Perinatal Treatments with the Dopamine D-2-Receptor Agonist Quinpirole Produces Permanent D-2-Receptor Supersensitization: a Model of Schizophrenia

摘要

Repeated daily treatments of perinatal rats with the dopamine D-2-receptor (D-2-R) agonist quinpirole for a week or more produces the phenomenon of 'priming'aEuro"gradual but long-term sensitization of D-2-R. In fact a daily dose of quinpirole as low as 50 A mu g/kg/day is adequate for sensitizing D-2-R. Primed rats as neonates and in adolescence, when acutely treated with quinpirole display enhanced eating/gnawing/nursing on dams, also horizontal locomotor activity. Between 3 and 5 weeks of age, acute quinpirole treatment of primed rats produces profound vertical jumping with paw treading-a behavior that is not observed in control rats. At later ages acute quinpirole treatment is associated with enhanced yawning, a D-2-R-associated behavior. This long-term D-2-R supersensitivity is believed to be life-long, despite the relatively brief period of D-2-R priming near the time of birth. D-2-R supersensitivity is not associated with an increase in the number or affinity of D-2-R, as assessed in the striatum of rats; nor is it induced with the D-3-R agonist 7-OH-DPAT. However, quinpirole-induced D-2-R supersensitivity is associated with cognitive deficits, also a deficit in pre-pulse inhibition and in neurotrophic factors, and low levels of the transcript regulator of G-protein signaling (RGS) RGS9 in brain; and acute reversal of these alterations by the antipsychotic agent olanzapine. In sum, rats ontogenetically D-2-R supersensitized have face validity, construct validity and predictive ability for schizophrenia.