Thomas H. Lanthorn

Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention

The memory-enhancing potential of D-cycloserine (cycloserine) a partial agonist at the glycine recognition site on the NMDA receptor, was evaluated in mice using a thirst-motivated linear maze learning task. Immediate acute post-training injections (10, 20 and 80 mg/kg) significantly improved retention relative to vehicle-injected controls. Retention was also facilitated if cycloserine (3 and 10 mg/kg but not 20 or 40 mg/kg) was administered 20 min before the retention test. Acquisition of the habit was accelerated if cycloserine (3 mg/kg) was injected 20 min before the training session. Acute post-training injections failed to facilitate retention if mice were pretreated with cycloserine (3 mg/kg) b.i.d. for 15 days before training on the maze. These results indicate that acute cycloserine administration can enhance consolidation and retrieval of memory but that desensitization may occur with chronic exposure to the drug.

d-Cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptor expressed inXenopus oocytes

In the Xenopus oocyte preparation, D-cycloserine (DCS) had the profile of a partial agonist at the glycine modulatory site of the NMDA receptor. Maximal NMDA responses in the presence of DCS were only 40-50% of those in the presence of glycine. Glycine and D-serine were agonists at this site. The actions of DCS were competitively antagonized by HA-966, a known glycine antagonist.

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Experimental ischemia induces a persistent depolarization blocked by decreased calcium and NMDA antagonists

Early physiological events induced by hypoxia plus low D-glucose were investigated by intracellular recording in the rat hippocampal slice. A rapid intracellular depolarization corresponded to the extracellularly recorded anoxic depolarization. This intracellular depolarization consisted of two pharmacologically distinct components, an initial depolarization and a persistent depolarization. The persistent phase of depolarization was selectively blocked by lowering calcium and raising magnesium and by N-methyl-D-aspartate (NMDA) antagonists. This persistent depolarization can account for the long-term synaptic failure seen following experimental ischemia in vitro.

A Review of the In Vitro and In Vivo Neurochemical Characterization of the NMDA/PCP/Glycine/Ion Channel Receptor Macrocomplex*

ConclusionsCurrent neurochemical studies of the NMDA receptor macromolecular complex are yielding new insights into the interactions of the subunits of this complex and the associated potential clinical benefits of selective modulation of these subnits. Such studies offer the great potential for a new generation of pharmacotherapies for a wide range of CNS disorders, including stroke, a condition for which there is currently no effective pharmacological treatment. However, it is essential to understand that the first generation products in this area may not be optimal pharmacotherapies, such that haracterization of possible receptor subtypes and understanding the molecular biology of the component proteins of the receptor complex will be crucial in the design of the optimal pharmacological modulators of the NMDA receptor complex.

Pharmacological characteristics of cyclic homologues of glycine at the N-methyl-d-aspartate receptor-associated glycine site

In Xenopus oocytes, injected with mRNA from the brain of the rat, the characteristics of the cyclic homologues of glycine, ACPC, ACBC and cycloleucine have been examined. 1-Aminocyclopropane-1-carboxylate was a potent agonist at the NMDA-associated glycine site (EC50 = 0.09 +/- 0.02 microM) and exhibited characteristics consistent with a partial agonist. 1-Aminocyclobutane-1-carboxylate, in addition to its previously described antagonist properties, was found to possess agonist properties of low efficacy. Furthermore, ACBC did not completely block NMDA/glycine-induced currents, which is also consistent with partial agonist characteristics. In addition, small concentrations of glycine (less than 3 microM) did not alter the potency of ACBC, possibly suggesting that it is not simply a competitive glycine antagonist. Cycloleucine was a very weak glycine antagonist. These results suggest that as the size of the ring of cyclic homologues of glycine increases, there is a resulting transition from agonist to mixed agonist/antagonist to antagonist properties.

