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 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.

Fig. 1

Histology. a, b Schematic representations of probe placements in the DStr and NAc, and stimulating electrode placements in the VTA, respectively. c Micrograph of a representative electrode placement in the VTA

Fig. 2

LY354740 pretreatment attenuates amphetamine-induced increases in dopamine release and hyperlocomotion. Rats were given an IP injection of 10.0 mg/kg of LY354740 (filled circles) or 0.9% saline (open circles) 20 min prior to an injection of 1.0 mg/kg of amphetamine. Dopamine release was measured in the a DStr (LY354740 group, n=9; mean baseline dopamine=1.7±0.3 fmol/μL; saline group, n=9; mean baseline dopamine=1.1±0.3 fmol/μL) and b NAc (LY354740 group, n=9; mean baseline dopamine= 1.6± 0.3 fmol/μL; saline group, n=7; mean baseline dopamine=0.6± 0.2 fmol/μL). Locomotor activity also was measured for each animal, expressed as c fine movements (LY354740 group, n=9; saline group, n=10) or d ambulations (LY354740 group, n=9; saline group, n=10). Peak fine movements were significantly correlated to peak dopamine release in the e DStr (one outlier was omitted from the LY354740 group) and f NAc (one outlier was omitted from the LY354740 group), but peak ambulations were not significantly correlated to peak dopamine release in g and h either brain region (one outlier was omitted from each treatment group in these two graphs). In graphs A, B, C, and D, baseline dopamine release or locomotor activity is represented by the first three time points displayed. Asterisks denote significant differences between treatment groups at a given time point (* p<0.05, ** p<0.01) while plus signs indicate significant differences compared to baseline within a given treatment group (+p<0.05, ++p<0.01)

Fig. 3

LY354740 pretreatment has no effect on dopamine release and locomotion elicited by electrical stimulation of the VTA. Rats were given an IP injection of 10.0 mg/kg of LY354740 (filled circles)or 0.9% saline (open circles) 20 min prior to electrical stimulation of the VTA. Dopamine release in the a NAc (LY354740 group, n=8; mean baseline dopamine=0.8±0.2 fmol/μL; saline group, n=9; mean baseline dopamine=0.6±0.2 fmol/μL) and locomotor activity were measured in each animal. Activity is expressed in terms of b fine movements (LY354740 group, n=8; saline group, n=9) or c ambulations (LY354740 group, n=8; saline group, n=9). d Peak fine movements were significantly correlated to peak NAc dopamine release. A nonsignificant trend toward a correlation was found between e peak ambulations and peak NAc dopamine release. In graphs A, B and C, baseline dopamine release or locomotor activity are represented by the first three time points displayed. Plus signs denote significant increases in dopamine release or activity compared to baseline (+ p<0.05; ++ p<0.01)

Fig. 4

LY354740 pretreatment has no effect on L-dopa-induced increases in dopamine release. Rats were given an IP injection of 10.0 mg/kg of LY354740 (filled circles) or 0.9% saline (open circles) 20 min prior to injecting 100.0 mg/kg of L-dopa. Dopamine release was measured in the a DStr (LY354740 group, n=8; mean baseline dopamine=1.2±0.1 fmol/μL; saline group, n=8; basal release=1.3± 0.3 fmol/μL) and b NAc (LY354740 group, n=7; mean baseline dopamine=0.7±0.2 fmol/μL; saline group, n=9; mean baseline dopamine=1.2±0.2 fmol/μL) for each animal. In addition, locomotor activity also was measured and is expressed as c fine movements (LY354740 group, n=9; saline group, n=14) or d ambulations (LY354740 group, n=9; saline group, n=14). No significant correlation was found between peak fine movements and dopamine release in e the DStr or f the NAc. Similarly, significant correlations were not found between g, h peak ambulations and dopamine release in either brain region. In graphs A, B, C and D, baseline dopamine release or locomotor activity is represented by the first three time points displayed. Plus signs denote significant increases in dopamine release or locomotor activity compared to baseline (+ p<0.05, ++ p<0.01). Note that the discrepancy in sample sizes between the DStr micro-dialysis graph and the related correlations is due to missing activity data for one subject. This missing data was caused by an unrecoverable computer error