a-77636 and Schizophrenia

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.

Topics: Acoustic Stimulation; Adamantane; Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Benzopyrans; Cognition; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Male; Memory; Motor Activity; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia; Schizophrenic Psychology; Sensory Gating; Stereotyped Behavior; Time Factors