The 5-HT1A receptor agonist flesinoxan increases aversion in a model of panic-like anxiety in rats.
Acute systemic administration of the selective serotonin (5-HT)1A receptor full agonist flesinoxan enhanced the sensitivity of rats to the panic-like aversion elicited by local stimulation of the dorsolateral periaqueductal grey (dPAG). This experimental paradigm in rats has previously been validated as a simulation of acute anxiety with particular relevance to panic disorder. The dose-dependent decrease in threshold for acute fear responses recorded in rats following intraperitoneal administration of flesinoxan (1-10 mg/kg) was similar to that induced by the panic precipitating agent yohimbine and opposite to the threshold increase induced by the antipanic drug alprazolam. The proaversive effect of flesinoxan observed in rats is consistent with the reported aggravation of the condition of panic patients following oral flesinoxan treatment. Thus, the model adequately detects drug-induced panicogenic-like properties. Data suggest that selective activation of 5-HT1A receptors (pre- and/or post-synaptic in brain and/or periphery) following systemic administration of 5-HT1A receptor full agonists exacerbates aversion in animals or patients with panic anxiety; activation of these receptor subtypes may probably mediate the panicogenic action reported under certain circumstances with non-selective 5-HT mimetics.
Jenck
F
F
ROCHE Pharma Division, Preclinical CNS Research, Basel, Switzerland. francois.jenck@roche.com
Martin
J R
JR
Moreau
J L
JL
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001362:Avoidance Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D010200:Panic / Q000187:drug effects*; D010487:Periaqueductal Gray / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C056895:flesinoxan