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-methy l-D-aspartic acid receptor antagonist MK-801 1-dihydroxy-5H-dibenzo(a, d)cyclohepten-5,10-imine; dizocilpine} was examined in unlesioned cont rol 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 behavior al activation. CGS-19755, a competitive NMDA antagonist, also increase d activity in neonatally lesioned animals. The increased activity leve l following MK-801 administration to neonatally lesioned rats was redu ced, but not eliminated, by pretreatment with a-methyltyrosine, indica ting that endogenous catecholamines were partially responsible for thi s action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antag onist was totally effective alone in reducing MK-801-induced behaviora l activation in the neonatally lesioned rats, but MK-801-induced activ ity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contras t to these results, alpha-methyl-tyrosine 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 mo st behaviors induced by specific D1- or D2-dopamine agonists, it block ed some behaviors produced after L-dihydroxyphenylalanine administrati on, including the self-injurious behavior. Repeated MK-801 treatment r esulted in increasingly greater motor activity, but this was not relat ed to increased D1-dopamine receptor sensitization. In support of a re gional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. Th e action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-8 01 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-l ike immunoreactivity in striatum. These data suggest that MK-801 not o nly can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists .