The group II metabotropic glutamate receptor agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat - PubMed (original) (raw)

The group II metabotropic glutamate receptor agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat

L Dawson et al. Br J Pharmacol. 2000 Feb.

Abstract

1. This study examined whether activation of group II metabotropic glutamate (mGlu) receptors in the substantia nigra pars reticulata (SNr) could reverse akinesia in a rodent model of Parkinson's disease (PD). 2. Male Sprague Dawley rats, stereotaxically cannulated above either the SNr or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg-1 s.c.). Eighteen hours later, the rotational behaviour induced by unilateral injection of the group II mGlu receptor agonist, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), was examined. 3. Following intranigral injection, DCG-IV (0.125-0.75 nmol in 0.1 microliter) produced a dose-dependent increase in net contraversive rotations (n = 6-8 animals per dose), reaching a maximum of 395 +/- 51 rotations 60 min-1 after 0.75 nmol. The effects of DCG-IV (0.5 nmol) were inhibited by 63.0 +/- 9.0% following 30 min pre-treatment with the group II mGlu receptor antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 100 nmol in 0.2 microliter; n = 6). 4. Following intraventricular injection, DCG-IV (0.125-1.5 nmol in 2 microliters) produced a dose-dependent increase in bilateral locomotor activity (n = 6-7 animals per dose), reaching a maximum of 180 +/- 21 locomotor units 30 min-1 after 0.5 nmol. Pre-treatment with EGLU (200 nmol in 2 microliters) inhibited the effects of DCG-IV (0.5 nmol) by 68.2 +/- 12.3% (n = 5). 5. These data show that activation of group II mGlu receptors in the SNr provides relief of akinesia in the reserpinized rat model of PD. The reversal seen following intraventricular administration supports the likely therapeutic benefit of systemically-active group II mGlu receptor agonists in PD.

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Figures

Figure 1

Figure 1

(a) Time-course of locomotor activity induced by a maximally-effective dose of the group II mGlu receptor agonist, DCG-IV (0.75 nmol in 0.1 μl) and (b) Dose-related locomotor effects of DCG-IV (0.125–0.75 nmol in 0.1 μl) or vehicle (0.1 μl PBS), following unilateral injection into the SNr of the reserpine-treated rat. Values represent mean±s.e.mean (_n_=6–8 animals per dose). *Indicates a significant difference compared to (a) baseline activity or (b) the previous dose (1-way ANOVA, P<0.05 in all cases).

Figure 2

Figure 2

Comparison of locomotor activity induced by intranigral injection of the group II mGlu receptor agonist, DCG-IV (0.5 nmol in 0.1 μl) prior to (open bars) and 30 min following (closed bars) treatment with the group II mGlu receptor antagonist, EGLU (100 nmol in 0.1 μl) or vehicle (0.1 μl of 0.3 m

M

NaOH in PBS). Data represent mean±s.e.mean (_n_=6 animals per treatment). *Indicates a significant difference between pre-treatment and post-treatment responses to DCG-IV (paired _t_-test, P<0.05).

Figure 3

Figure 3

(a) Time-course of locomotor activity induced by a maximally-effective dose of DCG-IV (0.5 nmol in 2 μl) and (b) dose-related locomotor effects of DCG-IV (0.125–1.5 nmol in 2 μl) or vehicle (2 μl of PBS), following intraventricular injection in the reserpine-treated rat. Values represent mean±s.e.mean (_n_=6–7 animals per dose). *Indicates a significant difference compared to (a) baseline activity or (b) the previous dose (1-way ANOVA, P<0.05 in all cases).

Figure 4

Figure 4

Comparison of locomotor activity induced by intraventricular injection of the group II mGlu receptor agonist, DCG-IV (0.5 nmol in 2 μl) prior to (open bars) and 30 min following (closed bars) treatment with the group II mGlu receptor antagonist, EGLU (200 nmol in 2 μl) or vehicle (2 μl of 0.3 m

M

NaOH in PBS). Data represent mean±s.e.mean (_n_=5 animals per treatment). *Indicates a significant difference between pre-treatment and post-treatment responses to DCG-IV (paired _t_-test, P<0.05).

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References

    1. BATTAGLIA G., MONN J.A., SCHOEPP D.D. In vivo inhibition of veratridine-evoked release of striatal excitatory amino acids by the group II metabotropic glutamate receptor agonist LY35470 in rats. Neurosci. Lett. 1997;229:161–164. - PubMed
    1. BENAZZOUZ A., GROSS C., FEGER J., BORAUD T., BIOULAC B. Reversal of rigidity and improvement of motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur. J. Neurosci. 1993;5:382–389. - PubMed
    1. BERGMAN H., WICHMANN T., DELONG M.R. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249:1346–1348. - PubMed
    1. BROTCHIE J.M., CROSSMAN A.R. D-[3H]Aspartate and [14C]GABA uptake in the basal ganglia of rats following lesions in the subthalamic region suggest a role for excitatory amino acids but not GABA-mediated transmission in subthalamic nucleus efferents. Exp. Neurol. 1992;113:171–181. - PubMed
    1. CALABRESI P., CENTONZE D., PISANI A., BERNARDI G. Metabotropic glutamate receptors and cell-type-specific vulnerability in the rat striatum: implication for ischaemia and Huntington's disease. Exp. Neurol. 1999;158:97–108. - PubMed

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