Regulation of intermittent oscillatory activity of pyramidal cell neurons by GABA inhibitory interneurons is impaired in schizophrenia: rationale for pharmacotherapeutic GABAergic interventions.

GABA, the major inhibitory neurotransmitter in the brain, is synthesized from L-glutamate and packaged within a family of highly differentiated inhibitory interneurons. Individual GABA inhibitory interneurons in the frontal cortex can make terminal synaptic connections with more than 200 distinct pyramidal neurons, the principal output neuron. Moreover, the sites of these synaptic connections include shafts of dendritic spines, soma, dendritic branches, and initial axon segments.

NMDA NR2B subtype-selective receptor antagonists fail to antagonize electrically-precipitated seizures and elicit popping in mice.

NR2B-subtype-selective antagonists differ from MK-801, a nonselective NMDA receptor antagonist. MK-801 antagonizes electrical seizures at doses as low as 0.1 to 0.

Genetically inbred Balb/C mice are more sensitive to an effect of flurazepam and more resistant to an effect of stress than a genetically outbred mouse strain.

The inbred Balb/c mouse strain was more sensitive than the outbred NIH Swiss mouse to flurazepam's ability to antagonize electrically precipitated seizures. In prior work, a reduction in flurazepam's antiseizure efficacy was not observed 24h after forcing Balb/c mice to swim for up to 10 min in ambient temperature water. Thus, we wondered if a stress-induced reduction would be observed after forcing mice to swim for up to 10 min in cold (6 degrees C) water, a more severe stress.

An epigenetic intervention interacts with genetic strain differences to modulate the stress-induced reduction of flurazepam's antiseizure efficacy in the mouse.

Stress induces changes in the endogenous tone of both GABA and NMDA receptor-mediated neurotransmission in the intact mouse. Because changes are observed 24 h after stress, epigenetically-regulated alterations in gene expression may mediate these effects. In earlier work, sodium butyrate, a centrally-active histone deacetylase inhibitor that promotes gene expression, was shown to modulate the stress-induced reduction of the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically-precipitated seizures.

Expression of NR1, NR2A and NR2B NMDA receptor subunits is not altered in the genetically-inbred Balb/c mouse strain with heightened behavioral sensitivity to MK-801, a noncompetitive NMDA receptor antagonist.

The genetically-inbred Balb/c mouse strain shows heightened sensitivity to the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to raise the threshold voltage necessary to precipitate tonic hindlimb extension and elicit irregular episodes of intense jumping behavior (referred to as "popping"), relative to other inbred mouse strains and the outbred NIH Swiss mouse. Moreover, an allosteric modulatory effect of sarcosine, a glycine reuptake inhibitor, on MK-801's antagonism of electrically precipitated seizures was detected 24 h after Balb/c mice were forced to swim in cold water for up to 10 min; this was not observed in unstressed Balb/c mice or stressed or unstressed NIH Swiss mice. Phencyclidine (PCP), a noncompetitive NMDA receptor antagonist that binds to the same hydrophobic channel domain as MK-801, precipitates a schizophreniform psychosis in susceptible individuals that shares descriptive similarities with schizophrenia.

Epigenetic therapeutic strategies for the treatment of neuropsychiatric disorders: ready for prime time?

Chromatin remodeling is recognized as a major regulator of gene expression that can be influenced by inhibition of epigenetic mechanisms that result in stable, heritable, covalent modifications of histone proteins and their associated DNA. Epigenetically regulated covalent modifications are implicated in the pathogenesis of some forms of cancer and stimulated clinical trials of compounds selected for their ability to arrest cell division and promote differentiation of malignantly transformed cells. Chromatin remodeling may also be considered as a therapeutic target in diverse neuropsychiatric disorders such as Huntington disease and other neurodegenerative disorders characterized by expression of mutant proteins with expanded tracts of polyglutamine repeats, schizophrenia, and major depression.

First administration of cytidine diphosphocholine and galantamine in schizophrenia: a sustained alpha7 nicotinic agonist strategy.

Converging lines of evidence suggest pathophysiology of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) in schizophrenia. This pilot study was designed to test the tolerability, safety, and preliminary efficacy of chronic administration of an alpha7 nAChR agonist strategy involving combination treatment of cytidine diphosphocholine (CDP-choline; 2 g/d), a dietary source of the alpha7 nAChR agonist choline, and galantamine (24 mg/d), a positive allosteric modulator of nAChRs that was prescribed to prevent choline from becoming a functional antagonist and improve the efficiency of coupling the binding of choline to channel opening. The combination of CDP-choline and galantamine was administered to 6 schizophrenic patients with residual symptoms in a 12-week, open-label trial.

Sodium butyrate, an epigenetic interventional strategy, attenuates a stress-induced alteration of MK-801's pharmacologic action.

