preproenkephalin and 6-methyl-2-(phenylethynyl)pyridine

Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs decrease L-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesias (LID); the implication of dopamine neurotransmission is not documented in this anti-LID activity. Therefore, we evaluated changes of dopamine receptors, their associated signaling proteins and neuropeptides mRNA, in normal control monkeys, in saline-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in L-DOPA-treated MPTP monkeys, without or with an adjunct treatment to reduce the development of LID: 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist. All de novo treatments were administered for 1 month and the animals were sacrificed thereafter. MPTP monkeys treated with l-DOPA + MPEP developed significantly less LID than MPTP monkeys treated with l-DOPA alone. [(3)H]SCH-23390 specific binding to D1 receptors of all MPTP monkeys was decreased as compared to controls in the basal ganglia and no difference was observed between all MPTP groups, while striatal D1 receptor mRNA levels remained unchanged. [(3)H]raclopride specific binding to striatal D2 receptors and mRNA levels of D2 receptors were increased in MPTP monkeys compared to controls; l-DOPA treatment reduced this binding in MPTP monkeys while it remained elevated with the l-DOPA + MPEP treatment. Striatal [(3)H]raclopride specific binding correlated positively with D2 receptor mRNA levels of all MPTP-lesioned monkeys. Striatal preproenkephalin/preprodynorphin mRNA levels and phosphorylated ERK1/2 and Akt/GSK3β levels increased only in L-DOPA-treated MPTP monkeys as compared to controls, saline treated-MPTP and l-DOPA + MPEP treated MPTP monkeys. Hence, reduction of development of LID with MPEP was associated with changes in D2 receptors, their associated signaling proteins and neuropeptides.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Basal Ganglia; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dynorphins; Dyskinesia, Drug-Induced; Enkephalins; Excitatory Amino Acid Antagonists; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Levodopa; Macaca fascicularis; MAP Kinase Signaling System; Parkinsonian Disorders; Protein Precursors; Proto-Oncogene Proteins c-akt; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D1; Receptors, Dopamine D2; RNA, Messenger

Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.

Topics: Aging; Animals; Anxiety; Benzamides; Benzphetamine; Central Nervous System Stimulants; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Enkephalins; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Long-Term Synaptic Depression; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Precursors; Pyrazoles; Pyridines; Receptors, Metabotropic Glutamate; Recognition, Psychology

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are positively coupled to phosphoinositide hydrolysis through G-proteins and are densely expressed in medium-sized projection neurons of striatum. Selective activation of Group I mGluRs upregulates preproenkephalin (PPE) mRNA expression in the rat dorsal striatum. This study investigated the role of one subtype of Group I receptors, mGluR5, in the regulation of PPE mRNA expression in the rat dorsal striatum using quantitative in situ hybridization. Unilateral injection of the mGluR5 selective agonist (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) into the dorsal striatum (caudoputamen) of chronically cannulated rats at doses of 50 and 200 nmol elevated basal levels of PPE mRNA in the injected dorsal striatum. The induction of PPE mRNA was evident at 1 h, remained at 3 h, and returned to normal level 6 h after CHPG injection. Pretreatment with an mGluR5 selective antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride (MPEP) at a dose of 10 mg/kg (i.p.) blocked CHPG-stimulated PPE expression. MPEP also attenuated PPE expression induced by dopamine D(2) receptor blockade with eticlopride (0.5 mg/kg, i.p.). Administration of MPEP alone had no significant effects on basal levels of PPE mRNA in the striatum. The results from the present study demonstrate that glutamatergic tone on mGluR5 possesses the ability to positively regulate PPE gene expression in striatal neurons in vivo. Moreover, activation of mGluR5 participates in the mediation of D(2) antagonist-induced PPE expression.

Topics: Animals; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Enkephalins; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Glycine; In Situ Hybridization; Male; Phenylacetates; Protein Precursors; Pyridines; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; RNA, Messenger; Salicylamides; Time Factors