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 noncompet itive NMDA receptor antagonist dizocilpine maleate (MK-801) on basal a nd d-amphetamine (AMPH)-induced release of dopamine (DA) in the striat um 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. Th ese data suggest that endogenous NMDA receptor activation exerts a ton ic inhibitory influence upon striatal DA efflux. Systemic administrati on of AMPH (2.0 mg/kg, IP) produced an 18-fold increase in extracellul ar 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-i nduced DA release in striatum. Intrastriatal application, via the micr odialysis probe, of 10 mu M AMPH increased striatal DA efflux by 19-fo ld, but this local effect of AMPH was not altered by the MK-801 pretre atment, Thus, MK-801 increased DA efflux in response to systemic but n ot local AMPH, suggesting that a mechanism requiring the involvement o f basal ganglia circuitry underlies this effect. It is hypothesized th at NMDA receptor blockade indirectly activates the nigrostriatal DA sy stem by opposing activation of inhibitory striatonigral GABAergic proj ection neurons.