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James A. Monn - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective effects of a systemically active group ii metabotropic Glutamate Receptor Agonist ly354740 in a gerbil model of global ischaemia
Neuroreport, 1998Co-Authors: Ann Bond, James A. Monn, Michael J Oneill, Caroline A Hicks, David M. LodgeAbstract:The neuroprotective effects of a novel Group II metabotropic Glutamate Receptor (mGluR) Agonist, LY354740, have been evaluated in a gerbil model of global ischaemia. When administered at 50 mg/kg, i.p., 30 min and 6 h after a 3 min period of bilateral carotid artery occlusion (BCAO), the compound reduced the damage to CA1 hippocampal neurones to a significant level. However, when the ischaemic insult was made more severe, by increasing the period of occlusion to 4 and 5 min, the neuroprotective effects of LY354740 were reduced. From these findings, it would appear that Group II mGluRs may play a role in ischaemic damage in the gerbil hippocampus and that Agonists at these Receptors are potential neuroprotective agents.
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ly354740 a metabotropic Glutamate Receptor Agonist which ameliorates symptoms of nicotine withdrawal in rats
Neuropharmacology, 1997Co-Authors: David R Helton, James A. Monn, Darryle D Schoepp, Joseph P Tizzano, Mary Jeanne KallmanAbstract:Abstract LY354740 is a conformationally constrained analog of Glutamate with high selectivity and nanomolar Agonist activity at Group II metabotropic Glutamate Receptors (mGluRs). This orally active compound is a new drug candidate which is being developed for the treatment of anxiety. In this study, LY354740 was investigated in a model of nicotine withdrawal using the acoustic startle reflex (sensorimotor reactivity) in rats. Nicotine (6 mg/kg/day) was administered for 12 days subcutaneously by osmotic minipumps. After 12 days the pumps were removed and the animals were allowed to go through spontaneous withdrawal. Cessation of chronic nicotine exposure led to increased startle responding for 4 days following withdrawal. Treatment with LY354740 (0.0001–0.1 mg/kg, i.p.; 0.03–3 mg/kg, oral) produced a dosedependent attenuation of the enhanced auditory startle responding following withdrawal of nicotine with intraperitoneal and oral ed 50 values of 0.003 mg/kg and 0.7 mg/kg, respectively. These effects were stereoselective since the (−)-enantiomer of LY354740, LY366563, was without effect in this model. LY354740 produced no changes in the sensorimotor reactivity of rats not exposed to nicotine at oral doses up to 10 mg/kg. These data support the functional role of mGluR Agonists in nicotine withdrawal and indicate that LY354740 may be efficacious in reducing the symptoms associated with nicotine withdrawal during smoking cessation in humans.
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A novel orally active group 2 metabotropic Glutamate Receptor Agonist: LY354740.
Neuroreport, 1997Co-Authors: Ann Bond, James A. Monn, David M. LodgeAbstract:Non-specific metabotropic Glutamate Receptor (mGluR) Agonists have previously been shown to potentiate responses of spinal neurones to ionotropic Glutamate Receptor Agonists. In this study we show that LY354740, which is a highly selective Group 2 mGluR Agonist with nanomolar potency in vitro, also mimics the above effects following local ejection on spinal neurones in vivo, an action which is blocked by a Group 2 antAgonist. Despite its polar nature, LY354740 is also active given either by the i.v. or the oral route (2.5-20 mg/kg) and thus will be a useful agent for investigating the role of Group 2 mGluRs both physiologically and clinically.
