N-METHYL-D-ASPARTATE RECEPTOR BLOCKADE ATTENUATES D1 DOPAMINE-RECEPTOR MODULATION OF NEURONAL-ACTIVITY IN RAT SUBSTANTIA-NIGRA

It has been proposed that dopamine and glutamate affect basal ganglia output, in part, through interactions between D1 receptors and NMDA re ceptors. The present study examined whether N-methyl-D-aspartate (NMDA ) receptor antagonists affect the neurophysiological responses of subs tantia nigra pars compacta (SNpc; dopaminergic) and pars reticulate (S Npr; non-dopaminergic) neurons to a systemically administered D1 dopam ine agonist in two animals models of Parkinson's disease, reserpine tr eatment and nigrostriatal lesion. Previous studies using extracellular single unit recording techniques have shown that the D1 dopamine agon ist SKF 38393 (10 mg/kg) exerts different effects on the firing rates of SNpr neurons after these two dopamine-depleting treatments, suggest ing the involvement of multiple mechanisms. SKF 38393 consistently inc reased the firing rates of SNpr neurons in rats treated subchronically with reserpine, and markedly decreased SNpr firing rates in rats with nigrostriatal damage, Pretreatment with the non-competitive NMDA anta gonist MK-801 (0.15 mg/kg i.v.) blocked, and the competitive NMDA anta gonist (+/-)CPP (30 mg/kg i.p.) attenuated, the rate effects of SKF 38 393 in both dopamine-depleted preparations. SKF 38393 consistently inh ibited the firing rate of SNpc dopamine neurons after acute reserpine treatment (10 mg/kg, 4-7 hours), an effect specifically mediated by D1 receptors. Pretreatment with MK-801 (0.1 mg/kg i.v.) or the competiti ve NMDA antagonist (+)-HW-966 (30 mg/kg i.v.) also effectively attenua ted SKF 38393's inhibitory effect on SNpc dopamine neurons. Therefore, NMDA receptor blockade markedly reduces the ability of D1 receptor st imulation to modulate firing rates of both dapaminergic and non-dopami nergic cells in the substantia nigra. Although multiple mechanisms app ear to underlie D1-mediated effects on substantia nigra firing rates i n reserpine and 6-OHDA-treated rats, these results demonstrate a commo n dependence on glutamatergic transmission and a permissive role for N MDA receptor activation in the ability of D1 receptor stimulation to b oth enhance and reduce neuronal activity in the substantia nigra. Syna pse 30:18-29, 1998. (C) 1998 Wiley-Liss, Inc.dagger