piperidines and 3-((2-methyl-1-3-thiazol-4-yl)ethynyl)piperidine

Although there are numerous strategies to counteract the death of dopaminergic neurons in Parkinson's disease (PD), there are currently no treatments that delay or prevent the disease course, indicating that early protective treatments are needed. Targeting axonal degeneration, a key initiating event in PD, is required to develop novel therapies; however, its underlying molecular mechanisms are not fully understood. Here, we studied axonal degeneration induced by 6-hydroxydopamine (6-OHDA) in vitro and in vivo. We found that metabotropic glutamate receptor 5 (mGluR5) expression increased during 6-OHDA-induced axonal degeneration in primary neurons and that blockade of mGluR5 by its antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1, 3-thiazol-4-yl) ethynyl]-pyridine (MTEP) almost completely attenuated the degenerative process in vitro. Furthermore, a rapid increase in intra-axonal calcium levels following 6-OHDA treatment was visualized using a calcium-sensitive fluorescence probe and a calcium chelator prevented the axonal degenerative process induced by 6-OHDA in vitro, whereas application of the mGluR5 antagonist MPEP partially attenuated the increase in intra-axonal calcium. The screening of calcium targets revealed that calpain activation and an increase in phosphorylated extracellular signal-regulated kinase (p-ERK) were calcium dependent during 6-OHDA-induced axonal degeneration in vitro. Consistent with these in vitro findings, blockade of mGluR5 with MPEP attenuated the degeneration of dopaminergic axons induced by 6-OHDA injection into the striatum prior to soma death in the early stage of PD in an in vivo animal model. In addition, MPEP inhibited the increase in mGluR5 expression levels, calpain activation and the elevation of p-ERK in the striatum triggered by 6-OHDA injection in vivo. Taken together, these data identify an mGluR5-calcium-dependent cascade that causes axonal degeneration, and suggest that mGluR5 antagonists could provide effective therapy to prevent the disease process of PD.

Topics: Animals; Axons; Calcium Signaling; Cells, Cultured; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Female; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Thiazoles

Cocaine use disorder (CUD) is associated with neurobehavioral deficits that are resistant to current treatments. While craving and high rates of relapse are prominent features of CUD, persistent cognitive impairments are common and linked to poorer treatment outcomes. Here we sought to develop an animal model to study post-cocaine changes in drug seeking and working memory, and to evaluate 'therapeutic' effects of combined glutamate mGlu5 and adenosine A2a receptor blockade. As mGlu5 antagonists reduce drug seeking, and A2a blockade ameliorates working memory impairment, we hypothesized that mGlu5 + A2a antagonist cocktail would reduce both cocaine relapse and post-cocaine working memory deficits. Adult male Sprague-Dawley rats were first trained and tested in an operant delayed match-to-sample (DMS) task to establish the working memory baseline, followed by 6 days of limited and 12 days of extended access cocaine self-administration. Chronic cocaine reduced working memory performance (abstinence day 30-40) and produced robust time-dependent cocaine seeking at 45-, but not 120-days of abstinence. Systemic administration of A2a antagonist KW-6002 (0.125 and 1 mg/kg) failed to rescue post-cocaine working memory deficit. It also failed to reverse working memory impairment produced by mGlu5 NAM MTEP (1 mg/kg). Finally, KW-6002 prevented the ability of MTEP to reduce cocaine seeking and increased locomotor behavior. Thus, despite mGlu5 and A2a being exclusively co-localized in the striatum and showing behavioral synergism towards reducing cocaine effects in some studies, our findings advocate against the use of mGlu5 + A2a antagonist cocktail as it may further compromise cognitive deficits and augment drug craving in CUD.

Topics: Adenosine A2 Receptor Antagonists; Animals; Cocaine-Related Disorders; Conditioning, Operant; Drug-Seeking Behavior; Male; Memory, Short-Term; Motor Activity; Piperidines; Psychomotor Performance; Purines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptor, Metabotropic Glutamate 5; Recurrence; Self Administration; Thiazoles

Understanding the neurobiological processes that incite drug craving and drive relapse has the potential to help target efforts to treat addiction. The NAc serves as a critical substrate for reward and motivated behavior, in part due to alterations in excitatory synaptic strength within cortical-accumbens pathways. The present studies investigated a causal link between cocaine-induced reinstatement of conditioned place preference and rapid reductions of cocaine-dependent increases in NAc shell synaptic strength in male mice. Cocaine-conditioned place preference behavior and