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ly354740 is a potent and highly selective group ii metabotropic Glutamate Receptor Agonist in cells expressing human Glutamate Receptors
Neuropharmacology, 1997Co-Authors: Darryle D Schoepp, Bryan G Johnson, Craig R Salhoff, Rebecca A Wright, N G Mayne, S L Cockerham, Paul J Burnett, Ramamoorthy Belegaje, David Bleakman, James A. MonnAbstract:The novel compound LY354740 is a conformationally constrained analog of Glutamate, which was designed for interaction at metabotropic Glutamate (mGlu) Receptors. In this paper the selectivity of LY354740 for recombinant human mGlu Receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 Receptors, LY354740 produced >90% suppression of forskolin-stimulated cAMP formation with an ec50 of 5.1 ± 0.3 nM. LY354740 was six-fold less potent in activating human mGlu3 Receptors (ec50 = 24.3 ± 0.5 nM). LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 Receptor-expressing cells was blocked by competitive mGlu Receptor antAgonists, including (+)-α-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S0-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no Agonist or antAgonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu Receptors) (ec50s > 100 000 nM). When tested at group I phosphoinositide-coupled human mGlu Receptors (mGlu1a and mGlu5a), LY354740 did not activate or inhibit mGlu Receptor Agonist-evoked phosphoinositide hydrolysis at up to 100 000 nM. Electrophysiological experiments also demonstrated that LY354740 also had no appreciable activity in cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) Receptors. Thus, LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) Receptor Agonist, useful to explore the functions of these Receptors in situ. © 1997 Elsevier Science Ltd. All rights reserved.
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inhibition of cyclic amp formation by a selective metabotropic Glutamate Receptor Agonist
Journal of Neurochemistry, 1992Co-Authors: Darryle D Schoepp, Bryan G Johnson, James A. MonnAbstract:It is well documented that the effects of excitatory amino acid (EAA) Agonists on phosphoinositide hydrolysis involve a GTP-binding protein-linked or "metabotropic" Receptor mechanism. The mechanisms by which EAAs alter cyclic AMP levels in brain slices, however, are not yet clear. In this study, the selective metabotropic EAA Agonist trans-(+-)-1-aminocyclopentane-1,3-dicarboxylic acid and its isomers were examined for effects on basal and forskolin-stimulated cyclic AMP formation in slices of the rat hippocampus. Trans-(+-)-1-Aminocyclopentane-1,3-dicarboxylic acid had little effect on basal cyclic AMP but inhibited forskolin-stimulated cyclic AMP formation in a biphasic manner. The 1S,3R isomer of 1-aminocyclopentane-1,3-dicarboxylic acid produced potent but only partial (approximately 50%) inhibition of forskolin-stimulated cyclic AMP formation. 1R,3S-1-Aminocyclopentane-1,3-dicarboxylic acid fully inhibited forskolin-stimulated cyclic AMP but with lower potency than the 1S,3R isomer. These results show that in addition to the formation of phosphoinositide-derived second messengers, the cellular consequences of selectively activating hippocampal metabotropic EAA Receptors include an alteration of cellular cyclic AMP levels.
Susan Duty - One of the best experts on this subject based on the ideXlab platform.
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the group ii metabotropic Glutamate Receptor Agonist dcg iv alleviates akinesia following intranigral or intraventricular administration in the reserpine treated rat
British Journal of Pharmacology, 2000Co-Authors: Lee Dawso, M Megalou, Anita Chadha, Susan DutyAbstract: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). 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. Following intranigral injection, DCG-IV (0.125–0.75 nmol in 0.1 μl) 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)-α-ethylglutamic acid (EGLU; 100 nmol in 0.2 μl; n=6). Following intraventricular injection, DCG-IV (0.125–1.5 nmol in 2 μl) 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 μl) inhibited the effects of DCG-IV (0.5 nmol) by 68.2±12.3% (n=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. Keywords: Akinesia, autoReceptor, basal ganglia, DCG-IV, metabotropic Glutamate Receptor, reserpine, substantia nigra, subthalamic nucleus, Parkinson's disease Introduction Current treatments for Parkinson's disease (PD) rely heavily on dopamine replacement therapies which, although effective in the early stages of treatment, are accompanied by debilitating dyskinesias and reduced efficacy with long-term use (Stocchi et al., 1997). For these reasons, alternative treatments that do not rely on dopamine replacement are being investigated. The loss of striatal dopamine innervation in PD produces many downstream changes in activity of the basal ganglia components. In particular, the subthalamic nucleus (STN), which innervates the output regions of the basal ganglia, the substantia nigra pars reticulata (SNr) and the internal globus pallidus (GPi) or rodent homologue, the entopeduncular nucleus (EPN), becomes markedly overactive (Mitchell et al., 1989). Being Glutamatergic in nature (Robledo & Feger, 1990; Brotchie & Crossman, 1992), overactivity of STN neurones results in increased Glutamate-mediated excitation of the SNr and GPi/EPN which is ultimately believed to lead to inhibition of thalamocortical feedback and subsequent generation of the akinetic symptoms seen in PD (Parent et al., 1995). Accordingly, previous studies have demonstrated that surgical inactivation of STN efferent transmission either through subthalamotomy (Bergman et al., 1990) or by high frequency stimulation-induced depolarizing blockade (Benazzouz et al., 1993) alleviates motor disturbances in animal models of PD. Moreover, direct injection of NMDA- and AMPA-type Glutamate Receptor antAgonists into the SNr and GPi/EPN has been shown to alleviate Parkinsonian symptoms in these animals (see Starr et al., 1997 for review). However, neither of these approaches is ideal. On the one hand, surgical intervention is often irreversible and, especially following STN lesion, leads to the generation of dyskinesias through excessive inhibition of STN activity (Bergman et al., 1990). On the other hand, systemic administration of NMDA- and AMPA-type Glutamate Receptor antAgonists is accompanied by unaccept-able side-effects such as psychostimulation, sedation or ataxia, that result from widespread blockade of these Receptors (Starr et al., 1997). An alternative approach to resolving this overactive Glutamatergic transmission might be to reduce the level of Glutamate release from the STN terminals in the SNr and GPi/EPN. Group II metabotropic Glutamate (mGlu) Receptors may provide an ideal means of achieving this. Group II mGlu Receptors are negatively coupled through Gi/o to adenylate cyclase and voltage-operated calcium channels and their activation brings about membrane hyperpolarization (reviewed by Conn & Pin, 1997). This functional response, coupled with their presynaptic localization in brain regions such as the striatum (Testa et al., 1998) and hippocampus (Shigemoto et al., 1997) has led to the suggestion that group II mGlu Receptors operate as autoReceptors controlling the release of Glutamate in target areas. Group II mGlu mRNA is expressed in the STN (Testa et al., 1994) and corresponding group II immunoreactivity is localized to presynaptic terminal regions in the SNr (Yung, 1998), suggesting that group II mGlu autoReceptors might be present on STN terminals. If this is so, their activation is predicted to reduce Glutamate release in basal ganglia output regions and thereby alleviate Parkinsonian symptoms. Therefore, the aim of this study was to assess whether injection of a group II mGlu Receptor Agonist, either directly into the SNr, or away from the target site (i.e. into the cerebral ventricles), could reverse the akinesia in the reserpine-treated rat model of PD. Some of this work has been published previously in abstract form (Dawson et al., 1999).
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The group II metabotropic Glutamate Receptor Agonist, DCG-IV, alleviates akinesia following intranigral or intraventricular administration in the reserpine-treated rat.
British Journal of Pharmacology, 2000Co-Authors: L. G. Dawson, Akshay Chadha, M Megalou, Susan DutyAbstract: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.
Darryle D Schoepp - One of the best experts on this subject based on the ideXlab platform.
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ly354740 a metabotropic Glutamate Receptor Agonist which ameliorates symptoms of nicotine withdrawal in rats
Neuropharmacology, 1997Co-Authors: David R Helton, James A. Monn, Darryle D Schoepp, Joseph P Tizzano, Mary Jeanne KallmanAbstract:Abstract LY354740 is a conformationally constrained analog of Glutamate with high selectivity and nanomolar Agonist activity at Group II metabotropic Glutamate Receptors (mGluRs). This orally active compound is a new drug candidate which is being developed for the treatment of anxiety. In this study, LY354740 was investigated in a model of nicotine withdrawal using the acoustic startle reflex (sensorimotor reactivity) in rats. Nicotine (6 mg/kg/day) was administered for 12 days subcutaneously by osmotic minipumps. After 12 days the pumps were removed and the animals were allowed to go through spontaneous withdrawal. Cessation of chronic nicotine exposure led to increased startle responding for 4 days following withdrawal. Treatment with LY354740 (0.0001–0.1 mg/kg, i.p.; 0.03–3 mg/kg, oral) produced a dosedependent attenuation of the enhanced auditory startle responding following withdrawal of nicotine with intraperitoneal and oral ed 50 values of 0.003 mg/kg and 0.7 mg/kg, respectively. These effects were stereoselective since the (−)-enantiomer of LY354740, LY366563, was without effect in this model. LY354740 produced no changes in the sensorimotor reactivity of rats not exposed to nicotine at oral doses up to 10 mg/kg. These data support the functional role of mGluR Agonists in nicotine withdrawal and indicate that LY354740 may be efficacious in reducing the symptoms associated with nicotine withdrawal during smoking cessation in humans.