Twenty-four hours after mice are exposed to a single session of forced swimming in cold water, the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically precipitated seizures is reduced. Conceivably, this reduction in MK-801's antiseizure efficacy reflects a stress-induced alteration in NMDA receptor-mediated neurotransmission due to changes in gene expression 24 h after a single stress. Recently, epigenetic interventional strategies impacting expression of genes whose regulation is controlled by the acetylation status of histone proteins in the nucleosome, an octomeric complex of histone proteins and promoter regions of double-stranded DNA, have been tested in preclinical models of various neuropsychiatric disorders, including Huntington disease and major depression.

Guanosine possesses specific modulatory effects on NMDA receptor-mediated neurotransmission in intact mice.

Guanosine, a purine nucleotide, promotes the reuptake of l-glutamate by astrocytes; astrocytic reuptake of glutamate is a major mechanism of its synaptic inactivation. The current experiments showed that guanosine reduced the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor "open-channel" blocker, to raise the threshold voltage for electrically-precipitated tonic hindlimb extension in unstressed intact mice. This modulatory effect may be due to guanosine's removal of glutamate from the synaptic cleft, resulting in a reduced proportion of NMDA receptor-associated ion channels in the open configuration.

Effects of CDP-choline and the combination of CDP-choline and galantamine differ in an animal model of schizophrenia: development of a selective alpha7 nicotinic acetylcholine receptor agonist strategy.

The regionally selective reduction of expression of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in schizophrenia underlies impaired sensory inhibition, a possible endophenotype of the disorder. This ligand-gated ion channel receptor has been proposed as a pharmacotherapeutic target in schizophrenia. The current study examined the effect of CDP-choline alone and the combination of CDP-choline and galantamine, administered acutely and once-daily for five consecutive days, in an animal model of NMDA receptor hypofunction that is relevant to schizophrenia.

Phencyclidine and dizocilpine induced behaviors reduced by N-acetylaspartylglutamate peptidase inhibition via metabotropic glutamate receptors.

Background: N-methyl-D-aspartate (NMDA) receptor open channel blockers phencyclidine (PCP) and dizocilpine (MK-801) elicit schizophrenia-like symptoms in humans and in animal models. Group II metabotropic glutamate receptor agonists reverse the behavioral effects of PCP and MK-801 in animal models. N-acetylaspartylglutamate (NAAG), the third most prevalent neurotransmitter in the mammalian nervous system, is a selective group II metabotropic glutamate receptor agonist.

Rare neurodevelopmental abnormalities of sarcosinemia may involve glycinergic stimulation of a primed N-methyl-d-aspartate receptor.

Sarcosinemia is a relatively rare autosomal recessive disorder that has a varied phenotypic presentation; rarely, it is associated with neurodevelopmental and neurological abnormalities. Sarcosine is a key intermediate in 1-carbon metabolism, and its elevation in blood and urine could reflect a deficient pool size of activated 1-carbon units. Sarcosine is also an inhibitor of an important glycine transporter in brain and is under clinical investigation as a glycinergic intervention for conditions with presumed N-methyl-d-aspartate (NMDA) receptor hypofunction, such as schizophrenia.

Imitation of facial expressions in schizophrenia.

Diminished facial expressivity is a common feature of schizophrenia that interferes with effective interpersonal communication. This study was designed to determine if real-time visual feedback improved the ability of patients with schizophrenia to imitate and produce modeled facial expressions. Twenty patients with schizophrenia and 10 controls viewed static images of facial expressions and were asked to imitate them.

Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain.

Abnormalities of NMDA receptor-mediated neurotransmission are involved in the pathophysiology of schizophrenia, Alzheimer's disease, substance abuse and seizure disorders. The NMDA receptor is implicated in schizophrenia because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, binds to a hydrophobic domain within the channel, precipitating a schizophreniform psychosis in susceptible persons. Pharmacological, environmental, and genetic variables alter NMDA receptor-mediated neurotransmission.

Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice.

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice.

Therapeutic implications of a selective alpha7 nicotinic receptor abnormality in schizophrenia.

A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of reduced expression and function of the alpha7 nicotinic receptor in patients with schizophrenia. The alpha7 nicotinic receptor is a member of a family of ligand-gated ion channels. The alpha7 nicotinic receptor may play an essential role in auditory sensory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in patients with schizophrenia and closely related unaffected biological relatives.

Hypothesized deficiency of guanine-based purines may contribute to abnormalities of neurodevelopment, neuromodulation, and neurotransmission in Lesch-Nyhan syndrome.

The Lesch-Nyhan syndrome is a devastating sex-linked recessive disorder resulting from almost complete deficiency of the activity of hypoxanthine phosphoribosyltransferase (HPRT). The enzyme deficiency results in an inability to synthesize the nucleotides guanosine monophosphate and inosine monophosphate from the purine bases guanine and hypoxanthine, respectively, via the "salvage" pathway and an accelerated biosynthesis of these purines via the de novo pathway. The syndrome is characterized by neurologic manifestations, including the very dramatic symptom of compulsive self-mutilation.