Topics: Animals; Cocaine; Conditioning, Operant; Electrophysiological Phenomena; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; Neuronal Plasticity; Nucleus Accumbens; Optogenetics; Patch-Clamp Techniques; Piperidines; Receptors, AMPA; Receptors, Kainic Acid; Signal Transduction; Synaptic Potentials; Thiazoles

2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions. We also evaluated the effects of mGluR5 blockade on viability in rat hepatocytes exposed to hypoxia. Furthermore, we studied the effects of MPEP treatment on mouse livers subjected to cold ischemia and warm ischemia reperfusion. We found that MPEP and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) deplete ATP in hepatocytes and acellular solutions, unlike fenobam. This finding suggests that mGluR5s may not be involved, contrary to previous reports. MPEP, as well as MTEP and fenobam, improved hypoxic hepatocyte viability, suggesting that protection against ischemic injury is independent of ATP depletion. Significantly, MPEP protected mouse livers in two different ex vivo models of ischemia reperfusion injury, suggesting its possible protective deployment in the treatment of hepatic inflammatory conditions.

Topics: Adenosine Triphosphate; Animals; Cell Hypoxia; Disease Models, Animal; Hepatocytes; Imidazoles; Liver; Mice; Mitochondria, Liver; Piperidines; Pyridines; Rats; Receptor, Metabotropic Glutamate 5; Reperfusion Injury; Thiazoles; Tumor Necrosis Factor-alpha

This study investigated the role of the hypogastric nerve and β-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a β-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition.

Topics: Adrenergic beta-Antagonists; Animals; Cats; Denervation; Electric Stimulation; Female; Hypogastric Plexus; Male; Nociception; Piperidines; Propranolol; Pudendal Nerve; Rats; Receptors, Adrenergic, beta; Reflex; Thiazoles; Urinary Bladder

The ability of the ventral hippocampus (VH) for long-lasting long-term potentiation (LTP) and the mechanisms underlying its lower ability for short-lasting LTP compared with the dorsal hippocampus (DH) are unknown. Using recordings of field excitatory postsynaptic potentials (EPSPs) from the CA1 field of adult rat hippocampal slices, we found that 200-Hz stimulation induced nondecremental LTP that was maintained for at least 7 h and was greater in the DH than in the VH. The interaction of NMDA receptors with L-type voltage-dependent calcium channels appeared to be more effective in the DH than in the VH. Furthermore, the LTP was significantly enhanced in the DH only, between 2 and 5 h post-tetanus. Furthermore, the mGluR5 contributed to the post-tetanic potentiation more in the VH than in the DH.

Topics: Animals; CA1 Region, Hippocampal; Calcium Channel Blockers; Calcium Channels, L-Type; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Long-Term Potentiation; Male; Nimodipine; Piperazines; Piperidines; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, N-Methyl-D-Aspartate; Thiazoles

Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD).. The aim of the present study was to investigate the possible role of the serotonergic system in the antidepressant-like activity of MTEP in the tail suspension test (TST) in C57BL/6J mice, using selected antagonists of serotonergic receptors and by applying two different methods of serotonin (5-HT) depletion.. The results of our studies showed that the mGlu5 receptor antagonist, MTEP, similar to the fluoxetine used as reference AD, did not induce antidepressant-like effects in mice pretreated with tryptophan hydroxylase inhibitor, parachlorophenylalanine. On the other hand, MTEP worked as a potential AD in the TST in mice fed on a tryptophan-free (TRP-free) diet for 3 weeks. However, fluoxetine, which was used as a reference control was also active in this experiment, suggesting that a TRP-free diet was not sufficiently effective in reducing the 5-HT level. Furthermore, we showed that the 5HT2A/2C antagonist, ritanserin, yet not the 5-HT1A antagonist, WAY100635, 5HT1B antagonist, SB224289 or 5HT4 antagonist, GR125487, reversed the antidepressant-like effects of MTEP in the TST. Finally, a sub-effective dose ofMTEP coadministered with a sub-effective dose of citalopram induced an antidepressant-like effect in the TST in mice.. The results of our studies suggest the involvement of serotonergic system activation in the antidepressant-like effects of the mGlu5 antagonist, MTEP, in the TST in mice.