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ly354740 is a potent and highly selective group ii metabotropic Glutamate Receptor Agonist in cells expressing human Glutamate Receptors
Neuropharmacology, 1997Co-Authors: Darryle D Schoepp, Bryan G Johnson, Craig R Salhoff, Rebecca A Wright, N G Mayne, S L Cockerham, Paul J Burnett, Ramamoorthy Belegaje, David Bleakman, James A. MonnAbstract:The novel compound LY354740 is a conformationally constrained analog of Glutamate, which was designed for interaction at metabotropic Glutamate (mGlu) Receptors. In this paper the selectivity of LY354740 for recombinant human mGlu Receptor subtypes expressed in non-neuronal (RGT) cells is described. At human mGlu2 Receptors, LY354740 produced >90% suppression of forskolin-stimulated cAMP formation with an ec50 of 5.1 ± 0.3 nM. LY354740 was six-fold less potent in activating human mGlu3 Receptors (ec50 = 24.3 ± 0.5 nM). LY354740 inhibition of forskolin-stimulated cAMP formation in human mGlu2 Receptor-expressing cells was blocked by competitive mGlu Receptor antAgonists, including (+)-α-methyl-4-carboxyphenylglycine (MCPG) and LY307452 ((2S,4S0-2-amino-4-(4,4-diphenylbut-1-yl)-pentane-1,5-dioic acid). LY354740 had no Agonist or antAgonist activities at cells expressing human mGlu4 or mGlu7 (group III mGlu Receptors) (ec50s > 100 000 nM). When tested at group I phosphoinositide-coupled human mGlu Receptors (mGlu1a and mGlu5a), LY354740 did not activate or inhibit mGlu Receptor Agonist-evoked phosphoinositide hydrolysis at up to 100 000 nM. Electrophysiological experiments also demonstrated that LY354740 also had no appreciable activity in cells expressing human recombinant AMPA (GluR4) and kainate (GluR6) Receptors. Thus, LY354740 is a highly potent, efficacious and selective group II (mGlu2/3) Receptor Agonist, useful to explore the functions of these Receptors in situ. © 1997 Elsevier Science Ltd. All rights reserved.
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enzymatic resolution and pharmacological activity of the enantiomers of 3 5 dihydroxyphenylglycine a metabotropic Glutamate Receptor Agonist
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Richard S Baker, John Goldsworthy, Raymond C Harden, Craig R Salhoff, Darryle D SchoeppAbstract:Abstract 3,5-Dihydroxyphenylglycine (3,5-DHPG) was resolved using an aminoacylase enzyme in solution, and the enantiomers characterised for ability to stimulate metabotropic Glutamate Receptor (mGluR) mediated phosphoinositide hydrolysis in rat hippocampus. The mGluR activity resided mainly in the (S) enantiomer, which should thus be a useful tool to further explore mGluR pharmacology and function.
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inhibition of cyclic amp formation by a selective metabotropic Glutamate Receptor Agonist
Journal of Neurochemistry, 1992Co-Authors: Darryle D Schoepp, Bryan G Johnson, James A. MonnAbstract:It is well documented that the effects of excitatory amino acid (EAA) Agonists on phosphoinositide hydrolysis involve a GTP-binding protein-linked or "metabotropic" Receptor mechanism. The mechanisms by which EAAs alter cyclic AMP levels in brain slices, however, are not yet clear. In this study, the selective metabotropic EAA Agonist trans-(+-)-1-aminocyclopentane-1,3-dicarboxylic acid and its isomers were examined for effects on basal and forskolin-stimulated cyclic AMP formation in slices of the rat hippocampus. Trans-(+-)-1-Aminocyclopentane-1,3-dicarboxylic acid had little effect on basal cyclic AMP but inhibited forskolin-stimulated cyclic AMP formation in a biphasic manner. The 1S,3R isomer of 1-aminocyclopentane-1,3-dicarboxylic acid produced potent but only partial (approximately 50%) inhibition of forskolin-stimulated cyclic AMP formation. 1R,3S-1-Aminocyclopentane-1,3-dicarboxylic acid fully inhibited forskolin-stimulated cyclic AMP but with lower potency than the 1S,3R isomer. These results show that in addition to the formation of phosphoinositide-derived second messengers, the cellular consequences of selectively activating hippocampal metabotropic EAA Receptors include an alteration of cellular cyclic AMP levels.
