Alterations in preproenkephalin and adenosine‐2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with l‐DOPA

Abstract

Chronic treatment with L-DOPA induces dyskinesia in patients with Parkinson's disease (PD) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated monkeys, but is not thought to do so in normal humans or primates. However, we have shown that chronic oral high dose L-DOPA administration, with the peripheral decarboxylase inhibitor, carbidopa and with or without the peripherally acting catechol-O-methyl transferase (COMT) inhibitor, entacapone, to normal macaque monkeys for 13 weeks induced dyskinesia in a proportion of animals. In the present study, in situ hybridization histochemistry was used to investigate the effect of chronic L-DOPA administration on the activity of the direct and indirect striatal output pathways by measuring striatal preprotachykinin (PPT), preproenkephalin-A (PPE-A) and adenosine-2a (A2a) receptor gene expression in these monkeys. Overall there was no significant difference in striatal PPT, PPE-A and A2a receptor mRNA levels between normal animals and all L-DOPA (plus carbidopa and/or entacapone)-treated animals irrespective of whether or not dyskinesia occurred. However, when the level of PPE-A and A2a receptor mRNA was analysed in eight monkeys displaying marked dyskinesias as a result of L-DOPA (plus carbidopa with or without entacapone) treatment, there was a significant increase in PPE-A and A2a receptor mRNA message levels in the striatum compared with animals receiving identical treatment, but displaying few or no involuntary movements, and compared with normal controls. There was no difference in striatal PPT mRNA levels in monkeys exhibiting severe dyskinesia compared with those showing little or no dyskinesia after L-DOPA treatment or to normal controls. These results suggest that prolonged L-DOPA treatment alone has no consistent effect on either the direct or indirect pathways, as judged by striatal PPT, PPE-A or A2a receptor mRNA levels in normal monkeys. However, in monkeys exhibiting marked dyskinesia resulting from chronic L-DOPA treatment, abnormal activity is detected in the indirect striato-pallidal output pathway, as judged by striatal PPE-A and A2a receptor mRNA levels, indicating an imbalance between the direct and indirect striatal pathway which may explain the emergence of dyskinesia in these animals.

Pathophysiology of Drug-Induced Dyskinesias

“…It has been shown that neuropeptide mRNA levels of striatal preproenkephalin (PPE) and preprodynorphin (PPD) are increased in dyskinetic MPTP-lesioned monkeys compared to control MPTP-lesioned monkeys, similar to previous reports in the 6-OHDA lesioned parkinsonian rat (Gerfen et al, 1990;Zeng et al, 2000;Morissette et al, 2006;Guan et al, 2007;Tamim et al, 2010). Using opioid receptor-stimulated G-protein activation techniques, Chen and colleagues demonstrated that µ-opioid receptor-mediated G-protein activation is increased in the brain, specifically the cortex and basal ganglia in dyskinetic monkeys treated with LD.…”

“…LD treatment (Zeng et al, 2000). Recently, it had been shown that genetic knock-out of forebrain A2A receptors in mice can attenuate dyskinesias after LD treatment (Xiao et al, 2006).…”

A Crucial Role for Forebrain Adenosine A2A Receptors in Amphetamine Sensitization

“…In addition, the interaction among A 2A and mGluR5 metabotropic glutamate receptors in the basal ganglia could also modulate psychostimulant-induced sensitization (Chiamulera et al, 2001). Changes in the expression of presumably postsynaptic A 2A Rs after repeated dopaminergic exposures might also play a functional role in the nucleus accumbens or dorsal striatum (Zeng et al, 2000;Calon et al, 2004;Tomiyama et al, 2004). Potential downstream postsynaptic mediators of sensitization that are also known to be regulated by the A 2A R include cytoplasmic signal transducers (eg dopamineand cAMP-regulated phosphoprotein of 32 kDa or DARPP-32) and nuclear transcriptional targets (eg DFosB, enkephalin, and dynorphin gene expression in striatal neurons; Fienberg et al, 1998;Canals et al, 2003;Lundblad et al, 2003;Hakansson et al, 2004).…”

Forebrain Adenosine A2AReceptors Contribute to l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice

“…However, with prolonged use of L-DOPA (over years), patients often develop involuntary movements called L-DOPAinduced dyskinesia (LID) (including chorea, athetosis, ballism, and dystonia), which can be disruptive and for some disabling (Chase, 1998;Obeso et al, 2000). Recently, adenosine A 2A receptors have been directly linked to L-DOPA-induced dyskinesia in humans and nonhuman primates (Zeng et al, 2000;Calon et al, 2004) and to models of LID in rodents (Fredduzzi et al, 2002;Tomiyama et al, 2004). CNS A 2A receptors are predominantly expressed in the basal ganglia, particularly in the striatum (Schiffmann et al, 1991).…”