Lesions of the Nigrostriatal Dopamine Projection Increase the Inhibitory Effects of D, and D, Dopamine Agonists on Caudate-Putamen Neurons and Relieve D, Receptors from the Necessity of D, Receptor Stimulation

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D, and D, dopamine (DA) receptors in the caudate putamen (CPU) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (B-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPU were reduced to 4 1.8% of control. Current-response curves revealed that the inhibitory responses of CPU neurons to microiontophoretic administration of both the selective D, receptor agonist SKF-38393 and the selective D, receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D, receptor activation is normally required for (enables) the inhibitory effects of selective D, agonists in the CPU, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor a-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPU neurons, longterm DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D, agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D, receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D, receptors from the need for D, receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPU neurons in lesioned rats. Similar findings (i.e., supersensitivity and