Group II mGlu Receptor Activation Suppresses Norepinephrine Release in the Ventral Hippocampus and Locomotor Responses to Acute Ketamine Challenge

Lorrain, Daniel S.; Schaffhauser, Hervé; Campbell, Una C.; Baccei, Christopher; Correa, Lucia; Rowe, Blake A.; Rodriguez, Dana E.; Anderson, Jeffrey J.; Varney, Mark A.; Pinkerton, Anthony B.; Vernier, Jean‐Michel; Bristow, Linda J.

doi:10.1038/sj.npp.1300238

Cited by 90 publications

(77 citation statements)

References 45 publications

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“…142 Finally, these drugs reverse ketamine-induced stimulation of ventral hippocampal norepinephrine release, which may also be linked to prefrontal hyperglutamatergia. 143 In contrast to its effects on glutamate, group II agonists do not inhibit, 90 and may enhance, 134 NMDAR antagonist effects on PFC DA release, suggesting a dissociation in the regulation of prefrontal glutamate and dopamine systems. Group II agonists also do not reverse PCP-induced behavioral sensitization, 141 PCP-or apomorphine-induced disruption of PPI, 144 or MK-801-induced disruption in delayed alternation.…”

Section: Metabotropic Receptorsmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Glutamatergic neurotransmission may be modulated at multiple levels, only a minority of which are currently being exploited for pharmaceutical development. Ionotropic receptors for glutamate are divided into N-methyl-D-aspartate receptor (NMDAR) and AMPA receptor subtypes. NMDAR have been implicated in the pathophysiology of schizophrenia. The glycine modulatory site of the NMDAR is currently a favored therapeutic target, with several modulatory agents currently undergoing clinical development. Of these, the full agonists glycine and D-serine have both shown to induce significant, large effect size reductions in persistent negative and cognitive symptoms when added to traditional or newer atypical antipsychotics in double-blind, placebo-controlled clinical studies. Glycine (GLYT1) and small neutral amino-acid (SNAT) transporters, which regulate glycine levels, represent additional targets for drug development, and may represent a site of action of clozapine. Brain transporters for D-serine have recently been described. Metabotropic glutamate receptors are positively (Group I) or negatively (Groups II and III) coupled to glutamatergic neurotransmission. Metabotropic modulators are currently under preclinical development for neuropsychiatric conditions, including schizophrenia, depression and anxiety disorders. Other conditions for which glutamate modulators may prove effective include stroke, epilepsy, Alzheimer disease and PTSD. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Approximately 60% of neurons in the brain, including all cortical pyramidal neurons and thalamic relay neurons, utilize glutamate as their primary neurotransmitter. 1 As a result, virtually all thalamocortical, corticocortical and corticofugal neurotransmission in the brain is mediated by glutamate. Glutamate is released from presynaptic terminals in response to neuronal depolarization, and is recycled by excitatory amino acid (EAA) transporters located on both neurons and glia. 2 Within glia, glutamate is converted to glutamine and released into extracellular fluid from which it is reabsorbed into presynaptic terminals and converted back to glutamate via action of neuronal glutaminase. Up to 2/3 of brain energy metabolism is related to reuptake and recycling of glutamate. 3 As such, functional imaging modalities, such as PET and fMRI, indexing activity primarily of brain glutamatergic systems. 4 The exchange of glutamine from glia to neurons is accomplished by coordinated actions of two transport systems, systems N and A, both of which are members of sodium-dependent neutral amino acid (SNAT) family of transporters. 5 These transport systems also transport precursors for cysteine and glycine, which are precursors to glutathione synthesis. 6 As these transporters are electrogenic, glutamate transporters may also participate in cellular signaling. 7 As with glutamate and GABA transporters, these recycling systems may constitute interesti...

