Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice

O’Neill, Michael F.; Heron-Maxwell, C.; Conway, Michael W.; Monn, James A.; Ornstein, Paul L.

doi:10.1016/s0028-3908(03)00232-6

Cited by 38 publications

(45 citation statements)

References 43 publications

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“…The present finding that LY341495 (3 mg/kg) reduced both nicotine and food intake in a non-specific manner contrasts with a previous observation that LY341495 had no effect on ethanol self-administration at doses as high as 10 mg/kg in rats (Schroeder et al, 2005). Motor impairments are unlikely to explain our findings, since LY341495 had no effect on locomotor activity (Linden et al, 2005) or even increased spontaneous locomotion in mice (O'Neill et al, 2003). In addition, the mGlu2/3 receptor antagonist MGS0039 did not affect mouse or rat spontaneous locomotor activity at doses that were behaviorally active (Chaki et al, 2004).…”

Section: Effects Of Co-administration Of Mpep and Ly341495 On Nicotincontrasting

confidence: 99%

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Liechti

Markou

2007

European Journal of Pharmacology

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Stimulatory actions of nicotine on mesocorticolimbic dopamine transmission are partly mediated by nicotine-induced glutamate release acting on ionotropic and metabotropic glutamate (mGlu) receptors. Because both presynaptic inhibitory mGlu2/3 and postsynaptic excitatory mGlu5 receptors provide potential targets for treatment of aspects of nicotine dependence, we examined interacting effects of mGlu5 (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and mGlu2/3 (LY341495) receptor antagonists on nicotine self-administration and brain reward threshold elevations associated with spontaneous nicotine withdrawal in rats. We hypothesized that increasing glutamate transmission by blocking presynaptic inhibitory mGlu2/3 autoreceptors would antagonize MPEP-induced decreases in nicotine self-administration. We also hypothesized that blocking postsynaptic actions of glutamate on mGlu5 receptors would exacerbate nicotine withdrawal-induced reward deficits, and that this effect would be attenuated by co-administration of the mGlu2/3 receptor antagonist LY341495. MPEP selectively decreased nicotine, but not food, self-administration in rats. LY341495 slightly decreased both nicotine and food self-administration. Co-administration of LY341495 with MPEP attenuated the effectiveness of MPEP in decreasing nicotine intake, although MPEP was still effective. Spontaneous nicotine withdrawal induced somatic signs of withdrawal and reward threshold elevations indicating reward deficits. MPEP increased somatic signs and reward deficits in both nicotine-and saline-withdrawing rats. Thus, while mGlu5 receptor antagonists may be therapeutically useful in decreasing tobacco smoking, they worsen nicotine withdrawal. Coadministration of LY341495 reduced MPEP-induced reward deficits in both nicotine-and salinewithdrawing rats. Thus, increasing glutamate transmission via mGlu2/3 autoreceptor blockade reduces the effects of mGlu5 receptor blockade on nicotine self-administration and MPEP-induced exacerbation of brain reward deficits associated with nicotine withdrawal.

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Section: Effects Of Co-administration Of Mpep and Ly341495 On Nicotincontrasting

confidence: 99%

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Liechti

Markou

2007

European Journal of Pharmacology

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“…Consistent with a previous study (57), our data provide no evidence that these doses of either ZJ43 or LY341495 induce changes in basal locomotor activity. Also important in the assessment of the effects of ZJ43 is the finding that this compound has no detectable activity at a series of receptors and transporters including the NMDA and mGluR receptors (31;58;59;51) These data are consistent with the concept that NAAG peptidase inhibition represents a completely novel therapeutic approach to the design of adjuvant therapy for schizophrenia.…”

Section: Naag Peptidase Inhibition As Potential Pharmacotherapysupporting

confidence: 86%

Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Olszewski

Wegorzewska

Monteiro

et al. 2008

Biological Psychiatry

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“…LY341495 had no significant effect on response latencies in the 5CSRTT (present study) or locomotor activity at the dose of 1 mg/kg (O'Neill et al, 2003;Cartmell et al, 1999).…”

Section: Effects Of Mpep and Ly341495 On 5csrtt Performancementioning

confidence: 42%

The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

Semenova¹,

Markou²

2007

Neuropharmacology

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Schizophrenia is characterized by attentional deficits possibly associated with glutamate dysfunction. The role of postsynaptic metabotropic glutamate 5 (mGluR5) or presynaptic inhibitory mGluR2/3 on attention is currently unknown. We investigated the effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on attention in the 5-choice serial reaction time task (5CSRTT), as well as on food intake to evaluate their effects on food motivation. The effects of pre-feeding and the muscle relaxant curare were examined to characterize the effects of alterations in motivation or the ability to perform the task, respectively. MPEP had no effect on accuracy but overall decreased performance in the 5CSRTT, including decreased speed of responding and decreased premature responses. LY341495 had no significant effect on rats' performance in the 5CSRTT. LY341495 decreased food intake in the home cage to a greater extent than MPEP. Curare decreased the speed of correct responding, reflecting motor impairment. Free feeding decreased overall performance, number of trials completed and number of head entries into the feeder, reflecting decreased motivation to perform the task. Thus, blockade of mGluR5, but not mGluR2/3, decreased overall responding without affecting accuracy in the 5CSRTT. Keywordsattention; metabotropic glutamate receptors; MPEP; LY341495; schizophrenia; rat Cognitive deficits are now regarded as a core feature of schizophrenia (Elvevag & Goldberg, 2000;Lewis et al., 2004), and include disturbances in selective attention (Mirsky, 1969;Carter et al., 1992;Hagan & Jones, 2005;an der Heiden & Hafner, 2000;Hughes et al., 2003) and working memory (Carter et al., 1996;Gold et al., 1997). Presently available pharmacological treatments produce little improvement in the cognitive and attentional deficits in schizophrenia patients.Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors induced schizophrenia-like cognitive deficits in healthy subjects, and exacerbated positive and negative symptoms in schizophrenia patients (Krystal et al., 1994;Adler et al., 1999;Lahti et al., Correspondence to: Athina Markou.Athina Markou, Ph.D., Department of Psychiatry, School of Medicine, University of California San Diego, 9500 Gilman Drive, M/C 0603, La Jolla, California 92093-0603, USA; tel: (858) 534-1572, fax: (858) 858-534-7653, e-mail: amarkou@ucsd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Krystal et al., 2003;Moghaddam, 2003Moghaddam, , 2004Tamminga, 1998). Glutamate mediates its actions via activation of both ionotropic and metabotropic (...

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Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice

Cited by 38 publications

References 43 publications

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task

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