The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward.
MK-801 is a ligand at phencyclidine recognition sites associated with NMDA-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate/aspartate (NMDA-type) receptors. Low doses (10-100 micrograms/kg IP) produced a dose-related and prolonged (greater than 1 h) enhancement of variable-interval self-stimulation responding. Higher doses (300 micrograms/kg) caused flaccid ataxia and disrupted responding. Ketamine HCl (3.0-100 mg/kg IP), a dissociative anaesthetic binding to the phencyclidine site, produced a similar response pattern, but facilitation was less prolonged and occurred over a narrower dose range. Kynurenic acid (3.0-300 mg/kg IP), a nonselective competitive antagonist of glutamate receptors, produced only depression of responding, possibly the result of kynurenate-induced blockade of central kainate and/or quisqualate receptors. The behavioural stimulant effects of MK-801 appear to be an intrinsic and essential feature of selective NMDA antagonists, and these effects of MK-801 differ qualitatively and quantitatively from the well-known facilitatory effects of dopamine-dependent stimulants.
Herberg
L J
LJ
Experimental Psychology Laboratory, Institute of Neurology, London, UK.
Rose
I C
IC
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001921:Brain / Q000187:drug effects*; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000494:pharmacology; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate; D051381:Rats; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D012653:Self Stimulation / Q000187:drug effects*
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D007736:Kynurenic Acid