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Section: Metabotropic Receptorsmentioning

confidence: 99%

Glutamate as a therapeutic target in psychiatric disorders

2004

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“…Both PCP and ketamine dramatically increase noradrenaline release and turnover in brain (Bowers and Morton, 1994;Deutch et al, 1987;Kubota et al, 1999a;Lorrain et al, 2003;Rasmussen et al, 1991). In a recent study, Harkin et al (2001) demonstrated that the potent alpha-2 agonist, clonidine, strongly attenuated NMDA antagonist-induced hyperlocomotion in mice, while the potent alpha-2 receptor antagonist, yohimbine, produced opposite effects; Swanson and Schoepp (2003)reported similar effects of clonidine in rats.…”

Section: Introductionmentioning

confidence: 99%

Alpha-2 Adrenoceptor Activation Inhibits Phencyclidine-Induced Deficits of Spatial Working Memory in Rats

Marrs

Kuperman

Avedian

et al. 2005

Neuropsychopharmacol

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N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, such as phencyclidine (PCP), induce behavioral abnormalities (locomotor hyperactivity, sensorimotor gating deficits, impairments of cognition) in animals that are thought to model aspects of schizophrenia. The administration of PCP increases noradrenaline transmission in the rat prefrontal cortex, a brain structure required for normal cognitive processes. Noradrenaline, in turn, works through a set of receptors that have themselves been implicated directly in NMDA antagonist-induced deficits; we recently reported that the alpha-2 agonist, clonidine, is effective at preventing PCP-induced deficits of working memory and visual attention in rats. Here, we further investigated the role for alpha-2 adrenoreceptors in the effects of PCP on spatial working memory performance. The alpha-2 agonist clonidine (0.001-0.01 mg/kg, subcutaneously (s.c.)) produced a significant amelioration of PCP-induced working memory deficits; the effects of PCP (1.0 mg/kg, s.c.), but not clonidine, were reduced in noradrenaline-depleted rats. In addition, the alpha-2A-preferring agonist guanfacine (0.05-1.0 mg/kg, s.c.) dose-dependently prevented the deficits of spatial working memory performance produced by PCP. Although the highly selective alpha-2 receptor antagonist, atipamezole (ATI), failed to affect spatial working memory on its own, at the doses studied (0.1-0.5 mg/kg, s.c.), it dramatically enhanced the working memory deficit produced by PCP. These data indicate that alpha-2 adrenoreceptors tonically inhibit PCP-induced deficits of spatial working memory, suggesting an important role for these receptors in cognitive deficits associated with NMDA receptor hypofunction.

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“…Recently, highly selective mGlu2 receptor allosteric potentiators have been developed (Johnson et al, 2003;Lorrain et al, 2003b;Schaffhauser et al, 2003;Pinkerton et al, 2004). These small molecules do not activate the mGlu2 receptor directly but act at an allosteric site on the receptor to potentiate glutamateinduced activation of the receptor (Schaffhauser et al, 2003).…”

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confidence: 99%

A Selective Allosteric Potentiator of Metabotropic Glutamate (mGlu) 2 Receptors Has Effects Similar to an Orthosteric mGlu2/3 Receptor Agonist in Mouse Models Predictive of Antipsychotic Activity

Galici

Echemendia²,

Rodriguez³

et al. 2005

J Pharmacol Exp Ther

160

155

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Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine-and phencyclidine (PCP)-induced hyperlocomotor activity in rodents, two actions that may predict potential antipsychotic activity of these compounds. We now report that LY487379 [N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2-trifluoroethylsulfonyl)pyrid-3-ylmethylamine], a recently described selective allosteric potentiator of mGlu2 receptor, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268 [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], an ortho-steric mGlu2/3 receptor agonist, induced similar dosedependent reductions in PCP-and amphetamine-induced hyperlocomotor activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid]. LY487379 had a short duration of action compared with LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition of the acoustic startle reflex. When LY379268 was given chronically, it failed to block amphetamine-and PCP-induced hyperlocomotor activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 receptor could have utility as a novel approach for the treatment of schizophrenia.

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Group II mGlu Receptor Activation Suppresses Norepinephrine Release in the Ventral Hippocampus and Locomotor Responses to Acute Ketamine Challenge

Cited by 90 publications

References 45 publications

Glutamate as a therapeutic target in psychiatric disorders

Glutamate as a therapeutic target in psychiatric disorders

Alpha-2 Adrenoceptor Activation Inhibits Phencyclidine-Induced Deficits of Spatial Working Memory in Rats

A Selective Allosteric Potentiator of Metabotropic Glutamate (mGlu) 2 Receptors Has Effects Similar to an Orthosteric mGlu2/3 Receptor Agonist in Mouse Models Predictive of Antipsychotic Activity

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