MODULATION OF BASAL GANGLIA NEUROTRANSMISSION BY THE CLASSICAL ANTIPSYCHOTIC FLUPHENAZINE IS DUE IN PART TO THE BLOCKADE OF DOPAMINE D-1-RECEPTORS

Classical antipsychotics, such as fluphenazine, influence neurotransmi ssion by blocking both dopamine D-1-and D-2-receptors which in turn re sults in widespread adaptive changes in the neurochemistry of the basa l ganglia. The purpose of the present study was to determine the role of D-1-receptors in mediating some of these neurochemical events, incl uding changes in D-1-and D-2-receptor binding, and the expression of p reproenkephalin and glutamic acid decarboxylase mRNAs. For these exper iments, rats were given a depot injection of fluphenazine decanoate or injected twice daily for 21 days with the D-1-receptor antagonist SCH -23390. An additional group received both fluphenazine and SCH-23390 a nd controls were given saline. Fluphenazine administration decreased D -2-receptor binding throughout the basal ganglia while SCH-23390 was w ithout effect. In contrast to the uniform reduction in D-2-receptor bi nding, fluphenazine altered D-1-receptor binding in a region-dependent manner. Region-dependent changes were also observed in animals given SCH-23390 which increased binding in the entopeduncular nucleus and po sterior caudate-putamen without affecting other brain regions. Both fl uphenazine and SCH-23390 significantly enhanced preproenkephalin and g lutamic acid decarboxylase (GAD) mRNA expression in the anterior stria tum. Fluphenazine also increased CAD mRNA levels in the entopeduncular nucleus. Together, these results indicate that the attenuation of D-1 -receptor-mediated neurotransmission modulates a number of clinically relevant neurochemical processes in the basal ganglia. (C) 1997 Elsevi er Science B.V.