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

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.

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity.

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.

Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism.

RATIONALE: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. OBJECTIVE: This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. METHODS: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. RESULTS: RO4917523 (0.1-1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. CONCLUSIONS: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.