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.