Topics: Animals; Antidepressive Agents; Citalopram; Diet; Excitatory Amino Acid Antagonists; Fenclonine; Fluoxetine; Hindlimb Suspension; Male; Mice; Mice, Inbred C57BL; Motor Activity; Piperidines; Receptors, Kainic Acid; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Thiazoles; Tryptophan

Pre-clinical studies suggest that negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5), including 2-methyl-6-(phenylethynyl)pyridine (MPEP), 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and fenobam are highly effective in attenuating drug-taking and drug-seeking behaviors. However, both MPEP and MTEP have no translational potential for use in humans because of their off-target effects and short half-lives. Here, we report that 3-fluoro-5-[(6-methylpyridin-2-yl)ethynyl]benzonitrile (MFZ 10-7), a novel mGluR5 NAM, is more potent and selective than MPEP, MTEP and fenobam in both in vitro binding and functional assays. Similar to MTEP, intraperitoneal administration of MFZ 10-7 inhibited intravenous cocaine self-administration, cocaine-induced reinstatement of drug-seeking behavior and cocaine-associated cue-induced cocaine-seeking behavior in rats. Although MFZ 10-7 and MTEP lowered the rate of oral sucrose self-administration, they did not alter total sucrose intake. Further, MFZ 10-7 appeared to be more potent than MTEP in inducing downward shifts in the cocaine dose-response curve, but less effective than MTEP in attenuating sucrose-induced reinstatement of sucrose-seeking behavior. MFZ 10-7 and MTEP had no effect on basal locomotor behavior. These findings not only provide additional evidence supporting an important role for mGluR5 in cocaine reward and addiction, but also introduce a new tool for both in vitro and in vivo investigations with which to further characterize this role.

Topics: Allosteric Regulation; Analysis of Variance; Animals; Binding, Competitive; Cocaine; Cues; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Enzyme-Linked Immunosorbent Assay; Excitatory Amino Acid Antagonists; HEK293 Cells; Humans; Imidazoles; In Vitro Techniques; Infusions, Intravenous; Inhibitory Concentration 50; Male; Motor Activity; Nitriles; Piperidines; Pyridines; Random Allocation; Rats; Receptor, Metabotropic Glutamate 5; Reinforcement Schedule; Reward; Secondary Prevention; Self Administration; Sucrose; Thiazoles

Small intestine luminal nutrient sensing may be crucial for modulating physiological functions. However, its mechanism of action is incompletely understood. We used a model of enteral nutrient deprivation, or total parenteral nutrition (TPN), resulting in intestinal mucosal atrophy and decreased epithelial barrier function (EBF). We examined how a single amino acid, glutamate (GLM), modulates intestinal epithelial cell (IEC) growth and EBF. Controls were chow-fed mice, T1 receptor-3 (T1R3)-knockout (KO) mice, and treatment with the metabotropic glutamate receptor (mGluR)-5 antagonist MTEP. TPN significantly changed the amount of T1Rs, GLM receptors, and transporters, and GLM prevented these changes. GLM significantly prevented TPN-associated intestinal atrophy (2.5-fold increase in IEC proliferation) and was dependent on up-regulation of the protein kinase pAkt, but independent of T1R3 and mGluR5 signaling. GLM led to a loss of EBF with TPN (60% increase in FITC-dextran permeability, 40% decline in transepithelial resistance); via T1R3, it protected EBF, whereas mGluR5 was associated with EBF loss. GLM led to a decline in circulating glucagon-like peptide 2 (GLP-2) during TPN. The decline was regulated by T1R3 and mGluR5, suggesting a novel negative regulator pathway for IEC proliferation not previously described. Loss of luminal nutrients with TPN administration may widely affect intestinal taste sensing. GLM has previously unrecognized actions on IEC growth and EBF. Restoring luminal sensing via GLM could be a strategy for patients on TPN.

Topics: Animal Nutrition Sciences; Animals; Atrophy; Cell Proliferation; Disease Models, Animal; Down-Regulation; Epithelial Cells; Epithelium; Food; Glucagon-Like Peptide 2; Glutamic Acid; Intestinal Mucosa; Jejunum; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Parenteral Nutrition, Total; Permeability; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, G-Protein-Coupled; Signal Transduction; Thiazoles

Metabotropic glutamate receptors (mGluRs) have been implicated in the regulation of anxiety, stress responses and the neurobehavioral effects of psychostimulants. The present study was designed to examine whether antagonizing mGluR5 or activating mGluR2/3 prevents stress-induced reinstatement of cocaine seeking. Male Wistar rats were trained to self-administer cocaine and then subjected to daily extinction training for 2 weeks. Subsequent exposure to 15 minutes of intermittent footshock elicited robust reinstatement of responding at the previously active lever. Both the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) (0-3 mg/kg, intraperitoneally) and the selective mGluR2/3 agonist (-)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) (0-3 mg/kg, subcutaneously) prevented cocaine seeking induced by footshock stress following the same dose-response function. The data show that although mGluR2/3 and mGluR5 are differentially located on synaptic compartments, both LY379268 and MTEP produced the same behavioral effects in reducing stress-induced reinstatement. These results are important because they demonstrate that a reduction in glutamate-mediated neural excitability (albeit via different mechanisms of action) reverses footshock-induced reinstatement and suggest that pharmacological manipulations of mGluR2/3 and mGluR5 can prevent the effects of stress, a major precipitating factor for relapse. These findings further confirm that mGluR2/3 or mGluR5 are promising targets for relapse prevention.