Haruhiko Shinozaki - One of the best experts on this subject based on the ideXlab platform.
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A new metabotropic Glutamate Receptor Agonist: developmental change of its sensitivity to Receptors in the newborn rat spinal cord.
Neuroscience letters, 1993Co-Authors: Michiko Ishida, Tomoko Saitoh, Haruhiko ShinozakiAbstract:A novel metabotropic Glutamate Receptor Agonist, (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), reduced the monosynaptic excitation in newborn rat spinal cord rather than polysynaptic discharges at the nanomolar range without causing postsynaptic depolarization of motoneurones. Its inhibitory action on the monosynaptic excitation reduced in due course of time after birth. On the contrary, the inhibitory action of a metabotropic GABAB Receptor Agonist, baclofen, did not show marked developmental change. DCG-IV should be expected to have the potential to provide further useful information on the physiological function of metabotropic Glutamate Receptors.
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A novel metabotropic Glutamate Receptor Agonist: marked depression of monosynaptic excitation in the newborn rat isolated spinal cord.
British journal of pharmacology, 1993Co-Authors: Michiko Ishida, Keiko Shimamoto, Tomoko Saitoh, Yasufumi Ohfune, Haruhiko ShinozakiAbstract:1. Neuropharmacological actions of a novel metabotropic Glutamate Receptor Agonist, (2S,1'R,2'R,3'R)-2(2,3-dicarboxycyclopropyl)glycine (DCG-IV), were examined in the isolated spinal cord of the newborn rat, and compared with those of the established Agonists of (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD). 2. At concentrations higher than 10 microM, DCG-IV caused a depolarization which was completely blocked by selective N-methyl-D-aspartate (NMDA) antAgonists. The depolarization was pharmacologically quite different from that caused by L-CCG-I and (1S,3R)-ACPD. 3. DCG-IV reduced the monosynaptic excitation of motoneurones rather than polysynaptic discharges in the nanomolar range without causing postsynaptic depolarization of motoneurones. DCG-IV was more effective than L-CCG-I, (1S,3R)-ACPD or L-2-amino-4-phosphonobutanoic acid (L-AP4) in reducing the monosynaptic excitation of motoneurones. 4. DCG-IV (30 nM-1 microM) did not depress the depolarization induced by known excitatory amino acids in the newborn rat motoneurones, but depressed the baseline fluctuation of the potential derived from ventral roots. Therefore, DCG-IV seems to reduce preferentially transmitter release from primary afferent nerve terminals. 5. Depression of monosynaptic excitation caused by DCG-IV was not affected by any known pharmacological agents, including 2-amino-3-phosphonopropanoic acid (AP3), diazepam, 2-hydroxysaclofen, picrotoxin and strychnine. 6. DCG-IV has the potential of providing further useful information on the physiological function of metabotropic Glutamate Receptors.
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A metabotropic L-Glutamate Receptor Agonist: pharmacological difference between rat central neurones and crayfish neuromuscular junctions.
