Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat.
N-methyl-D-aspartate receptor antagonism exerts suppressive influences over dopamine D1 receptor-mediated striatal gene expression and locomotor behavior in the intact rat. The present study examined the effects of the N-methyl-D-aspartate receptor antagonist MK-801 on locomotor activity and striatal preprotachykinin mRNA expression stimulated by the D1 agonist (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in rats with bilateral dopamine lesions. Two months after neonatal dopamine lesions with 6-hydroxydopamine, rats were challenged with (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) 15 min after administration of the N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg). In the intact rat, MK-801 prevented the induction of striatal preprotachykinin mRNA by D1 agonism. Similarly, direct infusion of (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (3.0 microg) into the intact striatum produced an increase in locomotor activity that was suppressed by MK-801 (1.0 microg) co-infusion. In the dopamine-depleted rat, MK-801 (0.1 mg/kg) administered prior to (+/-)6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1.0 mg/kg) increased, rather than suppressed, striatal preprotachykinin mRNA levels. Intrastriatal infusion of MK-801 (1.0 microg) failed to inhibit D1-mediated induction of motor activity in dopamine-depleted animals. Together, these data provide further support that N-methyl-D-aspartate receptor antagonists lose their ability to block D1-mediated behavioral activation following dopamine depletion. The activation, rather than suppression, of tachykinin neurons of the direct striatonigral pathway may play a facilitatory role in this mechanism.
Campbell
B M
BM
Cellular and Clinical Neurobiology Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Kreipke
C W
CW
Walker
P D
PD
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000503:physiopathology; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018491:Dopamine Agonists; D018691:Excitatory Amino Acid Antagonists; D011498:Protein Precursors; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D015320:Tachykinins; C044206:preprotachykinin; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D004298:Dopamine