ly-379268 and eglumetad

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the G

Topics: Allosteric Regulation; Allosteric Site; Amino Acids; Biphenyl Compounds; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Catalytic Domain; Cell Membrane; Cholesterol Esters; Diosgenin; Disaccharides; Fluorescence Resonance Energy Transfer; Gene Expression; Glucosides; Glutamic Acid; Glycolipids; HEK293 Cells; Humans; Indans; Micelles; Octoxynol; Protein Binding; Protein Conformation; Protein Multimerization; Receptors, Metabotropic Glutamate; Recombinant Proteins; Single Molecule Imaging; Xanthenes

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in a number of psychiatric disorders. They also control sleep-wake architecture and may offer novel therapeutic targets. However, the roles of the mGluR2 versus mGluR3 subtypes are not well understood. Here, we have taken advantage of the recently described mutant strain of Han Wistar rats, which do not express mGluR2 receptors, to investigate behavioural, sleep and EEG responses to mGluR2/3 ligands. The mGluR2/3 agonist, LY354740 (10 mg/kg), reversed amphetamine- and phencyclidine-induced locomotion and rearing behaviours in control Wistar but not in mGluR2 lacking Han Wistar rats. In control Wistar but not in Han Wistar rats the mGluR2/3 agonist LY379268 (3 & 10 mg/kg) induced REM sleep suppression with dose-dependent effects on wake and NREM sleep. By contrast, the mGluR2/3 antagonist LY3020371 (3 & 10 mg/kg) had wake-promoting effects in both rat strains, albeit smaller in the mGluR2-lacking Han Wistar rats, indicating both mGluR2 and mGluR3-mediated effects on wakefulness. LY3020371 enhanced wake cortical oscillations in the theta (4-9 Hz) and gamma (30-80 Hz) range in both Wistar and Han Wistar rat strains, whereas LY379268 reduced theta and gamma oscillations in control Wistar rats, with minimal effects in Han Wistar rats. Together these studies illustrate the significant contribution of mGluR2 to the antipsychotic-like, sleep and EEG effects of drugs acting on group II mGluRs. However, we also provide evidence of a role for mGluR3 activity in the control of sleep and wake cortical theta and gamma oscillations.

Topics: Amino Acids; Amphetamine; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclohexanes; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Gamma Rhythm; Locomotion; Male; Motor Activity; Mutation; Phencyclidine; Rats; Receptors, Metabotropic Glutamate; Sleep; Theta Rhythm; Wakefulness

LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-β (Rab GDIβ) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the α isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIα protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIα levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models.

Topics: Amino Acids; Animals; Antipsychotic Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; D-Aspartic Acid; Disease Models, Animal; Epigenesis, Genetic; Female; Guanine Nucleotide Dissociation Inhibitors; Hippocampus; Male; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Proteomics; Receptors, Metabotropic Glutamate; Restraint, Physical; Schizophrenia

We previously reported the absence of high-affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds. Both LY 354,740 and LY 379,268 exhibited potent agonist activity for mGluR₂ in the ³⁵S-GTPγS assay. Functionally, neither compound displayed antagonist activity in the GTPγS assay with recombinant D₂. At concentrations up to 10 μM, both compounds failed to displace [³H]-raclopride, [³H]-PHNO, or [³H]-domperidone in filter-binding assays under isotonic (120 mM NaCl or N-methyl glucamine) or low-ionic strength (no NaCl or N-methyl glucamine) conditions. Some displacement of [³H]-domperidone (20-40%) was observed at 30 μM of LY 354,740 under low-ionic strength and under isotonic conditions in the absence of NaCl. No displacement of [³H]-domperidone was detected in a two site model at lower (<100 nM) concentrations of either compound. Moreover, no D₂ activity was observed for LY 354,740 or LY 379,268 in the CellKey™ (cellular dielectric spectroscopy) assay. In this communication, we discuss the possible reasons for differences in our study and the previously published work and implications of these studies for mechanisms of antipsychotic action.

