dizocilpine-maleate and preproenkephalin

Intrathecal (i.t.) administration into mice of N-ethylmaleimide (NEM), a cysteine protease inhibitor, produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by NEM was inhibited by the intraperitoneal injection of morphine. We have recently reported that dynorphin A and, more potently big dynorphin, consisting of dynorphins A and B, produce the same type of nociceptive response whereas dynorphin B does not [Tan-No K, Esashi A, Nakagawasai O, Niijima F, Tadano T, Sakurada C, Sakurada T, Bakalkin G, Terenius L, Kisara K. Intrathecally administered big dynorphin, a prodynorphin-derived peptide, produces nociceptive behavior through an N-methyl-d-aspartate receptor mechanism. Brain Res 2002;952:7-14]. The NEM-induced nociceptive behavior was inhibited by pretreatment with dynorphin A- or dynorphin B-antiserum and each antiserum also reduced the nociceptive effects of i.t.-injected synthetic big dynorphin. The characteristic NEM-evoked response was not observed in prodynorphin knockout mice. Naloxone, an opioid receptor antagonist, had no effects on the NEM-induced behavior. Ifenprodil, arcaine and agmatine, antagonists at the polyamine recognition site on the N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and MK-801, an NMDA ion-channel blocker inhibited the NEM-induced effects. Ro25-6981, an antagonist of the NMDA receptor subtype containing NR2B subunit was not active. NEM completely inhibited degradation of dynorphin A by soluble and particulate fractions of mouse spinal cord. Collectively, the results demonstrate that endogenous prodynorphin-derived peptides are pronociceptive in uninjured animals, and required for the NEM-induced behavior. The NEM effects may be mediated through inhibition of the degradation of endogenous dynorphins, presumably big dynorphin that in turn activates the NMDA receptor ion-channel complex by acting on the polyamine recognition site.

Topics: Agmatine; Analysis of Variance; Animals; Behavior, Animal; Biguanides; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Dynorphins; Enkephalins; Enzyme Inhibitors; Ethylmaleimide; Excitatory Amino Acid Antagonists; Immune Sera; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Narcotics; Nociceptin Receptor; Piperidines; Protein Precursors; Receptors, Opioid; Spinal Cord; Time Factors

Intrathecal (i.t.) administration of big dynorphin (1-10 fmol), a prodynorphin-derived peptide consisting of dynorphin A and dynorphin B, to mice produced a characteristic behavioral response, the biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank, which peaked at 5-15 min after an injection. Dynorphin A produced a similar response, though the doses required were higher (0.1-30 pmol) whereas dynorphin B was practically inactive even at 1000 pmol. The behavior induced by big dynorphin (3 fmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-2 mg/kg) and also dose-dependently, by i.t. co-administration of D(-)-2-amino-5-phosphonovaleric acid (D-APV) (1-4 nmol), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (0.25-4 nmol), an NMDA ion-channel blocker, and ifenprodil (2-8 pmol), an inhibitor of the NMDA receptor ion-channel complex interacting with the NR2B subunit and the polyamine recognition site. On the other hand, naloxone, an opioid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, 7-chlorokynurenic acid, a competitive antagonist of the glycine recognition site on the NMDA receptor ion-channel complex, [D-Phe(7),D-His(9)]-substance P(6-11), a specific antagonist for substance P (NK1) receptors, and MEN-10376, a tachykinin NK2 receptor antagonist, had no effect. These results suggest that big dynorphin-induced nociceptive behavior is mediated through the activation of the NMDA receptor ion-channel complex by acting on the NR2B subunit and/or the polyamine recognition site but not on the glycine recognition site, and does not involve opioid, non-NMDA glutamate receptor mechanisms or tachykinin receptors in the mouse spinal cord.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Analgesics, Opioid; Animals; Behavior, Animal; Dizocilpine Maleate; Dynorphins; Endorphins; Enkephalins; Excitatory Amino Acid Antagonists; Injections, Spinal; Kynurenic Acid; Male; Mice; Morphine; Neurokinin A; Nociceptors; Peptide Fragments; Piperidines; Protein Precursors; Receptors, N-Methyl-D-Aspartate; Receptors, Tachykinin; Substance P

