Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate

Schoepp, Darryle D.; Johnson, Bryan G.; Salhoff, Craig R.; Valu, M.J.; Desai, Manisha; Burnett, J. Paul; Mayne, N.G.; Monn, James A.

doi:10.1016/0028-3908(95)00061-a

Cited by 77 publications

(53 citation statements)

References 32 publications

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“…The steep slope of the concentration-response curve for LY354740 is consistent with the dose-response relationship reported for a number other effects of this drug in both recom-binant and native systems Schaffhauser et al, 1997;Schoepp et al, 1997). The reduction of EPSC amplitude was mimicked by two other highly selective agonists of group II mGluRs, 2 R,4 R-APDC (Schoepp et al, 1995) and DCG-IV (Hayashi et al, 1993;Gereau and Conn, 1995a) (Fig. 1 D), and was completely blocked by previous application of LY341495 (100 nM) or CPPG (500 M) (Fig.…”

Section: Activation Of Group II Mglurs Inhibits Transmission At the Ssupporting

confidence: 70%

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Bradley¹,

Marino²,

Wittmann

et al. 2000

J. Neurosci.

131

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Loss of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) leads to increased activity of glutamatergic neurons in the subthalamic nucleus (STN). Recent studies reveal that the resultant increase in STN-induced excitation of basal ganglia output nuclei is responsible for the disabling motor impairment characteristic of PD. On the basis of this, it is possible that any manipulation that reduces activity at excitatory STN synapses onto basal ganglia output nuclei could be useful in the treatment of PD. We now report that group II metabotropic glutamate receptors (mGluRs) are presynaptically localized on STN terminals and that activation of these receptors inhibits excitatory transmission at STN synapses. In agreement with the hypothesis that this could provide a therapeutic benefit in PD, a selective agonist of group II mGluRs induces a dramatic reversal of catalepsy in a rat model of PD. These results raise the exciting possibility that selective agonists of group II mGluRs could provide an entirely new approach to the treatment of PD. These novel therapeutic agents would provide a noninvasive pharmacological treatment that does not involve the manipulation of dopaminergic systems, thus avoiding the problems associated with current therapies. Key words: substantia nigra pars reticulata; subthalamic nucleus; group II metabotropic glutamate receptors; Parkinson's disease; catalepsy; presynaptic inhibitionParkinson's disease (PD) is a common neurodegenerative disorder characterized by disabling motor impairments including tremor, rigidity, and bradykinesia. The primary pathological change giving rise to the symptoms of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta that modulate the function of neurons in the striatum and other nuclei in the basal ganglia (BG) motor circuit. Currently, the most effective pharmacological agents for the treatment of PD include levodopa (L-DOPA), the immediate precursor of dopamine, and other drugs that replace the lost dopaminergic modulation of BG function (Poewe and Granata, 1997). Unfortunately, dopamine replacement therapy ultimately fails in most patients because of loss of efficacy with progression of the disease and severe motor and psychiatric side effects (Poewe et al., 1986). Because of this, a great deal of effort has been focused on developing new approaches for the treatment of PD.Recent studies reveal that loss of nigrostriatal dopamine neurons results in a series of neurophysiological changes that lead to overactivity of a critical nucleus in the BG motor circuit termed the subthalamic nucleus (STN). The STN contains glutamatergic projection neurons that provide the major excitatory input to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr), the major output nuclei of the basal ganglia. Increased activity of STN neurons leads to an increase in glutamate release at STN synapses onto GABAergic projection neurons in the output nuclei. This glutamate-mediated overexcitation of BG output ultima...

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Section: Activation Of Group II Mglurs Inhibits Transmission At the Ssupporting

confidence: 70%

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Bradley¹,

Marino²,

Wittmann

et al. 2000

J. Neurosci.

131

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“…To confirm that DCG IV reduces thalamocortical EPSCs by stimulating group II mGluRs, we tested whether the effect of DCG IV could be reversed by the selective group II mGluR antagonist, LY 341495 (Bandrowski et al, 2003), and mimicked by another selective group II mGluR agonist, APDC (Schoepp et al, 1995). As shown in Figure 4A and B, 200 nM LY 341495 reversed the DCG IV-mediated inhibition of thalamocortical EPSCs in inhibitory neurons to 94 ± 6% of control (n = 4, t = 4.15, p = 0.025) and in excitatory neurons to 72 ± 9% of control (n = 4, t = 4.26, p = 0.024).…”

