Repeated Administration Of L-DOPA Research Articles

Repeated administration of high dose levodopa enhances hydroxyl radical production in the rat striatum denervated with 6-hydroxydopamine

We examined whether levodopa ( l-DOPA) might increase production of hydroxyl radicals in intact and dopamine-denervated rat striatum. Salicylate trapping combined with in vivo microdialysis provided measurements of 2,3-dihydroxybenzoic acid (2,3-DHBA) as a marker of hydroxyl radical production. Acute administration of high-dose l-DOPA (200, 500 mg/kg, i.p.) did not alter 2,3-DHBA levels in intact striatum or in striatum denervated with 6-hydroxydopamine. On the other hand, l-DOPA administration (200 mg/kg, i.p.) transiently increased 2,3-DHBA in dopamine-denervated striatum of rats after repeated administration of l-DOPA (200 mg/kg, i.p., once daily for 16 days). The results indicated that repeated administration of high dose l-DOPA increased production of hydroxyl radicals in dopamine-denervated striatum.

Dopamine-Deficient Mice Are Hypersensitive to Dopamine Receptor Agonists

Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons.

L-DOPA does not enhance hydroxyl radical formation in the nigrostriatal dopamine system of rats with a unilateral 6-hydroxydopamine lesion.

The debate about the toxicity of L-DOPA to dopaminergic neurons has not been resolved. Even though enzymatic and nonenzymatic metabolism of L-DOPA can produce hydrogen peroxide and oxygen free radicals, there has been controversy as to whether L-DOPA generates an oxidant stress in vivo. This study determined whether acute or repeated administration of L-DOPA caused in vivo production of hydroxyl radicals in striatum and other brain regions in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal projections. Salicylate trapping combined with in vivo microdialysis provided measurements of extracellular 2,3-dihydroxybenzoic acid (2,3-DHBA) in striatum following L-DOPA administration systemically (100 mg/kg, i.p.) or by intrastriatal perfusion (1 mM, via the microdialysis probe). Tissue concentrations of 2,3-DHBA and salicylate were also measured in striatum, ventral midbrain, and cerebellum following repeated administration of L-DOPA (50 mg/kg, i.p., once daily for 16 days). In each instance, treatment with L-DOPA did not increase 2,3-DHBA concentrations, regardless of the nigrostriatal dopamine system's integrity. When added to the microdialysis perfusion medium, L-DOPA resulted in a significant decrease in the striatal extracellular concentration of 2,3-DHBA. These results suggest that administration of L-DOPA, even at high doses, does not induce hydroxyl radical formation in vivo and under some conditions may actually diminish hydroxyl radical activity. Furthermore, prior damage to the nigrostriatal dopamine system does not appear to predispose surviving dopaminergic neurons to increased hydroxyl radical formation following L-DOPA administration. Unlike L-DOPA, systemic administration of methamphetamine (10 mg/kg, s.c.) produced a significant increase in the concentration of 2,3-DHBA in striatal dialysate, suggesting that increased formation of hydroxyl radicals may contribute to methamphetamine neurotoxicity.

Effect of Repeated[formula omitted]-DOPA, Bromocriptine, or Lisuride Administration on Preproenkephalin-A and Preproenkephalin-B mRNA Levels in the Striatum of the 6-Hydroxydopamine-Lesioned Rat

Abnormal involuntary movements, or dyskinesias, plague current symptomatic approaches to the treatment of Parkinson's disease. The neural mechanisms underlying the generation of dyskinesia following repeatedl-3,4-dihydroxyphenylalanine (l-DOPA) or dopamine agonist administration in Parkinson's disease remain unknown. However,de novoadministration of bromocriptine or lisuride to either l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates or patients can alleviate parkinsonian symptoms without the development of dyskinesia. In this study, we have investigated behavioral responses and alterations in the expression of opioid neuropeptide precursors preproenkephalin-A (PPE-A, encoding methionine- and leucine-enkephalin) and preproenkephalin-B (PPE-B), the precursor encoding dynorphins (dynorphin A1–17and B1–13, leucine-enkephalin, and α-neoendorphin) in striatal output pathways of the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. Expression was assessed following repeatedl-DOPA, bromocriptine, or lisuride administration. Given the functional organization of basal ganglia circuitry into anatomically discrete parallel circuits, we investigated alterations in peptide expression with reference to the detailed topography of the striatum. Following repeatedl-DOPA administration (6.5 mg/kg, b.d., 21 days) in the 6-OHDA-lesioned rat a rotational response was observed. This became markedly enhanced with repeated treatment. We have previously characterized the pharmacology of this enhanced response and have suggested that it is a useful model for the elucidation of the cellular and molecular mechanisms underlyingl-DOPA- and dopamine agonist-induced dyskinesia. In contrast tol-DOPA,de novoadministration of bromocriptine (1 or 5 mg/kg, b.d., 21 days) or lisuride (0.01 or 0.1 mg/kg, b.d., 21 days) did not lead to an enhanced behavioral response. In vehicle-treated, 6-OHDA-lesioned animals, PPE-A expression was elevated rostrally and dorsally, while PPE-B expression was reduced in the striatum at all rostrocaudal levels. Repeatedl-DOPA administration was accompanied by elevations in striatal PPE-B mRNA levels and a further elevation, above lesion-induced levels, in PPE-A expression. This further elevation was restricted to the dorsolateral striatum. However, following repeated bromocriptine or lisuride administration no increase in PPE-B expression was observed and the lesion-induced increase in PPE-A expression was normalized to prelesion levels. Increased PPE-A and PPE-B levels may, through decreasing GABA and glutamate release, respectively, in output nuclei of the basal ganglia, play a role in the development ofl-DOPA- and dopamine-agonist induced dyskinesia in Parkinson's disease. These studies suggest that anti-parkinsonian treatments which are not associated with an elevation in PPE-B and/or normalize elevated PPE-A precursor expression, such as NMDA-receptor antagonists or long-acting dopamine D2 receptor agonists, e.g., cabergoline or ropinirole, may reduce dyskinesia in Parkinson's disease.

