MK-801 prevents alterations in the mesoaccumbens dopamine system associated with behavioral sensitization to amphetamine.

Behavioral sensitization to psychomotor stimulants has been shown to be accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA), postsynaptic D1 receptor supersensitivity in the nucleus accumbens (NAc), and augmentation of the DA-releasing effects of stimulants in the NAc. The present study examined whether coadministration of the noncompetitive NMDA antagonist MK-801 with amphetamine, which has been shown to prevent the development of behavioral sensitization to amphetamine, would also prevent these changes in mesoaccumbens DA function. Rats were treated for 5 d with amphetamine according to a regimen known to produce lasting sensitization. Extracellular single-unit recordings from VTA DA neurons in amphetamine-treated rats, performed after 1 d of abstinence, revealed robust autoreceptor subsensitivity to DA agonists. This was prevented in rats coadministered MK-801 with amphetamine during the 5 d pretreatment period. Recordings from NAc neurons in amphetamine-treated rats demonstrated supersensitivity of D1 receptors to iontophoretic administration of selective agonists when tested after 7 d of abstinence. This was also prevented by MK-801 coadministration. Microdialysis studies performed in awake rats after 7 d of abstinence failed to demonstrate augmentation of amphetamine-stimulated DA release in amphetamine-treated rats as compared to water controls, despite the fact that behavioral sensitization was evident in the former group during microdialysis experiments. MK-801 coadministration prevented behavioral sensitization in microdialysis rats but did not alter amphetamine-stimulated DA release. These results suggest (1) NMDA receptor stimulation is required for the development of both autoreceptor subsensitivity in the VTA and postsynaptic D1 receptor supersensitivity in the NAc during repeated amphetamine treatment, (2) these functional changes therefore appear to be closely associated with the development of behavioral sensitization, and (3) a dissociation can be demonstrated between the intensity of amphetamine-stimulated behavioral responses and amphetamine-stimulated DA release in the NAc.