Targeting alpha-7 nicotinic neurotransmission in schizophrenia: a novel agonist strategy.

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) agonists may be valuable treatments for negative symptoms and cognitive impairment in schizophrenia. Unfortunately, chronic exposure to an agonist may reduce the receptor's sensitivity. Therefore, we combined CDP-choline, a dietary source of the direct agonist choline, with galantamine, a positive allosteric modulator (PAM) of nicotinic acetylcholine receptors, to improve the efficiency of transducing the choline signal and, possibly, preserve the receptor in a sensitive state.

The phantom limb experience and sensory phenomena in a relocated limb in a case of fillet flap used to reconstruct a massive wound proximal to an above-knee amputation.

Unlabelled: A 41-year-old male sustained a massive crushing injury to his left posterior thigh and buttock and transection of the sciatic nerve; he underwent an above-knee amputation with fillet flap. He was interviewed 24 months postoperatively to determine his phantom limb experience. At 37 and 42 months, testing for touch-pressure sensitivity of the residual limb and buttock was done with a 1-gram monofilament.

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.

Valproate-induced hyperammonemic encephalopathy and normal liver functions: possible synergism with topiramate.

A patient with valproate-induced hyperammonemic encephalopathy presented with altered mental status and hyperammonemia in the context of normal liver functions. Fortunately, altered mental status and elevated plasma ammonia level normalized 1 day after discontinuation of divalproex sodium (Depakote). The case analysis suggests a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy in the context of normal liver functions.

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.

Recognition memory probes affect what is remembered in schizophrenia.

Cognitive psychology offers tools to localize the memory processes most vulnerable to disruption in schizophrenia and to identify how patients with schizophrenia best remember. In this research, we used the University of Southern California Repeatable Episodic Memory Test (USC-REMT; Parker, E.S.

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.

Current status of cannabis treatment of multiple sclerosis with an illustrative case presentation of a patient with MS, complex vocal tics, paroxysmal dystonia, and marijuana dependence treated with dronabinol.

Pain, spasticity, tremor, spasms, poor sleep quality, and bladder and bowel dysfunction, among other symptoms, contribute significantly to the disability and impaired quality of life of many patients with multiple sclerosis (MS). Motor symptoms referable to the basal ganglia, especially paroxysmal dystonia, occur rarely and contribute to the experience of distress. A substantial percentage of patients with MS report subjective benefit from what is often illicit abuse of extracts of the Cannabis sativa plant; the main cannabinoids include delta-9-tetrahydrocannabinol (delta9-THC) and cannabidiol.

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.

Williams syndrome: a genetic deletion disorder presenting clues to the biology of sociability and clinical challenges of hypersociability.

Williams syndrome is a neurodevelopmental disorder that results from the deletion of approximately 25-30 genes spanning about 1.5 megabases in the q11.23 region of chromosome 7.

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.

Long-term ethanol consumption impairs reverse cholesterol transport function of high-density lipoproteins by depleting high-density lipoprotein sphingomyelin both in rats and in humans.

Moderate alcohol consumption has been linked to lower incidence of coronary artery disease due to increased plasma high-density lipoprotein (HDL), whereas heavy drinking has the opposite effect. Because of the crucial role of HDL in reverse cholesterol transport and positive correlation of HDL sphingomyelin (SM) content with cholesterol efflux, we have compared HDL SM content with its reverse cholesterol transport capacity both in rats fed ethanol on long-term basis and alcoholic individuals. In rats, SM HDL content was decreased in the ethanol group (-15.

Mitochondrial myopathy complicated by eating disorder: a case report highlighting the potential interaction of genetic, metabolic, and psychodynamic factors.

A case is presented of a 56-year-old woman with a history of an eating disorder that preceded recognition of a mitochondrial myopathy. The possibility exists that her eating disorder was causally related to a more fundamental defect in mitochondrial oxidative metabolism. This case report highlights the phenotypic variability of mitochondrial myopathies.

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.

Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications.

Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins.

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.

Configural processing in face recognition in schizophrenia.

Introduction: There is currently substantial literature to suggest that patients with schizophrenia are impaired on many face-processing tasks. This study investigated the specific effects of configural changes on face recognition in groups of schizophrenia patients.

Methods: In Experiment 1, participants identified facial expressions in upright faces and in faces inverted from their upright orientation.