title: Degree of immediate early gene induction in striatum by eticlopride determines sensitivity to N-methyl-D-aspartate receptor blockade.
abstract: 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 localization of activated PKA may determine if D2 antagonist-mediated gene expression is dependent on NMDA receptor activation. We have previously demonstrated that NMDA receptor antagonists block gene expression induced by a high dose of eticlopride in medial and central but not lateral striatum. Here, we examined the effects of NMDA receptor antagonists on striatal gene expression after administration of a low dose of eticlopride. The results showed that NMDA receptor antagonists blocked gene induction by eticlopride throughout striatum. Less PKA activation by the low dose of eticlopride might explain why the expression was more sensitive in the lateral striatum to NMDA receptor blockade than in our previous study. To increase levels of PKA activation to the extent that NMDA receptor blockade would have less effect on eticlopride-mediated gene induction in all regions of striatum, we administered the phosphodiesterase inhibitor IBMX to animals treated with eticlopride. The combined administration of IBMX and eticlopride induced gene expression that was only partially attenuated (c-fos) or unaffected (zif268) by 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 NMDA receptor activation.
authors: Department of Neurosurgery, University of Utah, Salt Lake City, UT 84112, USA.
authors: A C
authors: AC
authors: Adams
authors: K A
authors: KA
authors: Keefe
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012457:Salicylamides / Q000494:pharmacology*
chemical_list: D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D010726:Phosphodiesterase Inhibitors; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D012457:Salicylamides; C053672:selfotel; D016291:Dizocilpine Maleate; C045989:eticlopride; D015056:1-Methyl-3-isobutylxanthine