Behavioral effects of CCKB receptor ligands in a validated simulation of panic anxiety in rats.
Animals or human subjects receiving brain stimulation in the dorsal periaqueductal gray matter (dPAG) show sudden fear-suggestive behavioral reactions and physical signs of autonomic activation which are reminiscent of the symptom profile characterizing a panic attack. An experimental situation in rats measuring dPAG stimulation self-interruption thresholds has been validated as realistically simulating several aspects of panic anxiety with objective signs of symptomatic and predictive validity using established antipanic and panicogenic agents; it was utilized here to evaluate the effects of various cholecystokinin B receptor ligands. A dose-dependent increase in self-interruption thresholds (antipanic-like effect) was recorded following injection of L-365,260 (3.2, 10 and 32 mg/kg i.p.), a CCKB receptor antagonist with good brain penetration, whereas no significant changes in thresholds were recorded following CI-988 (3.2, 10 and 32 mg/kg i.p.), a dipeptoid CCKB receptor antagonist with poor brain penetration. Latencies for self-interruption were not modified, suggesting that motor functions remained intact. No significant changes in self-interruption thresholds were recorded following peripheral administration of the CCKB receptor agonists CCK4 (0.03 to 0.32 mg/kg i.v.; 0.01 to 3.2 mg/kg i.p.) or the metabolically stabilized analog Boc-CCK4 (0.1 to 10 mg/kg i.p.). Systemic administration of the panicogenic compounds caffeine and yohimbine enhance acute anxiety in this model. These data indicate that, in the dPAG simulation of panic anxiety, central CCKB receptor blockade by L-365,260 induces antiaversive effects analogous to those observed following benzodiazepine receptor activation by clonazepam or alprazolam. Potency and efficacy of L-365,260 were lower than those of clonazepam or alprazolam, suggesting modest, but nonetheless authentic, antiaversive properties for this CCKB receptor antagonist. Lack of effects observed following peripheral administration of the agonists CCK4, and Boc-CCK4 or of the dipeptoid antagonist CI-988 is likely to reflect restricted brain penetration of those compounds in rats; it furthermore excludes a contribution of peripheral gastrin and CCKA receptors to the antipanic-like properties of selective CCKB receptor antagonists such as L-365,260.
Jenck
F
F
Pharma Division, Preclinical CNS Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland. francois.jenck@roche.com
Martin
J R
JR
Moreau
J L
JL
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001570:Benzodiazepinones / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds; D051381:Rats; D017208:Rats, Wistar
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D007211:Indoles; D010671:Phenylurea Compounds; C065599:PD 134308; C058121:L 365260; D002110:Caffeine; D002998:Clonazepam; D008536:Meglumine