Inhibition of cocaine sensitization by MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: evaluation by ambulatory activity in mice.
Alterations of cocaine effects, which were induced by prior repeated 5-time administration of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (i.p.) alone or in combination with cocaine (s.c.) at 3- to 4-day intervals, were investigated by means of ambulatory activity in mice. The repeated administration of either cocaine (10 and 20 mg/kg) alone or MK-801 (0.3 mg/kg) alone progressively enhanced each drug's effect. The enhanced effects of cocaine and MK-801 were estimated to be 1.8-2.2 times and about 1.4 times, respectively, as great as those at the 1st administration. Although the coadministration of MK-801 with cocaine produced a significant enhancement in the ambulation-increasing effect, the comparatively higher doses of MK-801 (0.3 and 1 mg/kg) acted not only to reduce cocaine sensitivity but also to inhibit the development of cocaine sensitization. Thus, the mice that had been given MK-801 (0.3 and 1 mg/kg) alone 5 times showed lower sensitivities to cocaine (20 mg/kg) than the mice given saline alone. The mice coadministered MK-801 (0.3 and 1 mg/kg) with cocaine (10 and 20 mg/kg) also exhibited lower sensitivities to cocaine (10 and 20 mg/kg) than those given cocaine alone. However, MK-801 could not ameliorate the established sensitization to cocaine. Similar interactions have been demonstrated between MK-801 at 1 mg/kg, but not 0.3 mg/kg, and methamphetamine. The present results indicate that MK-801 can inhibit the development of sensitization to cocaine at a lower dose than that required to inhibit methamphetamine sensitization.
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Department of Neuropsychiatry, Gunma University School of Medicine, Maebashi, Japan.
Asami
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Kuribara
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D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013997:Time Factors
D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003042:Cocaine