Prefrontal Group II Metabotropic Glutamate Receptor Activation Decreases Performance on a Working Memory Task

Gregory, Mary Lee; Stech, Nicholas E.; Owens, Russell W.; Kalivas, Peter W.

doi:10.1196/annals.1300.037

Cited by 15 publications

(18 citation statements)

References 15 publications

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“…Lack of improvement in attention by LY341495 administration may be due to a ceiling effect because of the initially high level of accuracy/correct responses and low level of incorrect responses and omissions after extensive training in the 5CSRTT. Consistent with this notion, LY341495 improved performance during acquisition of spatial learning in the Morris water maze task (Higgins et al, 2004) but there was no effect on working memory in a forced choice delayedalternation task on a T-maze (Gregory et al, 2003), a delayed non-matching-to-position task (Higgins et al, 2004) and a spatial discrimination task (Gregory et al, 2003) after learning had occurred. Interestingly, administration of LY379268, a mGluR2/3 agonist, rather than an antagonist, also had no significant effect on accuracy in the 5CSRTT task in C57BL/6 and DBA/2J mice (Greco et al, 2005).…”

Section: Effects Of Mpep and Ly341495 On 5csrtt Performancesupporting

confidence: 63%

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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Section: Effects Of Mpep and Ly341495 On 5csrtt Performancesupporting

confidence: 63%

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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“…Whether decreased mGluR function in the PFC of IC subjects is causal in the working memory deficits is unknown. Supporting the involvement of mGluRs in regulating working memory, stimulating mGluR2/3 directly in the PFC and systemic administration of an mGluR2/3 agonist diminishes working memory performance (Aultman and Moghaddam, 2001;Gregory et al, 2003). However, based on these findings, it might be anticipated that reduced mGluR2/3 function in IC subjects would improve the working memory performance.…”

Section: Effects Of Rearing Environment On Working Memorymentioning

confidence: 68%

“…Within the PFC, both dopamine and glutamate transmission modulate working memory (Goldman-Rakic, 1996;Moghaddam et al, 1997;Romanides et al, 1999). Various studies show that group I and group II mGluRs are present in high density within the PFC (Romano et al, 1995;Wright et al, 2001;Xi et al, 2002b) and systemic or intra-PFC administration of drugs modulating group II metabotropic glutamate receptors (mGluR2/3) alters performance in a forced T-maze task requiring spatial working memory (Gregory et al, 2003;Aultman and Moghaddam, 2001;Moghaddam and Adams, 1998).…”

Section: Introductionmentioning

confidence: 99%

Impoverished Rearing Environment Alters Metabotropic Glutamate Receptor Expression and Function in the Prefrontal Cortex

Meléndez

Gregory

Bardo

et al. 2004

Neuropsychopharmacol

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Rearing rats in impoverished (IC) and enriched (EC) environmental conditions alters synaptic plasticity and cognitive processes. Metabotropic glutamate receptors (mGluRs) are known to play a key role in synaptic and behavioral plasticity. In the present study, the effect of rearing conditions on the expression of mGluR proteins in the prefrontal cortex (PFC) was assessed by immunoblotting. A significant difference in the content of prefrontal mGluR1 and mGluR5 (ie group I) and mGluR2/3 (ie group II) was observed between IC and EC rats. To functionally characterize this difference, in vivo microdialysis was used to verify differences in mGluR regulation of extracellular glutamate in the PFC. The results indicate that the capacity of group I and II mGluRs to elevate extracellular glutamate levels was significantly blunted in the PFC of IC rats compared to either EC subjects, or rats reared in normal environmental conditions (ie NIH standards). Group II mGluR receptors regulate performance in a forced T-maze spatial memory task that involves the PFC, and IC rats demonstrated deficits in this task relative to EC rats. These data suggest that reduced mGluR transmission in the PFC produced by impoverished, relative to enriched, rearing environments may contribute to cognitive deficits.

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“…Opposing actions of mGlu2/3 agonists and antagonists have also been reported on behavior under a delayed alternation task in a T-maze [Gregory et al, 2003]. The mGlu2/3 agonist, aminopyrrolidine dicarboxylate (APDC) (1 nmol), impaired whereas LY341495 (0.01 and 0.l nmol) tended to enhance memory performance when injected bilaterally in the prefrontal cortex.…”

Section: Disorders Of Cognitionmentioning

confidence: 95%

Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders

Witkin

Eiler

2006

Drug Dev. Res.

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The metabotropic glutamate Group II receptors (mGlu2 and mGlu3 receptors) regulate the synaptic availability of glutamate and thus control the broad-ranging neural transmission of glutamate as well as glutamate-modulated transmission. The present review focuses on the potential role of Group II mGlu receptor antagonism in neurological and neuropsychiatric disorders. Recent findings have determined that agonists of metabotropic glutamate type 2/3 receptors (mGlu2/3) have antianxiety efficacy. Although it could be assumed that blockade of these receptors might engender anxiogenic responses, new data have indicted that these compounds produce antidepressant-like, wake-promoting, and pro-cognitive effects in rodents. However, there are almost no data available to define the relative importance of mGlu2 versus mGlu3 receptors in these activities. Although there are some hints that antagonism of mGlu2/3 receptors could have additional therapeutic impact, the preponderance of data suggests that agonists of the mGlu2/3 receptors would be more likely to have efficacy in anxiety disorders, positive symptoms of schizophrenia, neurodegenerative disorders, and stroke, pain, and epilepsy. The pharmacology of antagonists of mGlu2/3 receptors suggests that such compounds could have a unique place in the medicinal arsenal for mood disorders as well as disorders of cognition and arousal. Given the activity surrounding the discovery of orally available antagonists for these receptors, there may be an opportunity for clinical investigation of these possibilities in the future. Drug Dev. Res. 67:757-769, 2006.

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Prefrontal Group II Metabotropic Glutamate Receptor Activation Decreases Performance on a Working Memory Task

Cited by 15 publications

References 15 publications

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

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

Impoverished Rearing Environment Alters Metabotropic Glutamate Receptor Expression and Function in the Prefrontal Cortex

Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders

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