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 dopamine-independent 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 hyperlocomotion 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.