Striatal neurons that contain GABA and enkephalin and project to the external segment of the pallidum are thought to be overactive in Parkinson's disease. Furthermore, it has been shown that the appearance of L-dopa-induced dyskinesias is correlated to an increase of preproenkephalin (PPE) mRNA expression and that some antagonists of glutamate receptors can prevent and reverse L-dopa-induced dyskinesias in parkinsonian rats. The aim of this study was therefore to analyse the effect of a systemic treatment with glutamate receptor antagonists, alone or in combination with L-dopa, on the PPE mRNA level in rats with a 6-hydroxydopamine-induced unilateral lesion of the nigrostriatal pathway. In vehicle-treated animals, PPE mRNA levels were markedly increased in the striatum on the lesioned side. Sub-chronic L-dopa treatment, with bi-daily injections for 22 days, induced a further increase in PPE mRNA expression in the denervated striatum. Administration of the AMPA receptor antagonist, LY293558, partially reversed the lesion-induced and L-dopa-induced increases in PPE mRNA expression. However, although the administration of the NMDA receptor antagonist MK801 showed a tendency to decrease this L-dopa induced overexpression, it did not reach significance. This study provides evidence that glutamatergic antagonists, and particularly AMPA antagonists, tend to reverse PPE neurochemical changes at the striatal level induced by L-dopa in hemiparkinsonian rats.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dyskinesia, Drug-Induced; Enkephalins; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Isoquinolines; Levodopa; Male; Membrane Glycoproteins; Membrane Transport Proteins; Neostriatum; Nerve Tissue Proteins; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Tetrazoles

In a previous study, we have shown in unilaterally dopamine-depleted rats that increased behavioral responsiveness to the dopamine D1-receptor agonist SKF-38393, which was induced by pretreatment with L-DOPA, is paralleled by specific alterations in striatal neuropeptide mRNA levels. The behavioral 'priming' effect of L-DOPA is prevented if L-DOPA is preceded by the NMDA-receptor antagonist MK-801. In the present study, the question is addressed whether blockade of the increased behavioral responsiveness with MK-801 also prevents the observed changes in striatal neuropeptide mRNA levels. After a challenge with SKF-38393 (3 mg/kg, s.c.), the striatal levels of preprodynorphin, preprotachykinin, and preproenkephalin mRNA were compared between unilaterally dopamine-depleted rats that were either primed with a single administration of L-DOPA (50 mg/kg, i.p.) or with L-DOPA preceded by MK-801 (0.1 mg/kg, i.p.). Priming with L-DOPA enhanced the increase in dynorphin mRNA levels in the dorsolateral part of the dopamine-depleted striatum that occurred after SKF-38393. On the other hand, it had no significant effect on substance P or enkephalin mRNA levels. MK-801 prior to L-DOPA prevented the increased responsiveness of dynorphin regulation. However, it induced a decreased response to dopamine D1-receptor stimulation in the substance P mRNA levels in dorsal regions of the dopamine-depleted striatum. The levels of enkephalin mRNA after challenge with SKF-38393 were not affected by the MK-801 administration. These results demonstrate that the increased behavioral responsiveness to the D1-receptor agonist SKF-38393 after priming with L-DOPA is primarily related to the upregulation of dynorphin mRNA levels in the dopamine-depleted striatum.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Disease Models, Animal; Dizocilpine Maleate; Dopamine Agents; Dopamine Agonists; Drug Interactions; Dynorphins; Dyskinesia, Drug-Induced; Enkephalins; Excitatory Amino Acid Antagonists; Immunohistochemistry; Levodopa; Male; Motor Activity; Neostriatum; Neurons; Neuropeptides; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Tachykinins; Tyrosine 3-Monooxygenase

Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in the treatment of obesity. It has been suggested that the effects of FE on the striatum are mediated by serotonergic mechanisms. However, several major afferent systems may be involved, and administration of FE may be useful to study interactions between these systems. In this work, the effects of FE on striatopallidal neurons and the possible involvement of the major striatal afferent systems were studied in rats by determination of FE-induced changes in striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization. Injection of FE induced a significant increase (60%) in striatal levels of PPE mRNA. This increase was blocked by pretreatment with the D(1) dopamine receptor antagonist SCH-23390 or with the NMDA glutamate receptor antagonist MK-801, or by lesion of the serotonergic system with 5,7-dihydroxytryptamine or p-chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the lesion-induced increase in PPE mRNA levels was not affected by injection of FE, but was reduced by simultaneous serotonergic deafferentation. The results suggest that the serotonergic, glutamatergic, and dopaminergic system interact to increase striatal PPE mRNA levels after FE administration.