Topics: Amino Acids; Animals; Binding, Competitive; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetinae; Cricetulus; Domperidone; Excitatory Amino Acid Agonists; Mass Spectrometry; Raclopride; Radioligand Assay; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate

Some recently published in vitro studies with two metabotropic glutamate 2/3 receptor (mGluR(2/3)) agonists [(-)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268) and 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740)] suggest that these compounds may also directly interact with dopamine (DA) D(2) receptors. The current in vitro and in vivo studies were undertaken to further explore this potential interaction with D(2) receptors. LY379268 and LY354740 failed to inhibit D(2) binding in both native striatal tissue homogenates and cloned receptors at concentrations up to 10 microM. LY379268 and LY354740 (up to 10 microM) also failed to stimulate [(35)S]GTPgammaS binding in D(2L)- and D(2S)-expressing clones in the presence of NaCl or N-methyl-d-glucamine. In an in vivo striatal D(2) receptor occupancy assay, LY379268 (3-30 mg/kg) or LY354740 (1-10 mg/kg) failed to displace raclopride (3 microg/kg i.v.), whereas aripiprazole (10-60 mg/kg) showed up to 90% striatal D(2) receptor occupancy. LY379268 (10 mg/kg) and raclopride (3 mg/kg) blocked d-amphetamine and phencyclidine (PCP)-induced hyperactivity in wild-type mice. However, the effects of LY379268 were lost in mGlu(2/3) receptor knockout mice. In DA D(2) receptor-deficient mice, LY379268 but not raclopride blocked both PCP and d-amphetamine-evoked hyperactivity. In the striatum and nucleus accumbens, LY379268 (3 and 10 mg/kg) was without effect on the DA synthesis rate in reserpinized rats and also failed to prevent S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine-induced reductions in DA synthesis rate. Taken together, the current data fail to show evidence of direct DA D(2) receptor interactions of LY379268 and LY354740 in vitro or in vivo. Instead, these results provide further evidence for a novel antipsychotic mechanism of action for mGluR(2/3) agonists.

Topics: Amino Acids; Animals; Binding, Competitive; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Membrane; CHO Cells; Cricetinae; Cricetulus; Domperidone; Dopamine; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Mice; Mice, Knockout; Motor Activity; Protein Binding; Raclopride; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Metabotropic Glutamate; Transfection

Because glutamate compounds alter the release of dopamine and prolactin, the present study examined whether group II metabotropic receptor agonists, LY 354,740 and LY 379,268, had any direct in vitro action on dopamine D2 receptors on rat striatal tissue, cloned D2Long receptors, and prolactin release from anterior pituitary cells. In competition versus the D2-specific ligand [(3)H]domperidone, LY 354,740 had a dissociation constant of 24 nM at D2(High) (the functional high-affinity state of dopamine D2 receptors), while the value for LY 379,268 was 21 nM. LY 354,740 also stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at a concentration of 120 nM, but its maximal stimulation was only 22% of the maximum elicited by dopamine. LY 379,268 stimulated by 50% the incorporation of [(35)S]-GTP-gamma-S at 280 nM, but its maximal stimulation was also only 22% of the maximum elicited by dopamine. However, both LY 354,740 and LY 379,268 potently inhibited the dopamine-induced incorporation of [(35)S]-GTP-gamma-S with inhibitory Ki values of 43 nM and 30 nM, respectively. The release of prolactin from rat isolated anterior pituitary cells in culture was 50% inhibited by 20 nM LY 379,268 and by 100 nM LY 354,740. These Ki values are similar to those known for the mGluR II receptor, suggesting that these compounds may have both glutamate and dopamine actions in vivo. The dopamine agonist and antagonist actions of these compounds indicate that these drugs have properties of a dopamine partial agonist, and may, therefore, have antipsychotic action.

