Degree of immediate early gene induction in striatum by eticlopride determines sensitivity to N-methyl-D-aspartate receptor blockade

Cortical afferents excite striatal efferent neurons through activation of N -methyl-D-aspartate (NMDA) receptors, which can be modulated by D2 dopamine receptors. It is suggested that activation of PKA by D2 receptor blockade leads to NMDA receptor phosphorylation in the dendrites or phosphorylation of transcription factors in the nucleus. Thus, the levels and cellular loca lization of activated PKA may determine if D2 antagonist-mediated gene expr ession is dependent on NMDA receptor activation. We have previously demonst rated that NMDA receptor antagonists block gene expression induced by a hig h dose of eticlopride in medial and central but not lateral striatum. Here, we examined the effects of NMDA receptor antagonists on striatal gene expr ession after administration of a low dose of eticlopride. The results showe d that NMDA receptor antagonists blocked gene induction by eticlopride thro ughout striatum. Less PKA activation by the low dose of eticlopride might e xplain why the expression was more sensitive in the lateral striatum to NMD A receptor blockade than in our previous study. To increase levels of PKA a ctivation to the extent that NMDA receptor blockade would have less effect on eticlopride-mediated gene induction in all regions of striatum, we admin istered the phosphodiesterase inhibitor IBMX to animals treated with eticlo pride. The combined administration of IBMX and eticlopride induced gene exp ression that was only partially attenuated (c-fos) or unaffected (zif268) b y NMDA receptor blockade. These data support the suggestion that the degree of second messenger activation by D2 receptor blockade determines whether D2 dopamine receptor antagonist-mediated gene expression is dependent on NM DA receptor activation. (C) 2000 Elsevier Science B.V. All rights reserved.