Repeated exposure to cocaine results in sensitization to many of the behavioral effects of the drug. The present study was undertaken to examine the role of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in the development of sensitization to the convulsive and lethal effects of cocaine in Swiss Webster mice. Repeated administration of subconvulsant doses of cocaine (45 mg/kg for 7 days) produced a progressive increase in the convulsive responsiveness to the drug. This phenomenon was accompanied by an increase in lethality rate after the 5th day of the treatment. Pretreatment with the non-competitive. NMDA receptor antagonist, MK-801 (5-methyl-10,11- dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine) abolished completely the development of sensitization to cocaine-induced seizures and lethality. In addition, MK-801 attenuated cocaine-induced loss in animals body weight after 7 days of drug treatment. The lethal effects of acute administration of increasing doses of cocaine were also reduced by pretreatment with MK-801. In vitro receptor binding experiments demonstrated an increase (139% of control) in the number of NMDA receptors, labeled with the competitive NMDA receptor antagonist [3H]CGP 39653 ([3H]-2-amino-4-propyl-5-phosphono-3-pentenoic acid), in cortical membranes derived from the mice treated for 7 days with cocaine (45 mk/kg). In agreement with the latter finding, binding of [3H]MK- 801 to the phencyclidine/NMDA site in cortical membranes of cocaine-treated mice was more sensitive to the stimulatory effect of glutamate compared to control (saline treatment). In contrast, binding of [3H]CGP 39653 and [3H] MK-801 in cortical membranes of mice treated with MK-801 before cocaine administration conveyed evidence for a slight down-regulation of the NMDA receptor. Taken together, these results suggest an important role of the NMDA receptor in the process of neurochemical events mediating the sensitization to the toxic effects of cocaine.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1992|
ASJC Scopus subject areas
- Molecular Medicine