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At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the α 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (−71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro . These functional changes were accompanied by reduced extracellular KYNA (−66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo . Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR ( N -methyl- d -aspartate receptor) antagonist ( R , S )-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2 R ,6 R )-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2 R ,6 R )-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of ( R , S )-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants. The metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and the (2R,6R)-HNK enantiomer lacks ketamine-related side effects but exerts rapid and sustained antidepressant actions in mice; these antidepressant effects are independent of NMDAR inhibition but require AMPAR activity. Antidepressant action of a ketamine metabolite The NMDAR antagonist ketamine has rapid and sustained antidepressant effects; this has prompted a search for alternative NMDAR antagonists that have the same antidepressant properties but lack the undesirable side effects of ketamine. Todd Gould and colleagues now show that the metabolism of ( R , S )-ketamine to (2 S ,6 S ;2 R ,6 R )-hydroxynorketamine (HNK) is essential for its antidepressant activity, and that the (2 R ,6 R )-HNK enantiomer exerts rapid and sustained antidepressant actions in mice. These effects are NMDAR-independent but require AMPAR activation. Importantly, (2 R ,6 R )-HNK lacks the side effects associated with ketamine. These findings suggest new options for the development of novel rapid-acting antidepressants.

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.

Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) is a putative fast-acting antidepressant candidate. Although inhibition of NMDA-type glutamate receptors (NMDARs) is one mechanism proposed to underlie ketamine’s antidepressant and adverse effects, the potency of (2R,6R)-HNK to inhibit NMDARs has not been established. We used a multidisciplinary approach to determine the effects of (2R,6R)-HNK on NMDAR function. Antidepressant-relevant behavioral responses and (2R,6R)-HNK levels in the extracellular compartment of the hippocampus were measured following systemic (2R,6R)-HNK administration in mice. The effects of ketamine, (2R,6R)-HNK, and, in some cases, the (2S,6S)-HNK stereoisomer were evaluated on the following: (i) NMDA-induced lethality in mice, (ii) NMDAR-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 field of mouse hippocampal slices, (iii) NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) and NMDA-evoked currents in CA1 pyramidal neurons of rat hippocampal slices, and (iv) recombinant NMDARs expressed in Xenopus oocytes. While a single i.p. injection of 10 mg/kg (2R,6R)-HNK exerted antidepressant-related behavioral and cellular responses in mice, the ED50 of (2R,6R)-HNK to prevent NMDA-induced lethality was found to be 228 mg/kg, compared with 6.4 mg/kg for ketamine. The 10 mg/kg (2R,6R)-HNK dose generated maximal hippocampal extracellular concentrations of ∼8 μM, which were well below concentrations required to inhibit synaptic and extrasynaptic NMDARs in vitro. (2S,6S)-HNK was more potent than (2R,6R)-HNK, but less potent than ketamine at inhibiting NMDARs. These data demonstrate the stereoselectivity of NMDAR inhibition by (2R,6R;2S,6S)-HNK and support the conclusion that direct NMDAR inhibition does not contribute to antidepressant-relevant effects of (2R,6R)-HNK.

Preclinical studies indicate that (2R,6R)-hydroxynorketamine (HNK) retains the rapid and sustained antidepressant-like actions of ketamine, but is spared its dissociative-like properties and abuse potential. While (2R,6R)-HNK is thought to exert its antidepressant-like effects by potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission, it is unknown how it exerts this effect. The acute synaptic effects of (2R,6R)-HNK were examined by recording field excitatory postsynaptic potentials (fEPSPs) and miniature excitatory postsynaptic currents (mEPSCs) in rat hippocampal slices. (2R,6R)-HNK bath application caused a rapid and persistent potentiation of AMPAR-mediated Schaffer collateral (SC)-CA1 fEPSPs in slices derived from male and female rats. The (2R,6R)-HNK-induced potentiation occurred independent of N-methyl-D-aspartate receptor (NMDAR) activity, was accompanied by a concentration-dependent decrease in paired pulse ratios, and was occluded by raising glutamate release probability. In additon, in the presence of tetrodotoxin, (2R,6R)-HNK increased the frequency, but not amplitude, of mEPSC events, confirming a presynaptic site of action that is independent of glutamatergic network disinhibition. A dual extracellular recording configuration revealed that the presynaptic effects of (2R,6R)-HNK were synapse-selective, occurring in CA1-projecting SC terminals, but not in CA1-projecting temporoammonic terminals. Overall, we found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration-dependent, NMDAR-independent, and synapse-selective increase in glutamate release probability with no direct actions on AMPAR function. These findings provide novel insight regarding (2R,6R)-HNK’s acute mechanism of action, and may inform novel antidepressant drug mechanisms that could yield superior efficacy, safety, and tolerability.

