Systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor antagonists inhibits morphine's rewarding properties in the conditioned place preference test. In this study, we investigated the anatomical loci implicated in the inhibition of expression of morphine's reward by bilateral microinjections of a selective NMDA antagonist into the mesolimbic areas, including ventral tegmental area and nucleus accumbens. During conditioning, injections of 1 mg/kg morphine were associated with placing rats in one chamber of the place preference box; the exposures to the other chamber were associated with placebo administration. On the test day, drug-free control subjects demonstrated a marked preference for the morphine-associated chamber. Systemic administration of 5 mg/kg and 10 mg/kg of the competitive NMDA antagonist, NPC 17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), significantly reduced the expression of morphine-induced conditioned place preference; the dose of 10 mg/kg produced also an inhibition of locomotor activity. Similar attenuation of the expression of morphine-induced conditioned place preference was observed in rats receiving 15.6 and 62.5 ng/0.5 ml side of NPC 17742 injected bilaterally into the nucleus accumbens and ventral tegmental area. While the higher intra-accumbal dose of NPC 17742 produced behavioral stimulation, intra-tegmental injection did not affect locomotor activity. These findings suggest that activation of NMDA receptors in the nucleus accumbens and ventral tegmental area is necessary for the elicitation of approach by environments previously associated with morphine's rewarding action.

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The new method described in this study was based on consecutive repeated measurements of the resistance of flexor and extensor muscles of the hind foot of the rat to forced flexions and extensions of the foot. Locomotor movements of the rat were restrained with a metaplex box which had a slot for the hind limb. The control muscle tone measured by this method was constant for more than 2 h, and amounted to approx. 25 g for flexor muscles, and approx. 45 g for extensors. Morphine (2.5, 5, 10, 20 mg/kg) enhanced dose-dependently the resistance of flexor muscles up to approx. 45 g, 70 g, 100 g and 140 g, respectively, and the resistance of extensors of the paw up to approx. 100 g, 140 g, 180 g and 240 g, respectively. Haloperidol (5 and 10 mg/kg) enhanced dose-dependently the resistance of flexor muscles up to approx. 45 g and 70 g, respectively, and that of extensors of the foot up to approx. 75 g and 120 g, respectively. Morphine rigidity, measured as resistance of respective muscles to forced movements, was almost completely inhibited by a consecutive injection of 0.2 mg/kg of naloxone. The new method seems to have considerable advantages in comparison with electromyographical (EMG) or other kinds of mechanographical measurements of the muscle tone.