TITLE:
Dopamine and GABA Interaction in Basal Ganglia: GABA-A or GABA-B Receptor Stimulation Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease
AUTHORS:
Sarah Lynch, Subbiah P. Sivam
KEYWORDS:
Dopamine; ERK1/2; Hemiparkinsonism; GABA; Striatum; Substantia Nigra; Muscimol; Baclofen
JOURNAL NAME:
Journal of Behavioral and Brain Science,
Vol.3 No.6,
October
31,
2013
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.