This study used in vivo magnetic resonance imaging (MRI) to identify age dependent brain structural characteristics in Dunkin Hartley guinea pigs. Anatomical T2-weighted images, diffusion kurtosis (DKI) imaging, and T2 relaxometry measures were acquired from a cohort of male guinea pigs from postnatal day (PND) 18–25 (juvenile) to PND 46–51 (adolescent) and PND 118–123 (young adult). Whole-brain diffusion measures revealed the distinct effects of maturation on the microstructural complexity of the male guinea pig brain. Specifically, fractional anisotropy (FA), as well as mean, axial, and radial kurtosis in the corpus callosum, amygdala, dorsal-ventral striatum, and thalamus significantly increased from PND 18–25 to PND 118–123. Age-related alterations in DKI measures within these brain regions paralleled the overall alterations observed in the whole brain. Age-related changes in FA and kurtosis in the gray matter-dominant parietal cerebral cortex and dorsal hippocampus were less pronounced than in the other brain regions. The regional data analysis revealed that between-age changes of diffusion kurtosis metrics were more pronounced than those observed in diffusion tensor metrics. The age-related anatomical differences reported here may be important determinants of the age-dependent neurobehavior of guinea pigs in different tasks.

RationaleCognitive benefits of nicotinic acetylcholine receptor (nAChR) agonists are well established but have generally been of small magnitude and uncertain clinical significance. A way of raising the effect size may be to facilitate agonist-induced responses by co-administering a nAChR positive allosteric modulator (PAM).ObjectiveThe aim was to test whether galantamine, a PAM at several nAChR subtypes, can potentiate the cognitive-enhancing effects of nicotine.MethodsTwenty-six adult never-smokers were treated, in a double-blind counterbalanced sequence, with nicotine (7 mg/24 h, transdermally) and galantamine (4 mg, p.o.) combined, nicotine alone, galantamine alone, and double placebo. A low dose of galantamine was chosen to minimize acetylcholinesterase inhibition, which was verified in blood assays. In each condition, participants were tested with three cognitive tasks.ResultsNicotine significantly improved reaction time (RT) and signal detection in a visuospatial attention task and the Rapid Visual Information Processing Task. Galantamine did not modulate these effects. A trend toward RT reduction by galantamine correlated with acetylcholinesterase inhibition. In a change detection task, there were no effects of nicotine or galantamine alone on accuracy or RT. However, both drugs combined acted synergistically to reduce RT. This effect was not associated with acetylcholinesterase inhibition.ConclusionsA pattern consistent with allosteric potentiation of nicotine effects by galantamine was observed on one of six performance measures. This may reflect specific nAChR subtype involvement, or additional pharmacological actions of galantamine may have overshadowed similar interactions on other measures. The finding suggests that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle.

The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits α7 nicotinic acetylcholine receptors (α7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the α7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by ( S )-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.

There have been continued efforts to develop effective antidotal therapies against poisoning with organophosphorus (OP) compounds, including nerve agents and pesticides. We reported recently that galantamine, a drug used to treat Alzheimer’s disease, administered before (up to 3 h) or soon after (up to 5 min) an exposure of guinea pigs to 1.5–2 × LD50 soman or sarin effectively counteracted the acute toxicity and lethality of the nerve agents provided that the animals were also post-treated with atropine. Here, we demonstrate that administered to guinea pigs at 30 min before or up to 15 min after an acute challenge with 1 × LD50 soman, galantamine (8 mg/kg, intramuscular) alone is sufficient to counteract the lethality and acute toxicity of the nerve agent. Evidence is also provided that 100% survival can be attained when the association of appropriate doses of galantamine and atropine is administered 30–45 min after the challenge of the guinea pigs with 1 × LD50 soman. Galantamine counteracts the neurodegeneration and the changes in the nicotinic cholinergic system that result from an acute exposure of guinea pigs to 1 × LD50 soman. The results presented herein corroborate that galantamine is an effective antidote against OP poisoning.