Abstract
Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous findings show that L-DOPA treatment induces extracellular signal-regulated kinase (ERK1/2), a MAP-kinase protein. γ-aminobutyric acid (GABA) is intimately involved in basal ganglia function. Our previous study using a unilaterally lesioned rat model of PD indicated that elevating GABA levels by GABA transaminase inhibitor, aminooxyacetic acid significantly attenuated L-DOPA-induced ERK phosphorylation in the striatum and substantia nigra (SN). The aim of the present study was to assess the role of GABA-A and GABA-B receptor by using a selective agonists, muscimol and baclofen respectively, on L-DOPA-induced ERK phosphorylation in the striatum and SN. Unilaterally 6-OHDA-lesioned rats were prescreened by apomorphine induced rotation test for the extent of DA loss. Lesioned rats were treated with L-DOPA alone or after muscimol or baclofen pretreatment. Appropriate control groups were used. Phospho-ERK levels, tyrosine hydroxylase (to ascertain DA loss) and substance P (an indirect marker for DA loss) levels were assessed by immunohistochemistry using coronal slices at the level of striatum and SN. L-DOPA administration induced a robust increase (>300%) in phospho-ERK1/2 levels in the striatum and SN. Muscimol as well as baclofen pretreatment attenuated the L-DOPA-induced increase in phospho-ERK1/2 levels by >60% in the striatum and SN. Muscimol and baclofen pretreatment also greatly reduced the number of L-DOPA induced phospho-ERK1/2 stained cells in the striatum as well as the contralateral rotational behavior. The present data taken together with our previous study indicate that the L-DOPA induced increase in ERK1/2 is attenuated by GABA via a GABA-A and GABA-B receptor linked mechanism. The study provides further insight into a dopamine-GABA-ERK interaction in the therapeutic and/or side effects of L-DOPA in the basal ganglia.
Highlights
Dopaminergic neurons in the nigrostriatal pathway of the basal ganglia degenerate in Parkinson’s disease (PD)
In animals pretreated with muscimol or baclofen followed by L-DOPA, averages of only 0.9 ± 0.6 and 0.9 ± 0.5 rotations, respectively, were observed, indicating that muscimol or baclofen pretreatment greatly attenuated L-DOPA-induced rotations (Figure 1)
We reported a new finding that pretreatment with GABA-A agonist, muscimol, or GABA-B agonist, baclofen attenuated the L-DOPA-induced rotational response as well as increase in phospho-ERK1/2 levels both in the striatum and substantia nigra (SN)
Summary
Dopaminergic neurons in the nigrostriatal pathway of the basal ganglia degenerate in Parkinson’s disease (PD). An imbalance in DA function leads to motor complications associated with the disease [1,2,3]. D1 receptors receive diminishing amounts of DA compensation by becoming supersensitive to the neurotransmitter. It is well established that L-DOPA and other DA agonists ameliorate certain motor deficits [4,5,6]. Tion of L-DOPA, often leads to side effects. These include dyskinesias, characterized by loss of voluntary motor control as well as the emergence of involuntary motor control [7,8]
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