Continuous and intermittent levodopa differentially affect basal ganglia function

Abstract

The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.

The effect of reserpine treatment in vivo upon L-dopa and amphetamine evoked dopamine and DOPAC efflux in vitro from the corpus striatum of male rats

“…It is evident that a thorough understanding of this issue will require additional data regarding the effects of L-DOPA under conditions of impaired striatal function. It has been suggested that differences may exist in response to L-DOPA as a function of mode of L-DOPA infusion (Bennett etal., 1989;Chase et al, 1989;Gauthier and Amyot, 1992;Mouradian et al, 1990); differences which cannot be necessarily attributable to the dose of L-DOPA Juncos et al, 1989). Therefore, in the present report we included a comparison between a brief 10-minute versus continuous 60-minute infusion of L-DOPA.…”

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…Levodopa induces shortening of the motor response (wearing-off) in parkinsonian rodents when it is given intermittently but not when it is administered continuously. 295 Short-acting dopaminergic agents such as levodopa are more prone to induce dyskinesia in MPTP-treated monkeys than are long-acting dopaminergic agents such as bromocriptine and ropinirole. 296,297 Of particular importance is the observation that the same short-acting dopaminergic agent that induces dyskinesia when administered in a pulsatile manner does not induce dyskinesia when administered continuously.…”

The effect of dopamine D1 receptor stimulation on the up‐regulation of histamine H3‐receptors following destruction of the ascending dopaminergic neurones

“…The up-regulation in striatal D2 dopamine receptor density observed in 6-OHDA lesioned rats is reduced, or further enhanced following chronic intermittent levodopa administration (Gnaalingham & Robertson, 1994;Rouillard et al, 1987). Chronic intermittent levodopa treatment has also been shown to reverse the DI-receptor upregulation observed in the denervated striatum (Juncos et al, 1989). However, in some studies, [3H]-SCH23390 binding in the striatum and nucleus accumbens was unaffected by levodopa treatments (Rioux et al, 1993).…”