Topics: 5,7-Dihydroxytryptamine; Adrenergic Agents; Animals; Benzazepines; Corpus Striatum; Dizocilpine Maleate; Enkephalins; Female; Fenfluramine; Oxidopamine; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Serotonin Agents

Induction of dopamine D3 receptor gene expression in 6-hydroxydopamine-lesioned rats by repeated administration of levodopa had been suggested to be responsible for behavioural sensitization developing in these animals. Using double in situ hybridization techniques, we show that D3 receptor mRNA induction after repeated administration of levodopa took place mainly in dynorphin/substance P-expressing neurons of the direct striatonigral pathway. In agreement, induction of D3 receptor binding sites was evidenced, using 7-[3H]hydroxy-N,N-di-propyl-2-aminotetralin ([3H]7-OH-DPAT), in substantia nigra pars reticulata, the projection area of the direct nigrostriatonigral pathway. Changes in D3 receptor binding and behavioural sensitization during intermittent administration of levodopa paralleled changes in prodynorphin/preprotachykinin rather than preproenkephalin/prodynorphin and preproenkephalin/preprotachykinin mRNA ratios. Behavioural sensitization, induction of D3 receptor binding and changes in prodynorphin/preprotachykinin ratio were all prevented together when levodopa was continuously delivered or intermittently delivered in combination with R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390), a selective D1 receptor antagonist. Our results indicate that functional changes of the direct striatal output pathway, possibly through an interaction between D1 and D3 receptors at the level of terminals in the substantia nigra pars reticulata, are important for the development of behavioural sensitization.

Topics: Animals; Antiparkinson Agents; Benzazepines; Binding, Competitive; Corpus Striatum; Denervation; Dizocilpine Maleate; Dopamine Agonists; Dopamine Antagonists; Enkephalins; Excitatory Amino Acid Antagonists; Gene Expression; Levodopa; Male; Neural Pathways; Neurons; Opioid Peptides; Oxidopamine; Parkinson Disease, Secondary; Protein Precursors; Rats; Rats, Wistar; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger; Substantia Nigra; Sympatholytics; Tachykinins; Tetrahydronaphthalenes; Tritium; Ventral Tegmental Area

The mechanisms by which dopaminergic and glutamatergic inputs interact to regulate striatal neuropeptide expression during physiological motor activity are poorly understood. In this work, striatal expression of preprotachykinin (PPT) and preproenkephalin (PPE) mRNA was studied by in situ hybridization in rats killed 2 h after treadmill running (36 m/min for 20 min). Treadmill running induced a significant increase in the levels of both PPT (60% increase) and PPE (90% increase) mRNA in the striatum of normal rats. The increase in the level of PPT mRNA was blocked in rats previously subjected to nigrostriatal deafferentation (i.e., 6-hydroxydopamine lesion) or pretreated with D1-receptor antagonist SCH-23390 (0.1 mg/kg), the D2-receptor antagonist eticlopride (0.5 mg/kg), or the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801 (0.1 mg/kg). The running-induced increase in the level of PPE mRNA was blocked in rats pretreated with SCH-23390 or MK-801. Rats subjected to nigrostriatal deafferentation or pretreated with eticlopride showed an increase in PPE mRNA levels (around 150% and 40% increase, respectively), that was enhanced by running (around 230% and 160% increase, respectively). These results suggest that locomotor activity increases, in a NMDA receptor dependent fashion, the excitatory influence of the corticostriatal glutamatergic system on the two populations of striatal projection neurons, as reflected by increases in the levels of PPT and PPE mRNA. The results obtained after dopamine depletion or injection of dopamine receptor antagonists suggest that a concomitant increase in dopamine release may enhance PPT mRNA level in striatonigral neurons via D1 receptors, and reduce PPE mRNA level in striatopallidal neurons via D2 receptors. Additionally, levels of dopamine and glutamate may be regulated by other complex indirect mechanisms.