3- O-Methyl-DOPA is not involved in the development of behavioral supersensitivity after repeated l-DOPA administration in 6-OHDA lesioned rats

The underlying cause of long-term complications of l-DOPA therapy in Parkinson's disease is largely unknown. Recently, centrally and peripherally acting catechol- O-methyltransferase (COMT) inhibitors became available. These drugs are capable of inhibiting the generation of 3- O-methyl-DOPA (3-OMD), a major metabolite of l-DOPA developing considerable plasma levels during l-DOPA therapy. The use of these drugs offers the opportunity to study the involvement of 3-OMD in the development of behavioral supersensitivity following repeated doses of l-DOPA over 11 days in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic system. Repeated daily administration of l-DOPA/Carbidopa produced continuous increase of contralateral rotations to both l-DOPA/Carbidopa and to challenge doses of apomorphine. This increase was not influenced by peripherally and peripherally plus centrally acting COMT inhibitors, OR-462 and OR-486, respectively, administered simultaneously with l-DOPA/Carbidopa. Both COMT inibitors suppressed the l-DOPA induced increase of 3-OMD plasma levels, OR-486 being more effective than OR-462. This indicates that 3-OMD is not involved in the development of behavioral supersensitivity following repeated l-DOPA treatment in rats with unilateral 6-OHDA lesion of the nigrostriatal system.

Repeated l-DOPA administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat

The “wearing-off” phenomenon is a clinically recognized adverse effect of long-term l-DOPA therapy in Parkinson's disease. Several causes of this phenomenon have been proposed, but no direct evidence has yet been obtained. The present study was therefore conducted to investigate the effects of long-term l-DOPA administration on the dopamine system. We examined in rats the time course of the levels of l-DOPA and its metabolites in the serum and striatum, the activities of tyrosine hydroxylase and cathechol O-methyltransferase, and the D1 and D2 dopamine receptor bindings in the striatum until 12 h after the final dose on the 28th day of repeated oral l-DOPA administration, and compared the results with those after a single l-DOPA administration. The results revealed that long-term l-DOPA administration induced (1) acceleration of DOPA absorption at the gut and the blood-brain barrier, (2) reduction of dopamine retention in the striatum, and (3) loss of “supersensitive response” of dopamine receptors. “Supersensitive response” induced by single l-DOPA administration was preceded by the increase of D1 messenger RNA. We suggest that these changes after long-term l-DOPA administration are causes of the “wearing-off” phenomenon in Parkinson's disease.

Fetal dopamine neuron transplants prevent behavioral supersensitivity induced by repeated administration of l-DOPA in the rat

We have studied in adult rats bearing a unilateral nigral lesion the effect of nigral grafts into the striatum on behavioral supersensitivity induced by chronic treatment of l-DOPA (100 mg/kg i.p.) plus benserazide (50 mg/kg i.p.). Repeated administration of l-DOPA increases contraversive circling. In rats without graft the contraversive circling was significantly increased after 8 and 14 daily injections of l-DOPA. On the other hand, the animals with transplants showed no such increase. Behavioral supersensitivity induced by repeated treatment of l-DOPA is often correlated with dyskinesia observed in the Parkinsonian patients. This suggests that the graft might be able to prevent this secondary effect.

Behavioural and biochemical alterations in the function of dopamine receptors following repeated administration of l-DOPA to rats

Rats received l-DOPA (40 or 200 mg/kg, i.p.) for 14 days, followed by a 3 day withdrawal period. Spontaneous locomotor activity was not altered by repeated administration of l-DOPA. Rats treated with l-DOPA (200 mg/kg) showed identical locomotor hypoactivity in response to small doses of apomorphine when compared to saline-treated control animals. However, hyperactivity induced by large doses of apomorphine was reduced by prior treatment with l-DOPA (200 mg/kg). The smaller dose of l-DOPA (40 mg/kg) did not alter the locomotion induced by apomorphine. Stereotyped behaviour induced by apomorphine was enhanced by prior treatment with both 40 and 200 mg/kg of l-DOPA. The treatment regimes with l-DOPA had no effect on the concentrations of apomorphine in the striatum. Administration of l-DOPA (40 or 200 mg/kg) followed by withdrawal for 3 days, had no effect on the concentrations of dopamine, homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. The B max and K D for the binding of [ 3H]spiperone. [ 3 H]N,n- propylnorapomorphme (NPA) and [ 3H]piflutixol in the striatum was not altered by drug treatment. Similarly, the formation of dopaminestimulated cyclic AMP in homogenates of striatum was unaltered by repeated administration of l-DOPA. Repeated administration of l-DOPA for 14 days in the rat appears to result in altered behaviour mediated by dopamine in the absence of any apparent change in the function of dopamine receptors in the striatum.

Changes in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in human cerebrospinal fluid after L-dopa and deprenyl administration.

The dopamine (DA) and DOPAC levels were measured in cerebrospinal fluid (CSF) using a radioenzymatic method. The influence of a specific monoamine oxidase B inhibitor (deprenyl) on changes in DA and DOPAC levels was studied in untreated patients or after L-dopa administration. A single dose of deprenyl alone did not change the CSF DA and DOPAC levels, a three days' treatment, however, decreased both the DOPAC and DA concentrations. The acute administration of L-dopa caused an increase in CSF DA and DOPAC levels. The changes were smaller following repeated treatment. Deprenyl diminished the increase in DOPAC level after repeated L-dopa administration.