Activation of dopamine D1 receptors enhances cholinergic transmission and social cognition: a parallel dialysis and behavioural study in rats.
Although dopaminergic mechanisms are known to modulate cognitive function and cholinergic transmission, their pharmacological characterization remains incomplete. Herein, the role of D1 sites was evaluated employing neurochemical and behavioural approaches. By analogy to the acetylcholinesterase inhibitor, galantamine (0.0025-0.63 mg/kg s.c.), the selective and high efficacy D1 receptor agonist, SKF 82958, dose-dependently (0.0025-0.63), robustly and potently enhanced extracellular levels of acetylcholine (ACh) in the frontal cortex and hippocampus of freely moving rats. A further agonist, SKF 81297 (0.04-0.63), mimicked this action whereas the selective antagonist, SCH 23390 (0.00063-0.63), decreased levels of ACh. In the presence of SCH 23390 (0.08), the facilitatory influence of SKF 82958 (0.04) upon ACh levels was abolished. In a model of social memory (recognition of a juvenile by an adult rat), galantamine (0.04-0.63), SKF 82958 (0.01-0.16) and SKF 81297 (0.001-0.16) dose-dependently abrogated amnesic effects of the muscarinic receptor antagonist scopolamine (1.25). Further, under conditions of spontaneous loss of recognition, mimicking the effects of galantamine (0.04-2.5), SKF 82958 (0.01-0.16) and SKF 81297 (0.04-1.25) dose-dependently and specifically facilitated social recognition. Conversely, SCH 23390 (0.0025-0.04) exerted a modest negative influence upon social recognition and, in its presence, the pro-cognitive properties of SKF 82958 were blocked. In conclusion, D1 receptors exert a tonic, facilitatory influence upon cholinergic transmission and social recognition. Although the relationship between these actions awaits further clarification, these data underpin the relevance of D1 receptors to CNS disorders in which cholinergic transmission and social cognition are disrupted.
Di Cara
Benjamin
B
Institut de Recherches Servier, Department of Psychopharmacology, 125 chemin de Ronde, 78290 Croissy-sur-Seine, France.
Panayi
Fany
F
Gobert
Alain
A
Dekeyne
Anne
A
Sicard
Dorothée
D
De Groote
Lotte
L
Millan
Mark J
MJ
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D005702:Galantamine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012601:Scopolamine / Q000494:pharmacology; D012919:Social Behavior; D009435:Synaptic Transmission / Q000502:physiology*
D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D018492:Dopamine Antagonists; D018727:Muscarinic Antagonists; D017447:Receptors, Dopamine D1; D011976:Receptors, Muscarinic; D005702:Galantamine; C067113:SK&F 81297; C071262:SK&F 82958; D012601:Scopolamine; D000109:Acetylcholine