Topics: Animals; Apomorphine; Benzazepines; Corpus Striatum; Denervation; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Enkephalins; Excitatory Amino Acid Antagonists; Female; Gene Expression Regulation; Glutamic Acid; In Situ Hybridization; Motor Activity; Nerve Tissue Proteins; Oxidopamine; Protein Precursors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Running; Tachykinins

We injected rats three times at 3 h intervals (from 0900 h to 1500 h) with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 at 0.1 or 0.5 mg/kg of body weight. Three hours after the last injection, animals were sacrificed and the brains were processed for in situ hybridization histochemistry. Preproenkephalin (PPE) mRNA levels were significantly decreased throughout the caudate-putamen (CPu) and nucleus accumbens (NAc) at the lower dose. The higher dose produced significant decreases only in anterior CPu (aCPu) and NAc. Concurrent administration of the muscarinic cholinergic receptor antagonist scopolamine at 2 or 5 mg/kg neither potentiated nor prevented the effect of MK-801 on PPE mRNA levels in the neostriatum. In contrast, co-administration of haloperidol (dopamine receptor antagonist) with MK-801 blocked the effect of the latter in the NAc, and elevated PPE mRNA levels throughout the CPu. The data demonstrate that the acute effects of glutamate receptor activity on striatal and accumbal PPE mRNA expression via the NMDA receptor can be modulated by the dopaminergic system in the brain of the rat.

Topics: Animals; Base Sequence; Brain Chemistry; Dizocilpine Maleate; Dopamine Antagonists; Enkephalins; Excitatory Amino Acid Antagonists; Haloperidol; In Situ Hybridization; Male; Molecular Sequence Data; Muscarinic Antagonists; Neostriatum; Nucleus Accumbens; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Scopolamine

N-methyl-D-aspartate antagonists have been proposed as potential therapeutic agents in different neurological diseases, including Parkinson's disease. The effects of gene expression of a chronic treatment with the non-competitive N-methyl-D-aspartate antagonist, dizocilpine maleate (0.8 mg/kg day, per os for 50 days) were analysed in rat striata. Using quantitative in situ hybridization, we measured the messenger RNA expression of the genes encoding D1, D2 dopamine receptors, N-methyl-D-aspartate receptor 1 subunit of N-methyl-D-aspartate receptor, preproenkephalin A and substance P. Chronic treatment with dizocilpine maleate induced a moderate but significant increase in messenger RNA of the N-methyl-D-aspartate receptor 1 subunit in the striatum and the adjacent cortex, suggesting an action of dizocilpine maleate in these two regions. This treatment did not induce any change in D1 receptor, preproenkephalin A or substance P messenger RNA content in the striatum, whereas D2 receptor messenger RNA was increased in the striatum of treated rats. Microscopic analysis revealed that it was the number of medium-sized neurons expressing D2 receptor messenger RNA that was significantly enhanced, while the mean amount of message per cell remained unchanged. These results demonstrate that glutamate via N-methyl-D-aspartate receptors, regulates the D2 receptor gene in striatal neurons. A chronic treatment with dizocilpine maleate increases the number of striatal neurons expressing the D2 receptor gene, suggesting a recruiting phenomenon.

Topics: Animals; Dizocilpine Maleate; DNA Probes; Enkephalins; In Situ Hybridization; Male; Neostriatum; Neurons; Nucleus Accumbens; Protein Precursors; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Substance P

The effect of N-methyl-D-aspartate (NMDA) receptor blockade on the expression of preproenkephalin (PPE), preprotachykinin (PPT) and preprodynorphin (PPD) mRNAs in the caudate-putamen and nucleus accumbens was assessed with the non-competitive NMDA receptor antagonist MK-801. Administration of MK-801 once daily for 7 consecutive days increased the abundance of all three neuropeptide mRNAs in the caudate-putamen (CPU) and nucleus accumbens (NAc). (1) PPE mRNA abundance was increased in the anterior CPU (26%) as well as dorsal and ventral CPU (46% and 39%, respectively) but was unaffected in the NAc. (2) PPT mRNA was increased in the NAc (33%), anterior CPU (27%), dorsal CPU (43%) and ventral CPU (67%). In the ventral CPU, PPT mRNA abundance doubled when the dose of MK-801 increased two-fold (from 67% to 119% above control). (3) PPD mRNA was elevated in dorsal and ventral regions of the CPU (49% and 24%, respectively) and in anterior CPU (50%). In the NAc PPD mRNA was increased only at the higher dose (0.1 mg/kg) of MK-801. Cellular analysis of the distribution of grains per cell shows that increases are due to increased accumulation of mRNA by previously expressing cells of the CPU and NAc. These observations demonstrate that NMDA receptor activity plays a significant role in the regulation of neuropeptide expression in the caudate-putamen and accumbens of the rat brain.

Topics: Animals; Base Sequence; Corpus Striatum; Dizocilpine Maleate; Dynorphins; Enkephalins; Male; Molecular Probes; Molecular Sequence Data; Neuropeptides; Nucleus Accumbens; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Tachykinins