; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000627:therapeutic use*; D020280:Sertraline / Q000037:antagonists & inhibitors* / Q000494:pharmacology*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D018687:Antidepressive Agents, Second-Generation; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D005473:Fluoxetine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D020280:Sertraline; C015068:1-(3-chlorophenyl)piperazine