Acute administration of SCH23390 increases D-1 receptors on nonpyramidal neurons in rat mPFC

Atypical antipsychotic drugs (APDs) such as clozapine and olanzapine antago nize both D-1 and D-2 receptors; however, little is known regarding their p harmacologic effect on specific neuronal elements within the local circuitr y of corticolimbic regions, such as medial prefrontal cortex (mPFC). To cha racterize the effect of short-term antagonism of the D-1 receptor a high-re solution autoradiographic technique was used to assess the density (B-max) and affinity (K-d) of this receptor on pyramidal cells (i.e., large neurons (LNs, greater than or equal to 100 pm(2))), nonpyramidal cells (i.e., smal l neurons (SNs, < 100 mu m(2))) and in the surrounding neuropil (NPL) of la yer VI in rat mPFC. Either normal saline or the selective D-1 antagonist SC H23390 (1.0 mg/kg/day) were administered for 48 h via Alzet osmotic pumps. Frozen sections were incubated in [H-3]SCH23390 (1-8 nM.) in the presence o r absence of the competitive inhibitor SKF38393 (10 mu M). A microscopic ad aptation to Scatchard analysis revealed a significant increase (82%) in B-m ax for neuronal cell bodies (P < 0.05), but not for neuropil of drug-treate d animals. Further analysis indicated that the increase in B-max was presen t on SNs (94%, P < 0.05), but not LNs in SCH23390-treated rats. In contrast , K-d values for LNs, SNs, and NPL were not significantly altered by drug t reatment. Since the vast majority of SNs are nonpyramidal in nature, short- term administration of a selective D-1 antagonist seems to be associated wi th a preferential upregulation of this receptor on interneurons. Overall, t hese results are consistent with the hypothesis that the mechanism of actio n of atypical antipsychotic medications involves changes in D-1 receptor ac tivity associated with local circuit neurons in rat mPFC. (C) 2000 Wiley-Li ss, Inc.