ly-341495 and Schizophrenia

Topics: Amino Acids; Cell Membrane; HEK293 Cells; Humans; Ligands; Protein Isoforms; Radioligand Assay; Receptors, Metabotropic Glutamate; Schizophrenia; Transfection; Tritium; Xanthenes

The glutamatergic system has recently been implicated in the pathogenesis and treatment of major depressive disorders(MDD) and mGlu2/3 receptors play an important role in regulating glutamatergic tone. We therefore measured cortical levels of mGlu2/3 to determine if they were changed in MDD.. Binding parameters for [(3)H]LY341495 (mGlu2/3 antagonist) were determined to allow optimized in situ binding with autoradiography to be completed using a number of CNS regions. Subsequently, density of [(3)H]LY341495 binding was measured in BA24(anterior cingulate cortex), BA17(visual cortex) and BA46(dorsolateral prefrontal cortex) from subjects with MDD, Bipolar Disorder(BPD), Schizophrenia(SCZ), and controls, as well as rats treated with imipramine (20mg/kg), fluoxetine (10mg/kg), or vehicle.. mGlu2/3 are widely expressed throughout the brain with high levels observed in cortex. [(3)H]LY341495 binding was significantly lower in BA24 from subjects with MDD (mean ± SEM=141.3 ± 14.65 fmol/ETE) relative to controls (184.9 ± 7.76 fmol/ETE; Cohen's d=1.005, p<0.05). There were no other differences with diagnoses, and chronic antidepressant treatment in rats had minimal effect on binding.. Using this approach we are unable to determine whether the change represents fluctuations in mGlu2, mGlu3, or both. Moreover, using postmortem tissue we are unable to dissociate the irrevocable confound of suicidality upon binding levels.. We have demonstrated lower [(3)H]LY341495 binding levels in MDD in BA24-a brain region implicated in depression. Moreover we show that the lower levels are unlikely to be the result of antidepressant treatment. These data suggest that levels of either mGlu2 and/or mGlu3 are affected in the aetiology of MDD.

Topics: Amino Acids; Animals; Antidepressive Agents; Bipolar Disorder; Brain; Depressive Disorder, Major; Excitatory Amino Acid Antagonists; Female; Fluoxetine; Gyrus Cinguli; Humans; Imipramine; Male; Middle Aged; Radioligand Assay; Radionuclide Imaging; Rats; Receptors, Metabotropic Glutamate; Schizophrenia; Tritium; Xanthenes

Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100mg/kg) significantly attenuated dizocilpine (0.1mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved.

Topics: Administration, Oral; Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds; Dipeptides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamate Carboxypeptidase II; Glutarates; Male; Mice; Neural Inhibition; Schizophrenia; Sensory Gating; Sulfhydryl Compounds; Xanthenes

Glutamatergic inputs to the nucleus accumbens (NAc) modulate both appetitive and fearful motivation. It has been suggested that pathological disturbances of glutamate signaling in NAc contribute to motivation disorders, ranging from excessive desire in drug addiction to paranoia in schizophrenia. Metabotropic glutamate receptors are of special interest, as metabotropic Group II receptor (mglu2/3) agonists have been proposed as potential treatments for both addiction and schizophrenia. Here we tested whether local mglu2/3 receptor blockade in the medial shell of the rat NAc can generate intense distortions of motivation or affect, which might model clinical dysfunction. We found that microinjection of the mglu2/3 antagonist LY341495 at sites throughout medial shell suppressed appetitive motivation to eat and drink. Simultaneously, LY341495 microinjections generated fearful motivation in the form of defensive treading or burying. To assess whether the valence shift extended into a parallel hedonic shift from affective 'liking' to 'disliking' we employed the taste reactivity test, which measures affective orofacial reactions to the sensory pleasure or displeasure of tastes. We found that LY341495 microinjections reduced positive 'liking' reactions to sucrose and enhanced 'disliking' reactions. Overall, mglu2/3 antagonism at most shell sites produced a similar valence shift from positive to negative. This pattern comprised (i) generation of fearful behaviors, and (ii) induction of aversive affective reactions, together with (iii) loss of appetitive ingestion and (iv) loss of 'liking' for rewards. These results are discussed in terms of implications for clinical disorders and the influence of corticolimbic glutamate inputs to NAc in the generation of motivation and affect.

