preproenkephalin and eticlopride

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

The purpose of this study was to investigate the effects of intrastriatal blockade of GABA(A) receptors on dopamine D(1)/D(2) receptor interactions in the intact rat striatum. Muscarinic receptors mediate the ability of the D(2) receptor antagonist, eticlopride, to block an increase in striatonigral neuropeptide messenger RNA stimulated by the full D(1) agonist, SKF-82958. However, because D(2) receptor antagonists activate striatopallidal neurons, it is possible that increased GABA release from local medium spiny axon collaterals also contributes to the ability of eticlopride to block the effects of SKF-82958. This hypothesis was addressed by infusing the GABA(A) receptor antagonist, bicuculline, into the dorsal striatum in rats treated with eticlopride and SKF-82958. In contrast to the actions of the muscarinic antagonist, scopolamine, bicuculline did not affect the increase in behaviors induced by SKF-82958 or the ability of eticlopride to block them. Quantitative in situ hybridization demonstrated that bicuculline did not significantly affect basal preprodynorphin messenger RNA, nor did it affect the ability of eticlopride to decrease SKF-82958-induced preprodynorphin messenger RNA. However, the level of the preprodynorphin hybridization signal in bicuculline plus SKF-82958-treated rats was significantly lower than in saline plus SKF-82958-treated rats. In contrast, bicuculline, eticlopride or SKF-82958 by themselves increased basal preproenkephalin messenger RNA. However, there was no significant interaction among bicuculline, eticlopride and SKF-82958 on preproenkephalin messenger RNA levels.These data indicate that blockade of striatal GABA(A) receptors has only a subtle effect on acute dopamine agonist-induced changes in gene expression. These results are discussed in the context of local intrastriatal interactions.

Topics: Animals; Behavior, Animal; Benzazepines; Bicuculline; Corpus Striatum; Dopamine Agonists; Dopamine Antagonists; Drug Administration Schedule; Dynorphins; Enkephalins; GABA Antagonists; GABA-A Receptor Antagonists; Gene Expression; In Situ Hybridization; Injections, Subcutaneous; Male; Microinjections; Protein Precursors; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, GABA-A; RNA, Messenger; Salicylamides

The present study examines dopaminergic regulation of neuropeptide gene expression within a relatively poorly characterized population of cells, the preproenkephalin (PPE) mRNA containing neurons of the globus pallidus (GP). Rats that received 6-hydroxydopamine (6-OHDA) lesions or repeated D1 or D2 antagonist administration were compared to control animals. One month after 6-OHDA lesions, PPE mRNA was elevated in the GP ipsilateral to the lesion, with a smaller elevation also being observed in the contralateral GP. Repeated administration of eticlopride, but not SCH 23390, also resulted in elevated PPE mRNA expression in the GP. These data reveal a novel effect of decreased dopamine transmission on the GP, and draw attention to this subpopulation of pallidal neurons.

Topics: Animals; Benzazepines; Dopamine; Dopamine Antagonists; Enkephalins; Gene Expression; Globus Pallidus; Male; Neurons; Oxidopamine; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Salicylamides; Substantia Nigra; Sulfur Radioisotopes; Sympatholytics

GABAergic modulation of enkephalin, substance P and glutamic acid decarboxylase (GAD67) gene expression and the alterations induced by dopamine receptor blockade were studied in the rat striatum. Following subchronic treatment with the GABA-A agonist muscimol, the GABA-B agonist baclofen or the GABA transaminase inhibitor gamma-vinyl GABA there were no significant changes in striatal peptide and GAD67 gene expression. Following repeated administration of the D-2 antagonists, eticlopride and haloperidol, there was an increase in enkephalin and GAD67 mRNA levels and parallel decrease in that of substance P. These were unaffected by co-administration of gamma-vinyl GABA. The D-1 antagonist, SCH 23390 administered alone or together with gamma-vinyl GABA did not alter peptide or GAD67 mRNA levels. It seems that pharmacological stimulation of GABA receptors has little effect on enkephalin, substance P or GAD67 mRNA expression in striatal output neurons.

Topics: Animals; Baclofen; Benzazepines; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Enkephalins; gamma-Aminobutyric Acid; Gene Expression Regulation; Glutamate Decarboxylase; Haloperidol; In Situ Hybridization; Male; Muscimol; Protein Precursors; Rats; Rats, Wistar; Receptors, GABA; RNA, Messenger; Salicylamides; Substance P; Tachykinins; Vigabatrin

The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Blotting, Northern; Corpus Striatum; Desipramine; Dopamine; Enkephalins; Ergolines; Gene Expression Regulation; Kinetics; Male; Nucleic Acid Hybridization; Oligonucleotide Probes; Oxidopamine; Protein Precursors; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Reference Values; RNA, Messenger; Salicylamides; Stereotaxic Techniques

The effect of administration of the muscarinic antagonist scopolamine on the increase in striatal preproenkephalin (PPE) mRNA following a 6-hydroxydopamine (6-OHDA) lesion or chronic D2 dopamine (DA) antagonist treatment was examined by dot-blot hybridization. Administration of scopolamine dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. Administration of the D2 DA antagonist eticlopride to naive rats increased striatal PPE mRNA in a dose- and time-dependent fashion. Chronic coadministration of scopolamine attenuated the eticlopride-induced increase in striatal PPE mRNA. Chronic administration of scopolamine alone did not alter striatal PPE mRNA levels. In contrast, chronic administration of eticlopride, scopolamine or the two combined decreased striatal preprotachykinin (PPT) mRNA to the same extent, suggesting that there was no direct interaction between D2 dopaminergic and cholinergic mechanisms in the regulation of striatal PPT mRNA. These data indicate that DA differentially regulates striatal PPE and PPT mRNA and suggest that dopaminergic regulation of striatal PPE mRNA is mediated in part through D2 DA effects on striatal cholinergic neurons.

Topics: Acetylcholine; Animals; Blotting, Northern; Corpus Striatum; Dose-Response Relationship, Drug; Enkephalins; Interneurons; Kinetics; Male; Models, Neurological; Nucleic Acid Hybridization; Oligonucleotide Probes; Oxidopamine; Phosphorus Radioisotopes; Protein Precursors; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; RNA, Messenger; Salicylamides; Scopolamine