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Metabotropic glutamate (mGlu) receptors impact learning and memory. Although some evidence indicates the importance of these receptors in conditioned taste aversion (CTA), the subtype-specific involvement of mGlu receptors in this associative learning task remains to be determined. These experiments examined the effects of (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a selective group II mGlu receptor agonist, cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanecarboxylic acid (VU0155041), a mGlu4 positive allosteric modulator, N,N'-dibenzhydrylethane-1,2-diamine (AMN082), a mGlu7 allosteric agonist, and 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), a mGlu7 negative allosteric modulator, on the acquisition of CTA using male Sprague-Dawley rats. Systemic injections of LY379268, AMN082, and MMPIP prior to conditioning decreased the acquisition of CTA, revealing that mGlu2/3 and mGlu7 are involved in CTA learning.

In conditioned taste aversion (CTA), animals learn to avoid a flavored solution (conditioned stimulus, CS) previously paired with internal malaise (unconditioned stimulus, US). Metabotropic glutamate receptor 5 (mGlu5) has been implicated in learning and memory processes and is necessary for CTA. In the present study, local microinjections of a mGlu5-selective antagonist, 3-[2-methyl-1,3-thiazol-4yl)ethynyl]pyridine (MTEP, 0, 1 or 5 μg) into the insular cortex and basolateral amygdala were used in male, Sprague-Dawley rats to examine the role of mGlu5 receptors in the encoding of taste memory. MTEP was infused 20 min before saccharin intake during CTA conditioning. MTEP injection into the basolateral amygdala resulted in robust CTA, similar to the vehicle-treated animals but slowed extinction; that is, MTEP enhanced CTA. MTEP injection into the insular cortex resulted in an increased saccharin intake on the conditioning trial, which potentially influenced the performance on the test trials; MTEP had no effect on CTA learning when controlled access to saccharin was used on the conditioning trial. These results indicate that mGlu5 receptors are involved in taste memories in a region-specific manner.

Metabotropic glutamate receptors (mGluRs) have been implicated in several types of cognitive and associative learning. Although recent evidence indicates an influence of mGluRs in conditioned taste aversion (CTA), the subtype-specific involvement of mGluRs in this learning paradigm remained to be determined. The aim of this study was to examine the role of Group I mGluR subtypes in CTA using a selective mGluR5 antagonist (2-methyl-6-(phenylethynyl)-pyridine, MPEP) and a selective mGluR1 antagonist (1-aminoindan-1,5-dicarboxylic acid, AIDA). Male, water-deprived, Sprague–Dawley rats were injected i.p. with 6 or 12 mg/kg MPEP or saline. Twenty-five minutes later, all rats received 15-min access to a 0.1% saccharin solution (Sac) immediately followed by an injection of 0.15 M LiCl at 1.33% body weight. The animals were tested with 15-min access to Sac on each of four test days. MPEP-treated animals consumed more Sac on the test trials than saline-treated rats. In another experiment, controlled access to Sac was used by infusing the solution on the conditioning trial. Consistent with the above results, MPEP attenuated the degree of CTA. Similar experiments using the mGluR1 antagonist AIDA, have found no effect on CTA learning. These results suggest that the two subtypes of Group I mGluRs are differentially involved in taste aversion learning.

Alzheimer's disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel-running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: (1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and (2) soluble amyloid-β (Aβ) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aβ1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.

The O2-dependent oxidation of urate catalyzed by urate oxidase has been examined in order to identify the immediate product of the enzymatic reaction. Specifically labeled [13C]urates were utilized as substrates, and the time courses were monitored by 13C NMR. On the basis of chemical shift values and 18O labeling, the product of the reaction was identified as 5-hydroxyisourate. This identification was substantiated by calculation of the 13C NMR spectrum of 5-hydroxyisourate using ab initio density functional theory methods. The predominant tautomers of urate and allantoin in aqueous solution were identified from 13C NMR titration data; the ionization behavior of urate and 5-hydroxyisourate were also examined by computational methods. The nonenzymatic pathway for production of allantoin from 5-hydroxyisourate was delineated; the reaction proceeds by the hydrolysis of the N1−C6 bond, followed by an unusual 1,2-carboxylate shift and decarboxylation to form allantoin.

The substrate specificity of tartrate dehydrogenase has been probed using a series of alternative substrates to identify the molecular interactions which determine whether a particular substrate undergoes enzyme-catalyzed decarboxylation or not. A series of 3-substituted malate analogs, in which F, Cl, Br, I, SH, or NH2 substituents were placed at the 3R- or 3S-position, was prepared, and the product resulting from the action of tartrate dehydrogenase on each compound was identified. All of the halomalates and both diastereomers of aminomalate underwent oxidative decarboxylation; both diastereomers of 3-thiomalate underwent net nonoxidative decarboxylation. The results were interpreted in terms of a model in which decarboxylation is conformationally controlled. The data are not consistent with a model which suggests that substrates assume the conformation that is necessary to avoid steric crowding between the enzyme and the substituent at the 3-position of the substrate. These data are consistent with a model in which the course of the reaction with (+)-tartrate and meso-tartrate is dictated by the coordination of the substrate hydroxyls to the active site Mn2+. However, the observed reactivities of the 3-methyltartrate diastereomers are not consistent with this model, either: (2R,3R)-3-methyltartrate undergoes oxidative decarboxylation, and (2R,3S)-3-methyltartrate undergoes simple oxidation. These results suggest that for these compounds the conformation is dictated by the positioning of the hydrophobic substituent in a specific binding pocket.(ABSTRACT TRUNCATED AT 250 WORDS)

Latent inhibition (LI) is a phenomenon by which pre-exposure of a conditioned stimulus (CS) prior to the CS-unconditioned stimulus (US) pairings retards conditioned responding (CR). LI has been demonstrated in a variety of learning tasks including conditioned taste aversion (CTA). Earlier work has shown that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 (mGlu5) antagonist, is able to disrupt classical conditioning in CTA. The present study investigated the involvement of mGlu5 receptors in LI using a CTA procedure. In the first experiment, rats received either water (non-pre-exposed, NPE) or a saccharin solution (pre-exposed, PE) on 2 consecutive days. The animals then received conditioning in which a fixed amount of saccharin was paired with lithium chloride and then the CR to the taste was tested. Either MPEP (3, 6, 12 mg/kg) or vehicle was injected intraperitoneally prior to taste pre-exposure or testing. Animals in the vehicle control groups displayed LI. MPEP injections before pre-exposure trials attenuated LI but also reduced consumption during pre-exposure, which obscured interpretation of the LI effect. The second experiment used four pre-exposure trials and controlled access to fixed amount of the solutions during the pre-exposure as well as the conditioning trials. Rats were injected before pre-exposure trials but not before the test trial. The results found that MPEP attenuates latent inhibition suggesting that the mGlu5 receptor exerts an influence on the processes that underlie the effects of taste pre-exposure on conditioning.