Section: The Dcg Iv-mediated Depression Is Reversed By Ly 341495 and mentioning

confidence: 99%

Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex

Mateo

Porter

2007

Neuroscience

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Thalamocortical synapses provide a strong glutamatergic excitation to cortical neurons that is critical for processing sensory information. Unit recordings in vivo indicate that metabotropic glutamate receptors (mGluRs) reduce the effect of thalamocortical input on cortical circuits. However, it is not known whether this reduction is due to a reduction in glutamate release from thalamocortical terminals or from a decrease in cortical neuron excitability. To directly determine whether mGluRs act as autoreceptors on thalamocortical terminals, we examined the effect of mGluR agonists on thalamocortical synapses in slices. Thalamocortical excitatory postsynaptic currents (EPSCs) were recorded in layer IV cortical neurons in developing mouse brain slices. The activation of group II mGluRs with DCG IV reduced thalamocortical EPSCs in both excitatory and inhibitory neurons, while the stimulation of group I or group III mGluRs had no effect on thalamocortical EPSCs. Consistent with a reduction in glutamate release, DCG IV increased the paired pulse ratio and the coefficient of variation of the EPSCs. The reduction induced by DCG IV was reversed by the group II mGluR antagonist, LY341495, and mimicked by another selective group II agonist, APDC. The mGluR2 subtype appears to mediate the reduction of thalamocortical EPSCs, since the selective mGluR3 agonist, NAAG, had no effect on the EPSCs. Consistent with this, we showed that mGluR2 is expressed in the barrels. Furthermore, blocking group II mGluRs with LY341495 reduced the synaptic depression induced by a short stimulus train, indicating that synaptically released glutamate activates these receptors. These results indicate that group II mGluRs modulate thalamocortical processing by inhibiting glutamate release from thalamocortical synapses. This inhibition provides a feedback mechanism for preventing excessive excitation of cortical neurons that could play a role in the plasticity and refinement of thalamocortical connections during this early developmental period.

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“…pretreatment with the selective group II agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R)-APDC)) [13] and the selective group III mGluR agonist (L-2-amino-4-phosphonobutyrate (L-AP4)) [14] on (RS)-DHPG-induced SNBs. To further implicate the involvement of glutamate release in mediating DHPG-induced SNBs, we also examined the effects of two sodium channel blockers known inhibit the release of glutamate, lamotrigine and riluzole on DHPG-induced SNBs.…”

Section: Introductionmentioning

confidence: 99%

Evidence that DHPG-induced nociception depends on glutamate release from primary afferent C-fibres

Lefebvre¹,

Fisher

Cahill

et al. 2000

NeuroReport

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We examined whether enhanced glutamate release contributes to the expression of persistent spontaneous nociceptive behaviours (SNBs) in rats induced by intrathecal (i.t.) administration of the selective group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine ((RS)-DHPG). Pretreatment with drugs that have been shown to inhibit glutamate release, including a group II metabotropic glutamate receptor (mGluR) agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a group III mGluR agonist L-2-amino-4-phosphonobutyrate (L-AP4), or the use-dependent sodium channel blockers 3,5-diamino-6-(2,3-diclorophenyl)-1,2,4-triazine (lamotrigine) and 2-amino-6-tri¯uoromethoxybenzothiazole (riluzole), produced dose-dependent reductions in (RS)-DHPG-induced SNBs. We have also shown that incubation of rat lumbar spinal cord slices with (RS)-DHPG potentiates 4-aminopyridine-evoked (4-AP) release of glutamate. Furthermore, we found that destruction of unmyelinated primary afferent C-®bres by neonatal capsaicin treatment signi®cantly reduced (RS)-DHPG-induced SNBs in adult rats. Together, these results suggest that (RS)-DHPGinduced nociception is dependent on spinal glutamate release, probably from primary afferent C-®bres.

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Selective inhibition of forskolin-stimulated cyclic AMP formation in rat hippocampus by a novel mGluR agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate

Cited by 77 publications

References 32 publications

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Activation of Group II Metabotropic Glutamate Receptors Inhibits Synaptic Excitation of the Substantia Nigra Pars Reticulata

Group II metabotropic glutamate receptors inhibit glutamate release at thalamocortical synapses in the developing somatosensory cortex

Evidence that DHPG-induced nociception depends on glutamate release from primary afferent C-fibres

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