Effects of the selective dopamine D(1) antagonists NNC 01-0112 and SCH 39166 on latent inhibition in the rat.
Dopamine D(1) receptor blockade does not appear to be a prerequisite for antipsychotic activity since many clinically effective antipsychotics have little or no affinity for this receptor subtype. Clozapine, however, which has minimal liability for extrapyramidal symptoms, possesses affinities of similar order for D(1) and D(2) receptors. In earlier animal models used to predict antipsychotic effect, selective D(1) antagonists have shown effects similar to standard antipsychotics with preferential D(2) or mixed D(1)/D(2) antagonism. We investigated the effects of haloperidol (0.1 mg/kg) and two selective D(1) antagonists, NNC 01-0112 (0.05, 0.1 and 0.2 mg/kg) and SCH 39166 (0.02, 0.2 and 2.0 mg/kg), on latent inhibition (LI) in rats. LI is a behavioural paradigm in which repeated nonreinforced preexposure to a stimulus retards subsequent associations to that stimulus. Disrupted LI has been suggested as a model for the attentional deficits in schizophrenia. Using preexposure to a flashing light stimulus, which subsequently served as a conditioned stimulus for suppression of water licking, we demonstrated a clear LI effect with haloperidol but with neither of the two D(1) antagonists. Since selective D(1) antagonists are not clinically effective, these results add further credibility for the relevance of LI as an animal model of psychosis.
Trimble
Karen M
KM
Department of Therapeutics and Pharmacology, Queen's University Belfast, Belfast BT7 1NN, Northern Ireland, UK.
Bell
Robert
R
King
David J
DJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D003213:Conditioning, Psychological; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004597:Electroshock; D005528:Foot; D006220:Haloperidol / Q000494:pharmacology; D007266:Inhibition, Psychological; D008027:Light; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*
D001552:Benzazepines; D018492:Dopamine Antagonists; C114704:NNC 01-0012; D017447:Receptors, Dopamine D1; C058081:ecopipam; D006220:Haloperidol