Topics: Amino Acids; Analysis of Variance; Animals; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Stimulants; Cocaine-Related Disorders; Conditioning, Operant; Excitatory Amino Acid Antagonists; Extinction, Psychological; Male; Piperidines; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Stress, Psychological; Thiazoles

The mGlu5 receptor (mGluR5) has been implicated in the rewarding effect of various drugs of abuse and drug-seeking behaviour. In the present study we investigated the impact of antagonism of mGluR5 with the selective negative allosteric, modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine as well as cue-induced drug-seeking in adult CD1 mice. Administration of MTEP (20 mg/kg, i.p.) attenuated operant responding for morphine (0.1 mg/kg/infusion) and cue-induced morphine-seeking after a period of forced abstinence. Collectively, these data implicate mGluR5 in the reinforcing effects of opiates and support the proposition that mGluR5 is a potential therapeutic target for treatment of drug addiction.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Conditioning, Operant; Cues; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Mice; Morphine; Motor Activity; Narcotics; Opioid-Related Disorders; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement, Psychology; Self Administration; Substance Abuse, Intravenous; Thiazoles

3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP) is a metabotropic glutamate receptor 5 (mGluR5) antagonist that may alter drug sensitivity in differentially reared rats due to its involvement in the psychostimulant reward pathway and plasticity.. The purpose of this study was to assess the effects of MTEP on acute amphetamine-induced hyperactivity, conditioned hyperactivity, and sensitization.. Rats were reared in an enriched (EC), isolated (IC), or standard (SC) condition after which rats were either administered MTEP (1.0 mg/kg, ip) or saline prior to an acute (0.5 or 1.0 mg/kg, sc) or repeated (0.3 mg/kg, sc) amphetamine exposure. Rats undergoing repeated amphetamine exposure were administered MTEP prior to conditioned hyperactivity and sensitization tests.. EC and SC rats administered with MTEP prior to acute amphetamine demonstrated attenuated amphetamine-induced locomotor activity compared to controls, while IC rats administered MTEP following repeated amphetamine exposure demonstrated attenuated amphetamine-induced locomotor activity. Interestingly, MTEP treatment only altered conditioned hyperactivity in EC rats, as MTEP pretreatment resulted in conditioned hyperactivity in EC rats while conditioned hyperactivity was not observed in EC rats pretreated with saline.. Glutamatergic pathways are altered during differential rearing, which differentially alters the role of mGluR5 in EC, IC, and SC rats when administered psychostimulant acutely versus repeatedly. These findings suggest that differential rearing alters glutamatergic function, which reduces sensitivity to psychostimulants.

Topics: Amphetamine; Animals; Behavior, Animal; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperkinesis; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Social Isolation; Thiazoles

Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate-putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate-putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID.

Topics: Animals; Anti-Dyskinesia Agents; Disease Models, Animal; Dyskinesia, Drug-Induced; Excitatory Amino Acid Antagonists; Infusions, Intraventricular; Levodopa; Male; Oxidopamine; Phenols; Piperidines; Putamen; Quinoxalines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, AMPA; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Substantia Nigra; Subthalamic Nucleus; Thiazoles

Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca fascicularis; Male; Motor Activity; MPTP Poisoning; Parkinson Disease, Secondary; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Thiazoles

Glutamatergic transmission is one of the main components of the stress response; nevertheless, its role in the emotional stress sequelae is not known. Here, we investigated whether interactions between group I metabotropic glutamate receptors (metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 [mGluR5]) and Homer proteins mediate the delayed and persistent enhancement of fear induced by acute stress.. Antagonists and inverse agonists of metabotropic glutamate receptor 1 and mGluR5 were injected into the hippocampus after immobilization stress and before contextual fear conditioning. Metabotropic glutamate receptor 5 was displaced from constitutive Homer scaffolds by viral transfection of Homer1a or injection of Tat decoy peptides. The effects of these manipulations on stress-enhanced fear were determined.. We show that stress induces interactions between hippocampal mGluR5 and Homer1a; causes a sustained, ligand-independent mGluR5 activity; and enhances contextual fear. Consistent with this mechanism, enhancement of fear was abolished by delayed poststress application of inverse agonists, but not antagonists, of mGluR5. The effect of stress was mimicked by virally transfected Homer1a or injection of Tat-metabotropic glutamate receptor C-tail decoy peptides into the hippocampus.. Constitutive activation of mGluR5 is identified as a principal hippocampal mechanism underlying the delayed stress effects on emotion and memory. Inverse agonists, but not antagonists, of mGluR5 are therefore proposed as a preventive treatment option for acute and posttraumatic stress disorders.

