Nanomolar L-DOPA facilitates release of dopamine via presynaptic .BETA.-adrenoceptors: Comparative studies on the actions in striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated C57 black mice, an animal model for parkinson's disease.

Abstract

ABSTRACT-Effects of L-DOPA (0.1-10,000 nM) on spontaneous release (Sp), evoked release (S) and tissue content (C) of dopamine (DA) were studied comparatively in superfused striatal slices from control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mice to obtain evidence for L-DOPA-induced facilitation of S via presynaptic 8-adrenoceptors. In control slices, isoproterenol-induced concentration-dependent increases in S were propranolol-sensitive. L-DOPA at 0.1-3 nM tended to increase the S of DA with a concomitant tendency of increases in Sp. L-DOPA at 10 -1 X 104 nM concentration-dependently increased Sp. L-DOPA at 1-10 ,u M tended to increase S and 10 ,u M increased C. In slices from MPTP-treated mice, the absolute amounts of Sp, S and C decreased by half compared to those in control slices. L-DOPA at 3 nM facilitated S without increasing Sp. This facilitation was antagonized by propranolol at 3 nM. L-DOPA at 30 nM decreased S from the peak facilitation, which contrasted with no effect in the control slices. However, 10-100 nM L-DOPA increased Sp more markedly than that in the control slices. L-DOPA at 100 nM increased S and C, which contrasted with no effect in the control slices. In conclusion, nanomolar L-DOPA facilitates the S of DA via presynaptic /9-adrenoceptors at concentrations lower than those required to induce conversion to DA even in striatal slices from the MPTP-treated mice model for Parkinson's disease. In model slices, susceptibilities of the Sp, S and C of DA to exogenous L-DOPA could be determined by a balance between degeneration-induced reduction in DOPAdecarboxylase activities and "up-regulation" on the activities of surviving DA neurons.

Behavioral and Cellular Modulation of l-DOPA-Induced Dyskinesia by β-Adrenoceptor Blockade in the 6-Hydroxydopamine-Lesioned Rat

“…Ample evidence exists showing that ␤AR activity modulates DA release in the striatum, suggesting a presynaptic mechanism for (Ϯ)propranolol in LID (Reisine et al, 1982;Goshima et al, 1991). Recent research has suggested an additional postsynaptic mechanism; antagonism of ␤ 1 AR was shown to reduce downstream phosphorylation of dopamine-and cyclic-AMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 (Hara et al, 2010), which is clinically important because high levels of pThr 34 -DARPP-32 are implicated in the expression of LID (Santini et al, 2007;Bateup et al, 2010).…”

“…The striatum was hypothesized to be the anatomical locus of the therapeutic action of (Ϯ)propranolol, given the evidence that LID is caused by aberrant striatal DA signaling Cenci, 2007) and that (Ϯ)propranolol directly effects striatal DA signaling (Reisine et al, 1982;Goshima et al, 1991). Microinjection of (Ϯ)propranolol (1 or 10 g) into the dorsal striatum reduced ALO AIMs when L-DOPA was given at a therapeutic dose (4 mg/kg; Fig.…”

“…Although most of the research has focused on ␣-adrenergic compounds (Savola et al, 2003;Rommelfanger and Weinshenker, 2007;, the striatum contains a high density of ␤ARs (Rainbow et al, 1984), which are preserved in PD patients (Waeber et al, 1991). These receptors represent a unique therapeutic target for LID because ␤AR blockade prevents drug-induced facilitation of DA release in intact and DA-depleted animals, which may blunt downstream signaling abnormalities associated with LID (Reisine et al, 1982;Goshima et al, 1991). In line with these findings (Ϯ)propranolol, a nonselective-␤AR antagonist, reduces the expression of LID in humans (Carpentier et al, 1996) and in animal models of LID (Gomez-Mancilla and Bedard, 1993;Dekundy et al, 2007;.…”

The Cardiovascular Actions of DOPA Mediated by the Gene Product of ocular albinism 1

“…However, this might not reflect the nature of OA1 in native cells because the possibility of a low expression of OA1 or other factors in such cell lines cannot be excluded. Indeed, nanomolar concentrations of DOPA can induce presynaptic regulation of impulse-evoked catecholamine release from brain slices (11,42). In in vivo experiments, DOPA at doses comparable to those of glutamate induces depressor and bradycardic response in the NTS of anesthetized rats (7,12).…”

The Noradrenergic System is a Major Component in Parkinson’s Disease

“…These studies indicate that propranolol also reduces L-DOPA-induced dyskinesia (Goshima et al, 1991;Reisine et al, 1982;Carpentier et al, 1996;Dekundy et al, 2007). α 1 -AR antagonist also reduces L-DOPAinduced dyskinesia; however, this receptor subtype has not been investigated to the same degree as α 2 -and β-AR antagonists (Buck and Ferbeger, 2010).…”