Comparative biochemistry and physiology. C Comparative pharmacology and toxicology, 1992Co-Authors: Haruhiko Shinozaki, M. IshidaAbstract:Abstract 1. 2 S ,3 S ,4 S -2-(carboxycyclopropyl)glycine ( l -CCG-I), a conformationally restricted Glutamate analogue, is a potent metabotropic l -Glutamate Receptor Agonist in the mammalian central nervous system. 2. Depolarizing actions of l -CCG-I and trans -(±)-1-amino-1,3-cyclopentanedicarboxylic acid ( trans -ACPD) in the newborn rat spinal motoneurone are temperature-sensitive, and are not depressed by 3-[(±)-2-carboxypiperazin-4- yl ] propyl-1-phosphonic acid (CPP) and/or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). 3. l -CCG-I and trans -ACPD induced oscillatory responses in Xenopus oocytes injected with rat brain mRNA. Oocytes with oscillatory responses to l -CCG-I and trans -ACPD showed reversal potential of about −20 mV, which was very close to the equilibrium potential of chloride ions. 4. In rat hippocampal synaptoneurosomes, l -CCG-I stimulated phosphoinositide hydrolysis in a concentration dependent manner. l -CCG-I was less potent than quisqualate but more potent than trans -ACPD. 5. At low concentrations, l -CCG-I did not cause any depolarization of newborn rat spinal motoneurones, but reduced substantially amplitudes of monosynaptic reflexes. 6. At the crayfish neuromuscular junction l -CCG-I, acting presynaptically, reduced the amplitude of excitatory junctional potentials. This action was prevented by application of picrotoxin but not pertussis toxin. The actions of trans -ACPD differ from those of either l -CCG-I or ibotenate at the crayfish neuromuscular junction. 7. l -CCG-I has a potential to provide further useful information on metabotropic l -Glutamate Receptor function.
Peter W. Kalivas - One of the best experts on this subject based on the ideXlab platform.
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The group II metabotropic Glutamate Receptor Agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats
Psychopharmacology, 2006Co-Authors: Jamie Peters, Peter W. KalivasAbstract:Rationale Group II metabotropic Glutamate Receptor (mGluR2/3) Agonists are proposed to serve as potential treatment for addiction. Objectives The present study examined the hypothesis that mGluR2/3 Agonists exert inhibitory effects on cocaine-induced reinstatement of cocaine-seeking. Methods Rats were trained to self-administer either cocaine or control reinforcer (food), then responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p. or 765 mg of food). In one experiment, rats were systemically pretreated with vehicle (Veh) or the mGluR2/3 Agonist LY379268 (0.3, 1, or 3 mg/kg, i.p.) 30 min before the reinstatement test session. In a second experiment, Veh or LY379268 (0.05, 0.5, or 5 nmol/side) was microinjected into the nucleus accumbens core (NAc core) 5 min before the reinstatement test session. The effects of LY379268 on cocaine- and food-induced reinstatement on reward seeking were assessed. Results Both systemic and intra-NAc core pretreatment with LY379268 inhibited both cocaine- and food-seeking behavior. However, the effect of LY379268 appeared somewhat more effective for cocaine-seeking than food-seeking. Conclusions These results support a potential therapeutic role for mGluR2/3 Agonists on relapse of cocaine-seeking. However, doses that inhibited cocaine-seeking were only threefold lower than those inhibiting food-seeking, indicating possible unacceptable nonspecific effects. In addition, the NAc core is one site of action where the mGluR2/3 Agonists elicit effects on reward-seeking behavior.
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the group ii metabotropic Glutamate Receptor Agonist ly379268 inhibits both cocaine and food seeking behavior in rats
Psychopharmacology, 2006Co-Authors: Jamie Peters, Peter W. KalivasAbstract:Rationale Group II metabotropic Glutamate Receptor (mGluR2/3) Agonists are proposed to serve as potential treatment for addiction.
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Glutamate Transmission in the Nucleus Accumbens Mediates Relapse in Cocaine Addiction
The Journal of Neuroscience, 2000Co-Authors: Jennifer L. Cornish, Peter W. KalivasAbstract:Elevated dopamine transmission in the nucleus accumbens is thought to be a primary mediator of addiction to cocaine. However, repeated exposure to cocaine is associated with the recruitment of Glutamate transmission. This poses the possibility that the behaviors characterizing cocaine addiction, such as craving-induced relapse, may not be preferentially mediated by dopamine transmission. An animal model of relapse was used to demonstrate that Glutamate, and not dopamine transmission in the nucleus accumbens, is a primary mediator of cocaine-induced reinstatement of drug-seeking behavior. Reinstatement was produced by a systemic injection of cocaine or by the microinjection of the Glutamate Receptor Agonist AMPA or dopamine into the nucleus accumbens. It was found that microinjection of an AMPA Receptor antAgonist into the nucleus accumbens blocked reinstatement by all compounds, whereas a dopamine Receptor antAgonist was effective only in blocking reinstatement by intra-accumbens dopamine administration. These data suggest an important role for nucleus accumbens Glutamate and not dopamine transmission in cocaine-induced relapse to drug-seeking behavior.