Dopamine depletion and subsequent treatment with l‐DOPA, but not the long‐lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum

Abstract

Dysregulation of signaling pathways is believed to contribute to Parkinson's disease pathology and L-DOPA-induced motor complications. Long-lived dopamine (DA) agonists are less likely to cause motor complications by virtue of continuous stimulation of DA receptors. In this study, we compared the effects of the unilateral 6-hydroxydopamine lesion and subsequent treatment with L-DOPA and DA agonist pergolide on signaling pathways in rats. Pergolide caused less pronounced behavioral sensitization than L-DOPA (25 mg/kg, i.p., 10 days), particularly at lower dose (0.5 and 0.25 mg/kg, i.p.). Pergolide, but not L-DOPA, reversed lesion-induced up-regulation of preproenkephalin and did not up-regulate preprodynorphine or DA D3 receptor in the lesioned hemisphere. Pergolide was as effective as L-DOPA in reversing the lesion-induced elevation of ERK2 phosphorylation in response to acute apomorphine administration (0.05 mg/kg, s.c.

Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease

“…Moreover, impairments of dopamine system as well as Akt/GSK-3 signaling are detectable in different dopamine attributed neurological and neuropsychiatric disorders such as schizophrenia and bi-polar disorders [116,117]. These observations imply that the Akt/GSK-3 cascade is one the most important signaling pathways that is affected by dopamine impairment and/or dopamine based therapies [118].…”

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development

“…This dose of L-dopa is the same as typically used in the behavioral sensitization paradigm [49][50][51][52][53][54] and this type of sensitized context was associated with LID in PD patients 6 . Amantadine or its vehicle was administered at 20, 30 and 40 mg/kg, i.p., 40 min before L-dopa/benserazide administration 16,55,56 .…”

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…46,47 Administration of amphetamine, methamphetamine or the nonselective DA receptor agonist apomorphine to normal mice also results in an inhibition of Akt activity and concomitant activation of GSK3, whereas striatal DA depletion has the opposite effect, thus firmly establishing the regulation of the Akt-GSK3 pathway by DA. 31,46,48,49 Further characterization of these signalling responses using selective D1 and D2 receptor antagonists, 46 the antipsychotic haloperidol 50,51 or mice lacking different subtypes of DA receptors have shown that Akt, GSK3α and GSK3β are regulated by D2 receptors. 52 More specifically, D2 receptors appear to be essential for the inhibition of striatal Akt by DA in mice.…”