ABSTRACT
After repeated administration of psychostimulant drugs, a sensitization rather than a tolerance to the behavioral effects can be observed. In our own previous studies, it was shown that both blockade of NMDA glutamate receptors and inhibition of NO synthase selectively inhibited the expression of associative but not non-associative sensitization to D-amphetamine. The present experiments were performed in order to study whether a similar selective inhibition of expression of associative sensitization to cocaine can be observed after blockade of NMDA receptors by MK-801 or inhibition of NO synthase by L-NAME. MK-801 as well as L-NAME inhibited the locomotor activity in acutely cocaine-treated rats. Both drugs did not prevent the sensitization either in the associative or the non-associative group. The results suggest that the acute locomotor effects of cocaine were inhibited by both drugs whereas both the non-associative and the associative sensitization to locomotor effects were not inhibited by blockade of NMDA receptors or inhibition of NO synthase. Accordingly, the expression of neither type of sensitization to cocaine was inhibited by any of these drugs.
Subject(s)
Behavior, Animal/drug effects , Cocaine/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Behavior, Animal/physiology , Cocaine/administration & dosage , Dizocilpine Maleate/administration & dosage , Dizocilpine Maleate/pharmacology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Injections, Intraperitoneal , Male , Motor Activity/drug effects , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/metabolism , Rats , Rats, Wistar , Time Factors , Vasoconstrictor Agents/administration & dosage , Vasoconstrictor Agents/pharmacologyABSTRACT
Blockade of glutamate receptors of the NMDA type inhibits the sensitization to psychostimulant drugs, such as amphetamine, that occurs after repeated administration. Both associative (conditioning) and non-associative (pseudo-conditioning) mechanisms may contribute to sensitization phenomena. The aim of the present study was, thus, to determine which type of sensitization is influenced by blockade of NMDA-type receptors by examining the expression (manifestation) of sensitization. Locomotor activity was assessed and, in some experiments, extracellular dopamine in the nucleus accumbens was also assessed using in vivo microdialysis in non-anaesthetized, almost freely moving rats. Male albino Wistar rats of 225-250 g were given 1 mg/kg i.p. d-amphetamine every 2nd day for 7 days and with saline on the other days. Half the rats were exposed to d-amphetamine in the presence of conditioning stimuli (test cage, auditory and olfactory stimulus) and to saline in the home cage in absence of these stimuli, the other half were treated with saline and exposed to the conditioning stimuli and were placed into their home cages (without conditioning stimuli) after treatment with d-amphetamine. Ten days after the end of this treatment, both groups were exposed to the conditioning stimuli and half of each group were pretreated with dizocilpine [(+)-MK-801, 0.1 mg/kg i.p.], a blocker of NMDA receptors, 30 min before administration of 1 mg/kg d-amphetamine. (+)-MK-801 reduced the locomotor activity in rats sensitized associatively, but not in those sensitized non-associatively. It had no significant effect on spontaneous locomotor activity or that induced by acute administration of 1 mg/kg d-amphetamine. Similarly, (+)-MK-801 inhibited the increase in extracellular dopamine in the nucleus accumbens induced by the test dose of d-amphetamine in rats sensitized associatively but not non-associatively. The results suggest that the expression of both types of sensitization to d-amphetamine are dependent on glutamatergic NMDA mechanisms, although in different ways. Inhibition of sensitization, in particular of the associative type, might be of therapeutic value in drug dependence.
