title: The melanin-concentrating hormone1 receptor antagonists, SNAP-7941 and GW3430, enhance social recognition and dialysate levels of acetylcholine in the frontal cortex of rats.
abstract: Melanin-concentrating hormone (MCH)1 receptors are widely expressed in limbic structures and cortex. Their inactivation is associated with anxiolytic and antidepressive properties but little information is available concerning cognition. This issue was addressed using the selective antagonists, SNAP-7941 and GW3430, in a social recognition paradigm in rats. The muscarinic blocker, scopolamine (1.25 mg/kg s.c.), reduced social recognition, an action dose-dependently blocked by SNAP-7941 and GW3430 (0.63-10.0 and 20.0-80.0 mg/kg i.p., respectively) which did not themselves display amnesic properties. Further, in a protocol where a spontaneous deficit was induced by a prolonged inter-session delay, SNAP-7941 and GW3430 dose-dependently enhanced social recognition. In dialysis studies, SNAP-7941 (0.63-40.0 mg/kg i.p.) and GW3430 (10.0-40.0 mg/kg i.p.) elevated extracellular levels of acetylcholine (ACh) in the frontal cortex (FCX) of freely moving rats. The SNAP-7941 effect was specific, as it did not increase levels of ACh in ventral and dorsal hippocampus: moreover, it did not modify levels of noradrenaline, dopamine, serotonin and glutamate in FCX. Active doses of SNAP-7941 and GW3430 corresponded to doses (2.5-40.0 and 10.0-80.0 mg/kg i.p., respectively) exerting anxiolytic properties in Vogel conflict and ultrasonic vocalization tests, and antidepressant actions in forced swim, isolation-induced aggression and marble-burying procedures. In contrast to SNAP-7941 and GW3430, the benzodiazepine, diazepam, decreased social recognition and dialysate levels of ACh, while the tricyclic, imipramine, reduced social recognition and failed to enhance cholinergic transmission. In conclusion, at anxiolytic and antidepressant doses, SNAP-7941 and GW3430 improve social recognition and elevate extracellular ACh levels in FCX. This profile differentiates MCH1 receptor antagonists from conventional anxiolytic and antidepressant agents.
authors.affiliation: Division of Psychopharmacology, Institut de Recherches Servier, Croissy-sur-Seine, France. mark.millan@fr.netgrs.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Alain
authors.initials: A
authors.lastname: Gobert
authors.forename: Fany
authors.initials: F
authors.lastname: Panayi
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rivet
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Mauricette
authors.initials: M
authors.lastname: Brocco
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Ortuno
authors.forename: Benjamin
authors.initials: B
authors.lastname: Di Cara
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000374:Aggression / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001259:Ataxia / Q000139:chemically induced; D001923:Brain Chemistry / Q000187:drug effects*; D003220:Conflict, Psychological; D003627:Data Interpretation, Statistical; D003863:Depression / Q000523:psychology; D003975:Diazepam / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D021641:Recognition, Psychology / Q000187:drug effects*; D012601:Scopolamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012919:Social Behavior; D013550:Swimming / Q000523:psychology
chemical_list: D006993:Hypnotics and Sedatives; C103263:MCHR1 protein, human; D018727:Muscarinic Antagonists; D010880:Piperidines; D011743:Pyrimidines; D017481:Receptors, Somatostatin; C464854:SNAP7941; D012601:Scopolamine; D000109:Acetylcholine; D003975:Diazepam