Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area

Rationale: The activation of NMDA receptors in the rat ventral tegmental area has been proposed to be necessary for the induction of locomotor sensitization by amphetamine, yet there has been no direct assessment of this view. Objective: The present study examined the ability of the competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) to block this effect when infused either into the ventral tegmental area or, for comparison, into the nucleus accumbens. These sites are known to be important for the induction and expression, respectively, of locomotor sensitization by amphetamine. Methods: Rats in different groups received four pairs of injections (one IC and one IP), one pair given every third day. The IC injection (0, 1 or 5 nmol/side AP-5) was administered immediately before the IP injection (saline or amphetamine, 1 mg/kg). Locomotor activity was measured following each pair of injections and again 2 weeks later when all rats were tested for sensitization following a challenge injection of amphetamine (1 mg/kg, IP). AP-5 was not administered on this test. Results: As expected, rats previously exposed to amphetamine alone showed higher levels of horizontal locomotion and rearing on the test for sensitization when compared to saline pre-exposed rats. Preceding the amphetamine pre-exposure injections with infusions of AP-5 into the ventral tegmental area, but not the nucleus accumbens, dose-dependently blocked the induction of this effect. Rats previously exposed to AP-5 alone in either site did not differ significantly from saline preexposed rats on the test for sensitization. Conclusion: The results indicate that NMDA receptor activation in the ventral tegmental area, but not the nucleus accumbens, is necessary for the induction of locomotor sensitization by amphetamine.