Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-D-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats.
Behavioral activation following systemic administration of the N-methyl-D-aspartic acid receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclohepten-5,10-imine; dizocilpine] was examined in unlesioned control and in neonatal-6-hydroxydopamine (OHDA) lesioned rats. Neonatal-6-OHDA lesioned animals were found more sensitive than control rats and female rats more sensitive than males to this MK-801-induced behavioral activation. CGS-19755, a competitive NMDA antagonist, also increased activity in neonatally lesioned animals. The increased activity level following MK-801 administration to neonatally lesioned rats was reduced, but not eliminated, by pretreatment with alpha-methyltyrosine, indicating that endogenous catecholamines were partially responsible for this action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antagonist was totally effective alone in reducing MK-801-induced behavioral activation in the neonatally lesioned rats, but MK-801-induced activity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contrast to these results, alpha-methyltyrosine virtually eliminated the MK-801-induced activity in adult-lesioned rats. When individual behaviors induced by MK-801 were examined in neonatal-6-OHDA lesioned rats, MK-801 did not produce the same behaviors as L-dihydroxyphenylalanine or a D1- or D2-dopamine agonist. Whereas MK-801 had no major effect on most behaviors induced by specific D1- or D2-dopamine agonists, it blocked some behaviors produced after L-dihydroxyphenylalanine administration, including the self-injurious behavior. Repeated MK-801 treatment resulted in increasingly greater motor activity, but this was not related to increased D1-dopamine receptor sensitization. In support of a regional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. The action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-801 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-like immunoreactivity in striatum. These data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.
Criswell
H E
HE
Department of Psychiatry, School of Medicine, University of North Carolina, Chapel Hill.
Johnson
K B
KB
Mueller
R A
RA
Breese
G R
GR
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D010875:Pipecolic Acids / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000031:analogs & derivatives; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008781:Methyltyrosines; D010875:Pipecolic Acids; D017447:Receptors, Dopamine D1; D012701:Serotonin; C027803:6-hydroxytryptamine; D007980:Levodopa; C053672:selfotel; D016202:N-Methylaspartate; D019805:alpha-Methyltyrosine; D016291:Dizocilpine Maleate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine