Antiaversive effects of 5HT2C receptor agonists and fluoxetine in a model of panic-like anxiety in rats.
Dose-dependent increases in threshold for operant fear/escape responses of rats submitted to aversive stimulation of the dorsolateral periaqueductal gray (dPAG) were recorded following intraperitoneal injection of three chemically unrelated but selective 5HT2C receptor agonists (Ro 60-0175, Org 12962 and Ro 60-0332) and fluoxetine. The decreased sensitivity of rats to the acute panic-like aversion elicited by stimulation of this limbic periventricular region was detected at dosages devoid of impairing effects on the latencies needed for operant brain stimulation interruption. In this paradigm which has been validated as a simulation of acute anxiety with relevance to panic disorder, the selective activation of 5HT2C receptors by Ro 60-0175, Org 12962 or Ro 60-0332 induces effects analogous to those observed following benzodiazepine receptor activation by antipanic agents such as clonazepam or alprazolam or following non-selective and indirect 5HT receptor activation by fluoxetine. Potency and efficacy of 5HT2C receptor agonists were intermediate between those of clonazepam and fluoxetine, indicating authentic antiaversive properties and suggesting antipanic potential for these 5HT2C receptor agonists. In addition, these data suggest that the 5HT2C receptor subtype may play a major role in the therapeutic properties of selective serotonin reuptake inhibitors. It is also speculated that serotonin/benzodiazepine interactions existing in the brain may functionally involve the 5HT2C receptor subtypes and that the anxiogenic action reported under certain circumstances for 5HT mimetics are not mediated by 5HT2C receptor subtypes.
Pharma Division, Preclinical CNS Research, Roche, Basel, Switzerland. francois.jenck@roche.com
F
F
Jenck
J L
JL
Moreau
H H
HH
Berendsen
M
M
Boes
C L
CL
Broekkamp
J R
JR
Martin
J
J
Wichmann
A M
AM
Van Delft
D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D005021:Ethylamines / Q000008:administration & dosage / Q000494:pharmacology; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D010200:Panic / Q000187:drug effects / Q000502:physiology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*
D005021:Ethylamines; D005473:Fluoxetine; D007211:Indoles; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C103848:Ro 60-0175