Effects of MK-801 on spontaneous and amphetamine-stimulated dopamine release in striatum measured with in vivo microdialysis in awake rats

In vivo microdialysis was used to examine the effects of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801) on basal and d-amphetamine (AMPH)-induced release of dopamine (DA) in the striatum of freely moving rats. MK-801 [0.2 or 0.5 mg/kg, intraperitoneally (IP)] significantly increased spontaneous DA release in the striatum, whereas treatment with vehicle elicited no change in this variable. These data suggest that endogenous NMDA receptor activation exerts a tonic inhibitory influence upon striatal DA efflux. Systemic administration of AMPH (2.0 mg/kg, IP) produced an 18-fold increase in extracellular DA; this effect was potentiated to 33-fold by pretreatment with 0.5 mg/kg MK-801. Pretreatment with 0.2 mg/kg MK-801 did not alter AMPH-induced DA release in striatum. Intrastriatal application, via the microdialysis probe, of 10 μM AMPH increased striatal DA efflux by 19-fold, but this local effect of AMPH was not altered by the MK-801 pretreatment. Thus, MK-801 increased DA efflux in response to systemic but not local AMPH, suggesting that a mechanism requiring the involvement of basal ganglia circuitry underlies this effect. It is hypothesized that NMDA receptor blockade indirectly activates the nigrostriatal DA system by opposing activation of inhibitory striatonigral GABAergic projection neurons.