Anabasine, a selective nicotinic acetylcholine receptor agonist, antagonizes MK-801-elicited mouse popping behavior, an animal model of schizophrenia.

The expression of the alpha7-nicotinic acetylcholine receptor is diminished in selected brain areas of patients with schizophrenia. This diminished expression may account for the pathophysiological deficits of sensory inhibition and smooth pursuit eye movement performance in these patients. Furthermore, the deficits in sensory inhibition and smooth pursuit eye movement performance in schizophrenia appear to be inherited in an autosomal dominant fashion; thus, the "alpha7-nicotinic acetylcholine receptor-deficiency" may be a necessary condition for expression of schizophrenia.

Behavioral consequences of methyllycaconitine in mice: a model of alpha7 nicotinic acetylcholine receptor deficiency.

Diminished expression of the alpha(7) nicotinic acetylcholine receptor occurs in selected brain regions of patients with schizophrenia, which may account for pathophysiological abnormalities and some of the deficits in attention and information processing. In view of this neurotransmitter receptor deficit, we wished to characterize the behavioral consequences associated with the administration of methyllycaconitine (MLA), a competitive alpha(7) nicotinic acetylcholine receptor antagonist, in mice. In this study, we injected groups of 12 outbred NIH Swiss male mice intraperitoneally with MLA (1.

Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha 7 nicotinic acetylcholine receptor: therapeutic implications.

In persons with Down syndrome, soluble Abeta peptides, which result from the processing of the amyloid precursor protein, appear in the brain decades before the extracellular deposition of neuritic plaques. These soluble amyloidogenic peptides accumulate intraneuronally and can be secreted extracellularly. Their appearance has been reported in the brains of fetuses with Down syndrome.

Modulation of MK-801-elicited mouse popping behavior by galantamine is complex and dose-dependent.

The ability of phencyclidine (PCP), a noncompetitive antagonist of NMDA receptor-mediated neurotransmission, to precipitate a schizophreniform psychosis in susceptible individuals is consistent with the hypothesized pathologic occurrence of NMDA receptor hypofunction in this disorder. Because the psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, investigators have sought to characterize animal models of NMDA receptor hypofunction. MK-801 (dizocilpine) binds to the same hydrophobic channel domain in the NMDA receptor-associated ionophore as PCP, and has been shown to elicit intense irregular episodes of jumping behavior in mice, termed "popping.

Adjuvant topiramate administration: a pharmacologic strategy for addressing NMDA receptor hypofunction in schizophrenia.

N-methyl-d-aspartate receptor hypofunction (NRH) and its downstream consequences, especially excitotoxicity, may explain the progressive psychosocial deterioration and ventriculomegaly observed in at least some patients with schizophrenia. Topiramate has several properties that address downstream consequences of NRH. In this open-label investigation, the authors examined the salutary therapeutic effects of adjuvant topiramate in 12 patients with schizophrenia and schizoaffective disorder.

Fluoxetine's effects on cognitive performance in patients with traumatic brain injury.

Objective: There are preclinical data showing that fluoxetine stimulated expression of Brain Derived Neurotrophic Factor (BDNF) and its specific tyrosine kinase receptor, and caused neuritic elongation and increased dendritic branching density of CA3 hippocampal pyramidal cell neurons in rodents. The latter effect of fluoxetine has been referred to as neuronal remodeling. In view of this preclinical data, we wondered if specific cognitive measures could serve as novel therapeutic targets for fluoxetine in head-injured patients.

Methyllycaconitine fails to inhibit electrically precipitated tonic hindlimb extension in mice.

Abnormalities of the transduction of the acetylcholine signal in the brain by the alpha(7) nicotinic receptor are thought to contribute substantially to a fundamental pathophysiologic mechanism in schizophrenia. Abnormal or diminished expression of the alpha(7) nicotinic receptor polypeptide subunit in the brains of patients with schizophrenia has encouraged consideration of the development of alpha(7) nicotinic receptor agonist strategies for the treatment of this disorder. These strategies would target negative symptoms, and attentional and cognitive abnormalities, which are domains of psychopathology that are associated with very poor functional outcomes and disability.

Interaction of stress and strain on glutamatergic neurotransmission: relevance to schizophrenia.

Psychosis caused by phencyclidine (PCP) stimulated interest in characterizing rodent behaviors elicited by PCP and its analogues. We have shown that MK-801 antagonizes electrically precipitated seizures (defined as tonic hindlimb extension) and elicits episodes of intense jumping behavior, referred to as "popping," in mice. Moreover, 24 h after stress, MK-801's ability to antagonize electrically precipitated seizures is reduced in outbred NIH Swiss mice.