Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition

Abstract

It has been proposed that activation of metabotropic glutamate receptor subtype 2/3 (mGluR2/3) may induce both antipsychotic and anxiolytic effects. The aim of this study was to evaluate further the effect of the mGluR2/3 agonist, LY354740 [(+)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylate monohydrate] in animal models relevant to both psychotic and cognitive impairment in schizophrenia. The elevated plus maze was used to select the doses for further experiments, LY354740 induced anxiolytic-like effects at doses of 3 and 10 mg/kg but not 1 mg/kg. At a dose of 10 mg/kg. LY354740 attenuated phencyclidine (PCP)-induced locomotor activity. Administered alone, it had no effect on horizontal activity, but at doses of 3 and 10 mg/kg, slightly decreased vertical activity (rearings). LY354740 (1-10 mg/kg intraperitoneally) affected neither prepulse inhibition in normal rats nor reversed the disruption of prepulse inhibition produced by PCP (2 mg/kg subcutaneously). Moreover, LY354740 (3-10 mg/kg) did not modify PCP-induced working memory deficits assessed in a spontaneous alternation task and had no effect on PCP-evoked amnesia in the passive avoidance test. LY354740 alone (3 and 10 mg/kg) induced working memory deficits, but had no effect on acquisition of passive avoidance. In conclusion, LY354740 was effective in models for anxiety and positive symptoms of schizophrenia but not in models for sensorimotor gating and cognitive impairment.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

“…The therapeutic potential has however been shown to vary between different mGluR2/3 agonists, as some agonists failed to improve PCP-induced behavioral impairments (Schlumberger et al, 2009). Treatment specifically with the mGluR2/3 agonist LY379268 used in this study has been shown to reduce MK-801-induced hippocampal-PFC synaptic transmission and gamma band oscillation; this supports the utility of LY379268 to restore the balance between glutamatergic and GABAergic neurotransmission in cortical and subcortical regions (Blot et al, 2013;Hiyoshi et al, 2014).…”

Stimulation of Metabotropic Glutamate (mGlu) 2 Receptor and Blockade of mGlu1 Receptor Improve Social Memory Impairment Elicited by MK-801 in Rats

“…mGlu2/3-receptor agonists have been reported not to improve either the NMDA-receptor antagonists-induced impairment of working memory (39) or the NMDAreceptor antagonist-induced impairment of object recognition (40), although mGlu2/3-receptor agonists improved object recognition impairment in rodents reared in social isolation or in mice lacking the pituitary adenylate cyclase-activating polypeptide (41 -43). Moreover, the stimulation of the mGlu2 receptor or the blockade of the mGlu1 receptor reportedly caused cognitive impairment itself (19,44,45).…”

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

“…It should be noted that there are negative results as well. More specifically, mGlu2/3 receptor agonists were shown not to be able to antagonize cognition-impairing effects of PCP in other studies in which experimental protocols may have been optimized to detect cognition-impairing effects of mGlu2/3 agents (Schlumberger et al, 2009). Furthermore, failures to reverse certain cognitive effects of PCP may be related to the fact that PCP-like agents are able to impair performance in behavioral tasks via a number of different mechanisms, including motor activation, behavioral disinhibition, and induction of state-dependence.…”