title: Selective blockade of dopamine D(3) versus D(2) receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis.
abstract: Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D(3) versus D(2) receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D(3) receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D(2) receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+)S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D(3) receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D(3) receptors as a target for treatment of disorders in which cognitive function is compromised.
authors.affiliation: Department of Psychopharmacology, Institut de Recherches Servier, Croissy/Seine, France. mark.millan@fr.netgrs.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Di Cara
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
authors.forename: Fany
authors.initials: F
authors.lastname: Panayi
authors.forename: Lotte
authors.initials: L
authors.lastname: De Groote
authors.forename: Dorothée
authors.initials: D
authors.lastname: Sicard
authors.forename: Laetitia
authors.initials: L
authors.lastname: Cistarelli
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Billiras
authors.forename: Alain
authors.initials: A
authors.lastname: Gobert
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005625:Frontal Lobe / Q000166:cytology / Q000378:metabolism*; D009483:Neuropsychological Tests; D051381:Rats; D017208:Rats, Wistar; D021641:Recognition, Psychology / Q000502:physiology* / Q000528:radiation effects; D012601:Scopolamine / Q000494:pharmacology; D012919:Social Behavior
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D012601:Scopolamine; D000109:Acetylcholine