The effect of a full agonist/antagonist of the D1 receptor on locomotor activity, sensorimotor gating and cognitive function in dizocilpine-treated rats.
Cognitive impairment has been found across all subtypes of schizophrenia. The location and function of dopamine-1 receptors (D1Rs) make them attractive targets for the treatment of cognitive impairment in schizophrenia. Here we investigate the systemic effect of a D1R agonist (A77636) and antagonist (SCH 23390) on hyperlocomotor activity and cognitive deficit induced by an NMDA receptor antagonist (MK-801). Wistar rats (250-300 g) received A77636 (0.1, 0.5 or 1 mg/kg) or SCH 23390 (0.02 or 0.05 mg/kg) with MK-801 (0.1 mg/kg) or saline for 4 d. On day 4 we assessed the prepulse inhibition of the acoustic startle response, locomotor activity in a novel arena and active allothetic place avoidance (spatial memory task) 15 min after the last injection. Systematic administration of the D1R agonist at 0.1 mg/kg ameliorates cognitive dysfunction in our model of schizophrenia, but increases stereotypy and locomotor activity (model of psychotic symptoms) at higher doses (0.5 or 1 mg/kg). Administration of the D1R antagonist had no effect on cognitive function, but decreased hyperlocomotion induced by MK-801. Thus, based on our results, over-activation of D1Rs may exacerbate psychotic symptoms in patients with schizophrenia.
Bubenikova-Valesova
Vera
V
Department of Brain Pathophysiology and Biochemistry, Prague Psychiatric Centre, Prague, Czech Republic. valesova@pcp.lf3.cuni.cz
Svoboda
Jan
J
Horacek
Jiri
J
Vales
Karel
K
D000161:Acoustic Stimulation; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D055139:Sensory Gating / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors
D001552:Benzazepines; D001578:Benzopyrans; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C534628:SCH 23390; C079415:A 77636; D016291:Dizocilpine Maleate; D000218:Adamantane