Impact of metabotropic glutamate 2/3 receptor stimulation on activated dopamine release and locomotion

Abstract

Rationale-Activation of metabotropic glutamate (mGlu) 2/3 receptors may provide a novel strategy for treating schizophrenia. This effect is thought to be mediated through dopamineindependent mechanisms because mGlu2/3-receptor agonists have no considerable affinity for dopamine receptors. These agonists, however, reduce amphetamine-induced hyperlocomotion suggesting that they influence dopamine neurotransmission.Objective-We evaluated whether the inhibitory effect of mGlu2/3-receptor activation on amphetamine-induced hyper-locomotion correlates with attenuated dopamine release. We also assessed whether mGlu 2/3 receptor activation has inhibitory effects on activity-dependent vesicular release of dopamine in behaving animals.Methods-Microdialysis was used to measure extracellular levels of dopamine in the dorsal striatum (DStr) and nucleus accumbens (NAc) of freely moving rats. The effect of the mGlu2/3-receptor agonist LY354740 on dopamine release and locomotion elicited by amphetamine, electrical stimulation of the ventral tegmental area, or L-dopa was assessed.Results-We find that the inhibitory effect of mGlu2/3 activation on amphetamine-induced hyperlocomotion correlates with an attenuated increase in dopamine release in the NAc and DStr. However, when dopamine levels were increased by electrical stimulation of dopamine neurons or by administration of the dopamine precursor L-dopa, activation of mGlu2/3 receptors had no effect on dopamine release or on behavior.Conclusions-Activation of mGlu2/3 receptors attenuates amphetamine-induced dopamine release through a mechanism that does not affect activity dependent vesicular release, reuptake or synthesis of dopamine.

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

“…A similar lack of effect on PCPinduced DA release was reported for a heterotropic group II mGluR agonist (1). In contrast, a group II agonist blocked D-amphetamine-induced motor activation and increases in DA release but not electrically evoked DA release in the mPAG, bringing into question its mechanism of action (27,29). Because ZJ43 and 2-PMPA also reduce D-amphetamine-induced motor activation, 5 it will be interesting to determine if the peptidase inhibitors affect DA release in the D-amphetamine model.…”

Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission

“…This is similar to the previous observations on the mGlu2/3 receptor agonists LY379268 and LY404039 in a hyperdopaminergic model using amphetamine (Cartmell et al 1999(Cartmell et al , 2000Fell et al 2008;RorickKehn et al 2007;Uslaner et al 2009;Woolley et al 2008). On the other hand, the other mGlu2/3 receptor agonist LY354740 does not affect amphetamine-induced increases in horizontal locomotor activity (Cartmell et al 1999;Schlumberger et al 2009), although there is one positive report (Pehrson and Moghaddam 2010). It is not known whether MGS0028 inhibits amphetamine-induced hyperlocomotion.…”

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

“…Recent studies showed that LY379268 (1 mg/kg) and the 5-HT 2A inverse agonist, M100907 (0.2 mg/kg), modestly decreased amphetamine-induced hyperlocomotion when given alone, whereas the combination markedly attenuated amphetamine-and MK-801-induced hyperlocomotion (Uslaner et al 2009). These considerations led Pehrson and Moghaddam (2010) to suggest that mGlu 2/3 agonists may be working, in part, through a serotonergic signaling mechanism to attenuate the ability of amphetamine to increase DA efflux. LY379268 may induce functional changes in these heterodimer complexes and 5-HT 2A receptor signal transduction, thereby producing the synergistic effects of LY379268 and sub-effective doses of the atypical APDs, clozapine and lurasidone.…”