Topics: Amino Acids; Animals; Binding, Competitive; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Domperidone; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Guanosine 5'-O-(3-Thiotriphosphate); Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Transfection

Topics: Amino Acids; Antipsychotic Agents; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic S-Oxides; Dopamine Agonists; Excitatory Amino Acid Agonists; Humans; Receptors, Dopamine D2; Schizophrenia

The asymmetric synthesis and biological activity of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-methylcyclopropyl) glycine 7 and its epimer at the C3' center 6 are described. Compound 7 is a highly potent and selective agonist for group 2 metabotropric glutamate receptors (mGluRs). It is also systemically 4 orders of magnitude more active in the fear-potentiated startle model of anxiety in rats than the rigid constrained bicyclic system LY354740. Therefore, we have shown that high molecular complexity of conformationally constrained bicyclic systems is not a requirement to achieve highly selective and potent group 2 mGluRs agonists.

Topics: Animals; Anti-Anxiety Agents; Bridged Bicyclo Compounds; Cell Line; Cyclopropanes; Glycine; Ligands; Models, Molecular; Rats; Receptors, Metabotropic Glutamate; Reflex, Startle; Stereoisomerism

It has been suggested that metabotropic glutamate (mGlu) receptor agonists selective for Group II mGlu receptors may have antipsychotic action. Therefore, we studied whether the effects, which could be related to psychotomimetic action of hallucinogenic drugs, are inhibited by Group II mGlu receptor agonists. The selective mGlu2/3 agonists LY354740 and LY379268 inhibited (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches in mice in a dose-dependent manner. Furthermore, LY379268 suppressed an increase in the frequency of spontaneous excitatory synaptic potentials induced by bath-applied DOI in layer V pyramidal cells recorded in the murine medial frontal cortex. The data indicate that Group II mGlu receptor agonists may counteract the effects of hallucinogenic drugs.

Topics: Amino Acids; Amphetamines; Animals; Behavior, Animal; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Electrophysiology; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; Male; Mice; Patch-Clamp Techniques; Prefrontal Cortex; Pyramidal Cells; Receptors, Metabotropic Glutamate; Serotonin Receptor Agonists

Topics: Amino Acids; Brain; Brain Ischemia; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Glycine; Hippocampus; Humans; Kainic Acid; Ligands; Nerve Degeneration; Neuroprotective Agents; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate

As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the

Topics: Amino Acids; Animals; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cyclic AMP; Excitatory Amino Acid Agonists; Humans; In Vitro Techniques; Mice; Models, Molecular; Rats; Receptors, Metabotropic Glutamate; Recombinant Proteins; Second Messenger Systems; Seizures; Stereoisomerism

In rat cortical neuronal cultures, metabotropic glutamate (mGlu) receptor agonists: LY354740 (+)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate); LY379268 (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate, and LY389795 (-)-2-thia-4-aminobicyclo[3.1.0]-hexane-4,6-dicarboxylate, were neuroprotective against toxicity induced by N-methyl-D-aspartic acid (NMDA), kainic acid and staurosporine as measured by release of lactate dehydrogenase (LDH) activity into culture supernatants and DNA fragmentation by oligonucleosome formation. The potencies of the agonists were at least 100 times greater in reducing nucleosome formation than LDH release indicating a differential effect on neurons dying by apoptosis than by necrosis. In vivo studies showed that LY354740 was able to mediate a partial protection against apoptosis in CA1 hippocampal cells under ischaemic conditions where substantial CA1 cell loss occurred. The effects of the agonists in vitro were: (a) reversed by mGlu receptor antagonist LY341495, (b) enhanced by the presence of glial cells, (c) abrogated by RNA and protein synthesis inhibitors, and (d) unaltered by inhibition of endogenous adenosine activity. These results suggest that group II mGlu receptor agonists may represent a novel therapeutic strategy for the treatment of neurodegenerative diseases.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Cerebral Cortex; DNA Fragmentation; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Gerbillinae; Kainic Acid; L-Lactate Dehydrogenase; N-Methylaspartate; Neuroprotective Agents; Rats; Staurosporine

Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In this article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozapine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)-evoked motor activities. LY354740 (1-10 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), and haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fine motor (nonambulatory) movements, and decreased time at rest evoked by PCP. Furthermore, the inhibitions of the PCP response by the mGlu2/3 agonist LY379268, but not by clozapine, were completely reversed by the selective mGlu2/3 receptor antagonist LY341495. Doses of LY354740 and LY379268 that blocked the effects on PCP had no effects on rotorod performance, and (with the exception of rearing behavior) had minimal effects on AMP-evoked motor activities. Clozapine blocked AMP-induced rearing but enhanced AMP-induced ambulations and fine movements at the lower doses (1 and 3 mg/kg). Unlike the mGlu2/3 agonists, the highest dose of clozapine tested (10 mg/kg) impaired animals on the rotorod. Haloperidol potently blocked all PCP and AMP effects, but only at doses associated with motor impairment. These data demonstrate that mGlu2/3 receptor agonists act via a unique mechanism to selectively block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.

Topics: Amino Acids; Animals; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dextroamphetamine; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; Motor Activity; Phencyclidine; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate

The neuroprotective effects of a selective Group II metabotropic glutamate receptor (mGluR) agonist, LY379268, have been evaluated against global and focal cerebral ischaemia. Loss of CA1 hippocampal neurones following 5 min bilateral occlusion of the carotid artery (BCAO) in the gerbil was almost completely prevented by LY379268 (10 mg/kg, i.p.) given 30 min post-occlusion (P < 0.001); 10 mg/kg 1 h after and 20 mg/kg 2 h after BCAO also produced significant neuroprotection (P < 0.05). Similarly the BCAO-induced increase in TUNEL positive cells at 5 days post-occlusion was reduced by LY379268. By contrast the size of the infarct following middle cerebral artery occlusion (MCAO) induced by endothelin-1 infusion in the rat was unaffected by either 10 or 20 mg/kg i.p. of LY379268. This contrast between the results from these two animal models with LY379268, agrees with previous data on a less potent but similarly selective mGluR2/3 agonist, LY354740. It further suggests that mGluR Group II agonists are likely to have more utility in global, than in focal, cerebral ischaemia.

Topics: Amino Acids; Animals; Brain Ischemia; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Excitatory Amino Acid Agonists; Gerbillinae; Hippocampus; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Stereoisomerism

The novel mGluR agonist LY354740 and a related analogue LY379268 are selective for mGluR2/3 receptors and are centrally active after systemic administration. In this study, rates of local cerebral glucose use were measured using the [14C]2-deoxyglucose autoradiographic technique to examine the functional consequences of their systemic administration in the conscious rat. Both LY354740 (0.3, 3.0, 30 mg/kg) and LY379268 (0.1, 1.0, 10 mg/kg) produced dose-dependent changes in glucose use. After LY354740 (3.0mg/kg), 4 of the 42 regions measured showed statistically significant changes from vehicle-treated controls: red nuclei (-16%), mammillary body (-25%), anterior thalamus (-29%), and the superficial layer of the superior colliculus (+50%). An additional 15 regions displayed significant reductions in function-related glucose use (P < .05) in animals treated with LY354740 (30 mg/ kg). LY379268 (0.1, 1.0, 10 mg/kg) produced changes in glucose metabolism in 20% of the brain regions analyzed. Significant increases (P < .05) in glucose use were evident in the following: the superficial layer of the superior colliculus (+81%), locus coeruleus (+57%), genu of the corpus callosum (+31%), cochlear nucleus (+26%), inferior colliculus (+20%), and the molecular layer of the hippocampus (+14%). Three regions displayed significant decreases: mammillary body (-34%), anteroventral thalamic nucleus (-28%), and the lateral habenular nucleus (-24%). These results show the important functional involvement of the limbic system together with the participation of components of different sensory systems in response to the activation of mGluR2 and mGluR3 with LY354740 and LY379268.

Topics: Amino Acids; Animals; Anterior Thalamic Nuclei; Autoradiography; Brain; Brain Chemistry; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebellar Cortex; Cochlear Nucleus; Excitatory Amino Acid Agonists; Glucose; Male; Mammillary Bodies; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Substantia Nigra; Visual Cortex