L-Dopa is more effective than direct dopamine (DA) agonists in relieving the motor deficits in Parkinson's disease. Using in vivo recording, we compared the effect of L-dopa and the direct DA agonist apomorphine on DA neurons in rat substantia nigra (SN). L-Dopa (50-100 mg/kg, i.v.) decreased the firing rate as well as the variability and slow oscillation (SO) of firing. All effects were blocked by raclopride and mimicked by quinpirole, suggesting that they are mediated through D2-like receptors. Autoreceptor-selective doses of apomorphine (5-20µg/kg, i.v.) also inhibited all three parameters. The magnitude of the inhibition, however, was significantly greater than that induced by L-dopa. Neither L-dopa nor apomorphine had a consistent effect on SN local field potentials (LFPs). The GABA agonist muscimol, known to preferentially inhibit SN non-DA neurons, consistently inhibited the SO in both DA cell firing and LFPs. These results suggest that SN LFPs reflect mainly the synaptic potentials in non-DA neurons, and L-dopa and apomorphine, unlike muscimol, affect DA neurons primarily through DA autoreceptors. DA autoreceptor activation is known to hyperpolarize DA cells by increasing the membrane conductance to K+. This increase in membrane conductance would shunt synaptic input to DA neurons, thereby decreasing the variability and SO in DA cell firing. The low potency of L-dopa to inhibit DA cell firing and to reduce their responses to synaptic input may partially account for its superior therapeutic efficacy in Parkinson's disease compared to apomorphine and other direct DA agonists.
- Received December 6, 2010.
- Revision received January 25, 2011.
- Accepted February 16, 2011.
- The American Society for Pharmacology and Experimental Therapeutics