Topics: Affect; Amino Acids; Analgesics, Non-Narcotic; Animals; Appetitive Behavior; Excitatory Amino Acid Antagonists; Fear; Male; Motivation; Nucleus Accumbens; Pleasure; Proto-Oncogene Proteins c-fos; Quinine; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Schizophrenia; Xanthenes

Dysregulation of glutamate neurotransmission may play a role in cognitive deficits in schizophrenia. Manipulation of glutamate signaling using drugs acting at metabotropic glutamate receptors has been suggested as a novel approach to treating schizophrenia-related cognitive dysfunction. We examined how the metabotropic glutamate receptor 2/3 agonist LY379268 and the metabotropic glutamate receptor 2/3 antagonist LY341495 altered phencyclidine-induced disruptions in performance in the 5-choice serial reaction time task. This test assesses multiple cognitive modalities characteristically impaired in schizophrenia that are disrupted by phencyclidine administration. Acute LY379268 alone did not affect 5-choice serial reaction time task performance, except for nonspecific response suppression at high doses. Acute LY379268 administration exacerbated phencyclidine-induced disruption of attentional performance in this task, while acute LY341495 did not alter 5-choice serial reaction time task performance during phencyclidine exposure. Chronic LY341495 impaired attentional performance in the 5-choice serial reaction time task by itself, but attenuated phencyclidine-induced excessive timeout responding. The mixed effects of metabotropic glutamate receptor 2/3 agonism and antagonism on cognitive performance under baseline conditions and after disruption with phencyclidine demonstrate that different aspects of cognition may respond differently to a given pharmacological manipulation, indicating that potential antipsychotic or pro-cognitive medications need to be tested for their effects on a range of cognitive modalities. Our findings also suggest that additional mechanisms, besides cortical glutamatergic transmission, may be involved in certain cognitive dysfunctions in schizophrenia.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cognition; Excitatory Amino Acid Agents; Male; Phencyclidine; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Schizophrenia; Time Factors; Xanthenes

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.

Topics: Acetylcysteine; Aged; Aged, 80 and over; Amino Acids; Analysis of Variance; Animals; Behavior, Animal; Cell Line, Transformed; Disease Models, Animal; Dose-Response Relationship, Drug; Extracellular Fluid; Female; Free Radical Scavengers; Glutamic Acid; Glycine; Humans; Interpersonal Relations; Male; Maze Learning; Microdialysis; Phencyclidine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Schizophrenia; Xanthenes

Group II mGlu receptor agonists (eg LY379268 and LY354740) have been shown to reverse many of the behavioral responses to PCP as well as glutamate release elicited by PCP and ketamine. In the present set of experiments, we used in vivo microdialysis to show that, in addition to reversing PCP- and ketamine-evoked glutamate release, group II mGlu receptor stimulation also prevents ketamine-evoked norepinephrine (NE) release. Pretreating animals with the mixed 2/3 metabotropic glutamate (mGlu2/3) receptor agonist LY379268 (0.3-10 mg/kg) dose-dependently inhibited ketamine (25 mg/kg)-evoked NE release in the ventral hippocampus (VHipp). Ketamine hyperactivity was also reduced in a similar dose range. Following our initial observation on NE release, we conducted a series of microinjection experiments to reveal that the inhibitory effects of LY379268 on VHipp NE release may be linked to glutamate transmission within the medial prefrontal cortex. Finally, we were able to mimic the inhibitory effects of LY379268 on ketamine-evoked NE release by using a novel mGlu2 receptor selective positive modulator. (+/-) 2,2,2-Trifluoroethyl [3-(1-methyl-butoxy)-phenyl]-pyridin-3-ylmethyl-sulfonamide (2,2,2-TEMPS, characterized through in vitro GTPgammaS binding) at a dose of 100 mg/kg significantly reduced the NE response. Together, these results demonstrate a novel means to suppress noradrenergic neurotransmission (ie by activating mGlu2 receptors) and may, therefore, have important implications for neuropsychiatric disorders in which aberrant activation of the noradrenergic system is thought to be involved.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Analysis of Variance; Animals; Area Under Curve; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Chromatography, High Pressure Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanosine 5'-O-(3-Thiotriphosphate); Hippocampus; Humans; Hyperkinesis; In Vitro Techniques; Ketamine; Male; Microdialysis; Motor Activity; Norepinephrine; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Metabotropic Glutamate; Schizophrenia; Serotonin; Sulfur Isotopes; Time Factors; Trifluoroethanol; Xanthenes