Evaluation of U-50,488H analogs for neuroprotective activity in the gerbil

U-50,488H, a kappa (kappa) opioid ligand with moderate potency at sigma (sigma) receptors, protects against mechanical and ischemia-induced injury. The purpose of this study was to evaluate the possibility that sigma-receptors may be involved in mediating the neuroprotective actions of U-50,488H. This possibility was examined by testing the potential of a series of U-50,488H analogs, which are potent sigma-ligands with minimal activity at kappa-opioid receptors, to protect against ischemia-induced neuronal damage in the gerbil. Like U-50,488H, BD-449 (20 mg/kg), the cis-diastereomer of U-50,4888H, protected against ischemia-induced neuronal damage as did BD-737 (50 and 30 mg/kg) and BD-738 (50 mg/kg). All 3 compounds interacted selectively with sigma-receptors. In contrast, BD-601 (50 mg/kg), did not protect against ischemia-induced neuronal damage, although it also interacted potently with sigma-receptors. One difference between the compounds that were neuroprotective and BD-601 is that only BD-601 produced sigma-like behavioral effects in the rat. Thus, it is possible that BD-601 may interact differently or at a different sigma-subtype than BD-449, BD-737 and BD-738 with sigma-receptors. However, these results clearly indicate that an interaction with kappa-opioid receptors is not required for anti-ischemic activity, and that sigma-receptors may play a role in neuroprotection.

cis-2,4-methanoglutamate is a potent and selective N-methyl-D-aspartate receptor agonist

Cis- and trans-2,4-methanoglutamate were compared with L-glutamate as acidic amino acid ligands. Cis-2,4-methanoglutamate had a Ki of 0.052 microM against N-methyl-D-aspartate (NMDA)-specific L-[3H]glutamate binding compared with 0.050 microM for L-glutamate. Cis-2,4-methanoglutamate exhibited no significant affinity against [3H]kainate or [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate ([3H]AMPA) binding. Trans-2,4-methanoglutamate had no significant affinity for any of these sites. Cis-2,4-methanoglutamate increased [3H]N-1[2-thienyl]cyclohexyl-3,4-piperidine [( 3H]TCP) binding with EC50 of 0.35 +/- 0.14 microM. It produced an inward current in rat brain mRNA-injected Xenopus oocytes which was blocked by the NMDA antagonist, D-2-amino-7-phosphonoheptanoate (D-AP7). Cis-2,4-methanoglutamate (EC50 = 15.9 microM) was 100-fold more potent than L-glutamate (EC50 = 1,584 microM) in reducing the excitatory postsynaptic potential in CA1 of hippocampal slices. Cis-2,4-methanoglutamate is the most potent, selective NMDA agonist known.

Opipramol, a potent sigma ligand, is an anti-ischemic agent: Neurochemical evidence for an interaction with the N-methyl-D-aspartate receptor complex in vivo by cerebellar cGMP measurements

Opipramol, a potent sigma ligand and a tricyclic antidepressant compound, provided significant neuronal protection (P less than 0.0001) against ischemia-induced neuronal cell loss in the hippocampus in Mongolian gerbils, at a dose of 50 mg/kg (30 min pretreatment). However, opipramol did not offer protection when given 60 min after the ischemic insult. Opipramol decreased basal levels of cGMP in the cerebellum of the mouse and harmaline-induced increases in levels of cGMP, with approximate ED50 values of 4 and 27 mg/kg. Opipramol antagonized methamphetamine- and pentylenetetrazol-induced increases in levels of cGMP. Parenteral administration of opipramol also antagonized the increases in levels of cGMP in the cerebellum of the mouse after the local administration of D-serine, an agonist at the N-methyl-D-aspartate (NMDA)-associated, strychnine-insensitive glycine receptor. These results indicate that opipramol attenuates responses mediated through the NMDA receptor complex. These results further support the functional modulation of the NMDA receptor complex by sigma ligands and provide a neurochemical correlate for the observed anti-ischemic properties of opipramol.

BMY-14802 protects against ischemia-induced neuronal damage in the gerbil

BMY-14802, a selective sigma ligand currently under investigation as an atypical antipsychotic agent, was tested for potential anti-ischemic activity. BMY-14802 (10, 30 and 50 mg/kg) did not produce any stereotyped behavior, ataxia or seizures. When gerbils were pretreated with 10, 30 or 50 mg/kg of BMY-14802 30 min prior to bilateral occlusion of carotid arteries for 5 min, BMY-14802 significantly protected against ischemia-induced neuronal loss in the hippocampus. Thus, BMY-14802 may also be useful as an anti-ischemic agent that does not produce psychotomimetic effects.