Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats

Abstract

Dysregulation of glutamate neurotransmission may play a role in cognitive deficits in schizophrenia. Manipulation of glutamate signaling using drugs acting at metabotropic glutamate receptors has been suggested as a novel approach to treating schizophrenia-related cognitive dysfunction. We examined how the metabotropic glutamate receptor 2/3 agonist LY379268 and the metabotropic glutamate receptor 2/3 antagonist LY341495 altered phencyclidine-induced disruptions in performance in the 5-choice serial reaction time task. This test assesses multiple cognitive modalities characteristically impaired in schizophrenia that are disrupted by phencyclidine administration. Acute LY379268 alone did not affect 5-choice serial reaction time task performance, except for nonspecific response suppression at high doses. Acute LY379268 administration exacerbated phencyclidine-induced disruption of attentional performance in this task, while acute LY341495 did not alter 5-choice serial reaction time task performance during phencyclidine exposure. Chronic LY341495 impaired attentional performance in the 5-choice serial reaction time task by itself, but attenuated phencyclidine -induced excessive timeout responding. The mixed effects of metabotropic glutamate receptor 2/3 agonism and antagonism on cognitive performance under baseline conditions and after disruption with phencyclidine demonstrate that different aspects of cognition may respond differently to a given pharmacological manipulation, indicating that potential antipsychotic or procognitive medications need to be tested for their effects on a range of cognitive modalities. Our findings also suggest that additional mechanisms, besides cortical glutamatergic transmission, may be involved in certain cognitive dysfunctions in schizophrenia.

Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression

“…However, it seemed that LY379268-treated rats made a higher number of omission errors which might indicate deficits in attentional processes. Similar effects were found in a previous study that also reported decreases in premature responses and in the number of trials completed (Amitai and Markou 2010). However, it has been shown that LY379268 produces hypolocomotor effects (Cartmell et al 1999) and also might interfere with motivational processes at doses ≥0.3 mg/kg (Pozzi et al 2011).…”

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

“…Another mGlu 2/3 agonist, LY487379, had no effect on cognitive impairment in active allothetic place avoidance induced by MK-801 (Vales et al 2010). LY354740 has been reported to induce memory impairments in rats (Aultman and Moghaddam 2001) whereas LY379268 exacerbated PCP-induced disruption of attentional performance in the five-choice serial reaction time task (Amitai and Markou 2010). Possible synergistic effects between mGlu 2/3 agonists and typical or atypical APDs have not yet been investigated.…”

Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia

“…The type-3 metabotropic glutamate receptor gene ( GRM3 ) encodes the mGluR3 protein which functions to modulate signaling through N -methyl-D-aspartate receptors (NMDARs) in ways that may reverse NMDAR hypofunction which is believed to be an important contributor to cognitive deficits and negative symptoms in schizophrenia (Cartmell and Schoepp 2000). Preclinical studies have indicated that pharmacologically altering mGluR3 can reverse behavioral effects of dopamine dysregulation in rodent models and may also have domain-specific cognitive effects (Amitai and Markou 2010; Bespalov et al 2007; Yoon et al 2008). While human genetic studies of GRM3 have identified associations with prefrontal physiology and associated cognitive processes in chronically treated patients (Egan et al 2004), pharmacogenetic relationships with cognitive or clinical outcomes have not been examined in first-episode treatment studies.…”