Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia

Abstract

Treatment of Parkinson’s disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression are altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD / dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD / dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets.

Altered Recruitment of Motor Cortex Neuronal Activity During the Grasping Phase of Skilled Reaching in a Chronic Rat Model of Unilateral Parkinsonism

“…Loss of dopaminergic projections can impinge on motor cortex function directly and indirectly. Dopamine released directly in cerebral cortex has an important role in modulating neurotransmission (Lewis and O'Donnell, 2000;Seamans et al, 2001a,b), and loss of this input occurs in Parkinson's disease patients (Gaspar et al, 1991) and in rats with dopamine lesions (Debeir et al, 2005;Lindenbach et al, 2015). Indirectly, loss of the large dopaminergic projections to the basal ganglia leads to disordered processing through the basal ganglia-thalamus-cortex loop, which is an important determinant of motor cortex neural activity (Albin et al, 1989;Boraud et al, 2002;Wichmann and Dostrovsky, 2011;Galvan et al, 2015).…”

D‐512, a novel dopamine D2/3 receptor agonist, demonstrates greater anti‐Parkinsonian efficacy than ropinirole in Parkinsonian rats

“…The test was performed twice in the week prior to drug treatment: first to habituate the rats to the test and a second time to assign rats to equivalently impaired treatment groups. In order to be considered sufficiently Parkinsonian, the total steps with the lesioned forelimb needed to be <60% of the steps taken with the intact forelimb (Lindenbach et al , , ). Among the 61 rats examined with the stepping test, 51 had received 6‐OHDA infusions and 50 of 51 met this behavioural criterion (yielding n = 60 usable rats in experiment 2, or n = 10 per group).…”

“…As a marker of dopaminergic neuron viability, sections were analysed for immunoreactivity of tyrosine hydroxylase (TH), the rate‐limiting enzyme in dopamine synthesis. Three coronal slices covering the anterior–posterior axis of the dorsal striatum were selected (at +1.60, +0.20 and −0.80 mm from bregma), stained and quantified using a previously published method (Lindenbach et al , ). Briefly, photomicrographs were taken of the striata, converted into 8 bit grayscale, and optical density was analysed using Image J software (National Institutes of Health, Bethesda, MD, USA).…”

Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion

“…Studies in numerous brain regions and cell types have established that D1 receptor activation is coupled to increased phosphorylation of a number of targets, including ERK1,2 and CREB (Gerfen et al, 2002; Voulalas et al, 2005; Beaulieu and Gainetdinov 2011; Xue et al, 2015), which can occur either directly or indirectly via D1 receptor-mediated activation of PKA (Rangel-Barajas, 2015). Our first approach was to determine whether in vivo exposure to the D1/5 agonist SKF 81297 (Gainetdinov et al, 2003; Lapointe and Guertin 2008; Ott et al, 2014; Lindenbach et al, 2015) would cause an increase in ERK or CREB phosphorylation in the PAG. This methodology has been employed in many studies examining the effect of various agonists and antagonists on cell function in discrete brain regions (Gangarossa and Valient, 2012; Brehm et al, 2015).…”