Blockade of the locomotor stimulant effects of cocaine and methamphetamine by glutamate antagonists.
The AMPA antagonist, NBQX, produced dose-dependent blockade of the locomotor stimulant effects of cocaine and methamphetamine in male, Swiss-Webster mice at doses which did not alter spontaneous locomotion. A similar finding was obtained with the competitive NMDA antagonist, NPC 12626, although blockade was only observed at the highest dose studied. The NMDA antagonists, (+)-HA-966 and 7-chlorokynurenic acid (7-CKA), which act at the strychnine-insensitive modulatory site of the NMDA receptor, only blocked the stimulatory effects of methamphetamine and with (+)-HA-966, blockade was only achieved at a dose that decreased spontaneous locomotor activity. These results provide evidence for the involvement of glutamatergic input in the control of behavior involving mesolimbic dopamine. Along with other findings these results suggest that glutamate receptors may be a target for the development of pharmacological therapies for the treatment of psychomotor stimulant abuse and for other disorders involving hyperfunction of the mesolimbic dopamine system (eg. schizophrenia).
Witkin
J M
JM
Drug Development Group, NIDA Addiction Research Center, Baltimore, MD 21224.
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D011810:Quinoxalines; C060212:NPC 12626; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D018698:Glutamic Acid; D008694:Methamphetamine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; D003042:Cocaine; C057013:7-chlorokynurenic acid