Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators

Abstract

Dysregulation of prefrontal cortical glutamatergic signalling via NMDA receptor hypofunction has been implicated in cognitive dysfunction and impaired inhibitory control in such neuropsychiatric disorders as schizophrenia, attention‐deficit hyperactivity disorder and drug addiction. Although NMDA receptors functionally interact with metabotropic glutamate receptor 5 (mGluR5), the consequence of this interaction for glutamate release in the prefrontal cortex (PFC) remains unknown. We therefore investigated the effects of positive and negative allosteric mGluR5 modulation on changes in extracellular glutamate efflux in the medial PFC (mPFC) induced by systemic administration of the non‐competitive NMDA receptor antagonist dizocilpine (or MK801) in rats. Extracellular glutamate efflux was measured following systemic administration of the positive allosteric mGluR5 modulator [S‐(4‐Fluoro‐phenyl)‐{3‐[3‐(4‐fluoro‐phenyl)‐[1,2,4]‐oxadiazol‐5‐yl]‐piperidin‐1‐yl}‐methanone] (ADX47273; 100 mg/kg, p.o.) and negative allosteric mGluR5 modulator [2‐chloro‐4‐{[1‐(4‐fluorophenyl)‐2,5‐dimethyl‐1H‐imidazol‐4‐yl]ethynyl}pyridine] (RO4917523; 0.3 mg/kg, p.o.), using a wireless glutamate biosensor in awake, freely moving rats. The effect of MK801 (0.03–0.06 mg/kg, s.c.) on mPFC glutamate efflux was also investigated in addition to the effects of MK801 (0.03 mg/kg, s.c.) following ADX47273 (100 mg/kg, p.o.) pre‐treatment. ADX47273 produced a sustained increase in glutamate efflux and increased the effect of NMDA receptor antagonism on glutamate efflux in the mPFC. In contrast, negative allosteric mGluR5 modulation with RO4917523 decreased glutamate efflux in the mPFC. These findings indicate that positive and negative allosteric mGluR5 modulators produce long lasting and opposing actions on extracellular glutamate efflux in the mPFC. Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders.

Amperometric measurements of cocaine cue and novel context‐evoked glutamate and nitric oxide release in the nucleus accumbens core

“…All solutions for in vitro calibrations were made in ddH 2 0, except for DETA (see above). The nA response of each electrode during in vivo recordings was converted to Δnm for glutamate and NO, as described previously (Isherwood, Robbins, Dalley, & Pekcec, ). Briefly, the ΔnM glutamate or NO was calculated using the slope of the linear regression of each electrode's in vitro calibration, relative to a 15‐min pre‐session homecage baseline.…”

“…The next morning the potentiostat was activated, the recordings began, and rats were placed in a dark room for 30–60 min until a steady baseline was achieved. Implantation of the electrode 15 hr prior to experimentation drastically improved the stability of the pre‐experiment baseline response of the electrode (Isherwood et al, ). Rats were then exposed to a novel MedPC operant chamber with two interactable levers, a grated floor, and a house light for 2 hr where lever presses had no programmed consequence.…”

“…Reinstatement behavioral data were analyzed with a two‐way repeated measures ANOVA with treatment (cocaine vs. saline) as a between‐subjects variable and time (extinction vs. reinstatement) as a within‐subjects variable followed by Bonferroni‐corrected multiple comparison test when a significant interaction was revealed. 1 Hz measurements of glutamate and NO during reinstatement and novel context exposure were averaged in 5‐min bins (low, temporal resolution first hour of session) or 1‐min bins (medium temporal resolution, first 15 min of session) (Isherwood et al, ). A two‐way repeated measures ANOVA was performed followed by Bonferroni‐corrected pairwise comparison tests to compare across treatments within bins when a significant treatment by time interaction was revealed.…”

Comparative gene pathway analysis during adolescent binge-EtOH exposure, withdrawal, and following abstinence

“…In the 'synaptic transmission' gene set the gene encoding for mGluR5 (GRM5) is enriched. This receptor is expressed on neurons and astrocytes in early development and is involved in regulation of glutamate availability (Isherwood et al, 2018). Six of the next 8 gene sets upregulated involved potassium ('potassium ion transport', 'voltage gated potassium channel activity', 'potassium channel activity', and 'voltage gated potassium channel complex'), voltage gated channels (voltage gated channel activity' and 'voltage gated cation channel activity') and 'synaptic transmission'.…”

Amperometric measurements of cocaine cue and novel context-evoked glutamate and nitric oxide release in the nucleus accumbens core

“…All solutions for in vitro calibrations were made in ddH20, except for DETA (see above). The nA response of each electrode during in vivo recordings was converted to nM for glutamate and NO, as described previously (Isherwood et al 2018). Briefly, the nM glutamate or NO was calculated using the slope of the linear regression of each electrode's in vitro calibration, relative to a 15-minute pre-session home-cage baseline.…”