Topics: Analysis of Variance; Animals; Association Learning; Blotting, Western; Carrier Proteins; Cells, Cultured; Conditioning, Psychological; Excitatory Amino Acid Antagonists; Fear; Hippocampus; Homer Scaffolding Proteins; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Neurons; Piperidines; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Restraint, Physical; Stress, Physiological; Stress, Psychological; Thiazoles

The type 5 metabotropic glutamate receptor (mGluR5) and the epsilon isoform of protein kinase C (PKCepsilon) regulate ethanol intake, and we have previously demonstrated that mGluR5 receptor antagonism reduces ethanol consumption via a PKCepsilon-dependent mechanism.. We explored the potential neuroanatomical substrates of regulation of ethanol reinforcement by this mGluR5-PKCepsilon signaling pathway by infusing selective inhibitors of these proteins into the shell or core region of the nucleus accumbens (NAc).. Male Wistar rats were trained to self-administer ethanol intravenously and received intra-NAc infusions of vehicle or the selective mGluR5 antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) alone and in combination with a PKCepsilon translocation inhibitor (epsilonV1-2) or a scrambled control peptide (svarepsilonV1-2). The effects of intra-NAc MTEP on food-reinforced responding and open-field locomotor activity were also determined.. MTEP (1 microg/microl) had no effect on ethanol or food reinforcement or locomotor activity when infused into either region. MTEP (3 microg/microl) reduced ethanol reinforcement when infused into the NAc shell but not the core, and this effect was reversed by epsilonV1-2 (1 microg/microl) but not sepsilonV1-2 (1 microg/microl). In both regions, this concentration of MTEP did not alter food-reinforced responding or locomotor activity, and infusion of epsilonV1-2 alone did not alter ethanol reinforcement. MTEP (10 microg/microl) reduced locomotor activity when infused into the shell; therefore, this concentration was not further tested on responding for ethanol or food.. Blockade of mGluR5 receptors in the NAc shell reduces ethanol reinforcement via a PKCepsilon-dependent mechanism.

Topics: Animals; Central Nervous System Depressants; Ethanol; Excitatory Amino Acid Antagonists; Feeding Behavior; Male; Motor Activity; Nucleus Accumbens; Piperidines; Protein Kinase C-epsilon; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement Schedule; Signal Transduction; Thiazoles

To advance understanding of the potential of metabotropic glutamate receptor (mGluR) 5 as treatment targets for cocaine addiction, the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]piperidine] (a selective mGluR5 antagonist) on conditioned reinstatement of cocaine seeking were examined. To test whether modification of conditioned reinstatement by MTEP is selective for drug-directed behavior or reflects general actions on motivated behavior, effects of MTEP on reinstatement induced by a stimulus conditioned to palatable conventional reward, sweetened condensed milk (SCM), were also evaluated. Previous data suggest that mGluR manipulations preferentially interfere with conditioned reinstatement compared with cocaine self-administration. Therefore, the effects of MTEP on cocaine self-administration were compared with MTEP's effects on SCM-reinforced behavior using the same cocaine doses and SCM concentrations employed for establishing conditioned reinstatement. Male Wistar rats were trained to associate a discriminative stimulus (S(D)) with response-contingent availability of cocaine or SCM and subjected to reinstatement tests after extinction of cocaine or SCM-reinforced behavior. MTEP (0.3-10 mg/kg i.p.) dose-dependently attenuated the response-reinstating effects of both the cocaine S(D) and SCM S(D). MTEP also decreased cocaine self-administration without a clear graded dose-response profile and did not modify SCM-reinforced responding. The findings implicate mGluR5-regulated glutamate transmission in appetitive behavior controlled by reward-related stimuli but without selectivity for cocaine seeking. However, the data suggest a differential role for mGluR5 in the acute reinforcing effects of cocaine versus conventional reward. These observations identify mGluR5 as potential treatment targets for cocaine relapse prevention, although the profile of action of mGluR5 antagonists remains to be more closely examined for potential anhedonic effects.

Topics: Animals; Behavior, Animal; Cocaine; Conditioning, Classical; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Extinction, Psychological; Locomotion; Male; Milk; Piperidines; Rats; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement Schedule; Reinforcement, Psychology; Self Administration; Thiazoles