RESUMEN
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. The phasic activity of GABAergic neurons regulate intermittent oscillations of assemblies of pyramidal cell neurons, which are critical for many higher cortical functions such as working memory. Potentially, there are several viable pharmacotherapeutic strategies for facilitating GABAergic neurotransmission. A major research question is whether tonically-administered, selective GABAergic therapeutic interventions can mimic and correct disruptions of the intermittent oscillatory activity of assemblies of cortical pyramidal cell neurons.
Asunto(s)
Lóbulo Frontal/metabolismo , Interneuronas/metabolismo , Inhibición Neural , Teoría Psicológica , Células Piramidales/metabolismo , Esquizofrenia/metabolismo , Transmisión Sináptica , Ácido gamma-Aminobutírico/metabolismo , Animales , Axones/metabolismo , Relojes Biológicos/efectos de los fármacos , Carisoprodol/metabolismo , Dendritas/metabolismo , Espinas Dendríticas/metabolismo , Lóbulo Frontal/efectos de los fármacos , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Humanos , Memoria , Inhibición Neural/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Transmisión Sináptica/efectos de los fármacosRESUMEN
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 0.18mg/kg and elicits popping at doses as low as 0.5mg/kg, whereas ifenprodil and Ro 8-4304 were unable to do so at the doses tested. Ro 25-6981, however, was able to antagonize electrically-precipitated tonic hindlimb extension at 100mg/kg, but was not able to elicit popping behavior at this dose.
Asunto(s)
Electrochoque , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/metabolismo , Convulsiones/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Electrochoque/métodos , Masculino , Ratones , Fenoles/farmacología , Piperidinas/farmacologíaRESUMEN
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. The current data show that 24 h after exposure to this stress, the ability of flurazepam to raise the threshold voltage for the elicitation of tonic hindlimb extension in the Balb/c mouse strain was reduced. The genetically inbred Balb/c mouse strain is emerging as an interesting animal model in which to study interactions of stress and genetic factors that affect endogenous neurotransmission mediated by l-glutamate and GABA at the NMDA and GABA(A) receptor complexes, respectively.
Asunto(s)
Ansiolíticos/uso terapéutico , Flurazepam/uso terapéutico , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/genética , Análisis de Varianza , Animales , Ansiolíticos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Flurazepam/farmacología , Miembro Posterior/efectos de los fármacos , Miembro Posterior/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Estrés Psicológico/etiologíaRESUMEN
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. In the current study, we extended this work to look at sodium butyrate's modulatory effect on stress-induced changes in the antiseizure efficacy of flurazepam, a benzodiazepine receptor agonist, in two strains of mice. Epigenetic mechanisms, genetic strain differences and a standard stress interacted to alter flurazepam's antiseizure efficacy. These data support examination and development of epigenetic treatment strategies.
Asunto(s)
Ansiolíticos/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/fisiopatología , Flurazepam/farmacología , Estrés Psicológico/fisiopatología , Animales , Conducta Animal , Butiratos/uso terapéutico , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Epilepsia/etiología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Flurazepam/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Especificidad de la EspecieRESUMEN
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. This observation has led to the hypothesis that NMDA receptor hypofunction (NRH) is involved in the pathophysiology of schizophrenia and the testing of pharmacotherapeutic strategies to facilitate NMDA receptor-mediated neurotransmission in patients with this disorder (e.g., glycine reuptake inhibitors). The heightened behavioral sensitivity of the Balb/c mouse to MK-801 suggests that this mouse strain may be a useful model to study "psychosis-proneness" and screen for positive allosteric modulators of NMDA receptor-mediated neurotransmission. Conceivably, strain differences in the pharmacology of the NMDA receptor are due to differences in the relative expression of individual NMDA receptor subunits to each other (i.e., combinatorial regulation). The current study compared the normal protein expression patterns of six of the eight identified splice variant isoforms of the NR1 NMDA receptor subunit, and NR2A and NR2B subunits in the hippocampus and cerebral cortex of Balb/c and NIH Swiss mice. The heightened behavioral sensitivity of the Balb/c genetically-inbred mouse strain to MK-801, compared to the outbred NIH Swiss mouse strain, does not appear to result from relative alterations of expression of these NMDA receptor protein subunits that were examined.
Asunto(s)
Conducta Animal/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/genética , Animales , Western Blotting , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Densitometría , Electroforesis en Gel Bidimensional , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Fenciclidina/farmacología , Receptores de N-Metil-D-Aspartato/biosíntesis , Especificidad de la EspecieRESUMEN
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. Ideally, these strategies will be relatively selective because epigenetic abnormalities may be most pronounced in specific cell types, and tissues and transcriptional dysregulation due to pathological covalent modifications involve only a small percentage of all the expressed genes in the human genome. To date, beneficial effects of epigenetic therapeutic interventions such as administration of histone deacetylase inhibitors have been observed in transgenic mice expressing mutant human DNA constructs of proteins with expanded polyglutamine repeats and other rodent models of neuropsychiatric disorders. The epigenetic therapeutic strategy has much promise, and its development will foster collaboration and cross fertilization between molecular and cell biologists, oncologists, psychiatrists, and neurologists.
Asunto(s)
Epigénesis Genética/fisiología , Trastornos Mentales/genética , Trastornos Mentales/terapia , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Animales , Ensamble y Desensamble de Cromatina , Metilación de ADN , HumanosRESUMEN
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. Patients were maintained on stable dose regimens of antipsychotic medications for 4 weeks before study entry and for the trial duration. All reached target doses of both agents and completed the trial. Transient side effects resolved without slowing of dose titration. Gastrointestinal adverse effects were most common. Of the 6 patients, 5 showed reduction in Clinical Global Impressions severity scores and Positive and Negative Syndrome Scale total scores. Three patients requested continuation of the adjunctive combination at the end of the trial. These results suggest further investigation of the combination of CDP-choline and galantamine as an alpha7 nAChR agonist intervention.
Asunto(s)
Citidina Difosfato Colina/uso terapéutico , Galantamina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nootrópicos/uso terapéutico , Proyectos Piloto , Esquizofrenia/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
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. These strategies have been studied extensively in cancer biology. In the current investigation, the severity of the stress-induced reduction of MK-801's ability to raise the threshold voltage for the elicitation of tonic hindlimb extension was reduced when sodium butyrate (1.5 g/kg, ip) was administered around the time of stress. Prior research showed that this dose of sodium butyrate reliably increased the acetylation status of H3 and H4 histone proteins in the hippocampus and cerebral cortex of mice. Thus, the attenuation of the stress-induced reduction of MK-801's antiseizure efficacy may be due to the increased acetylation of histone proteins in the nucleosomal core and promotion of gene expression. These data encourage development of epigenetic strategies to prevent some of the deleterious consequences of stress.
Asunto(s)
Butiratos/uso terapéutico , Maleato de Dizocilpina/efectos adversos , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Fármacos Neuroprotectores/efectos adversos , Estrés Psicológico/tratamiento farmacológico , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Masculino , Ratones , Estrés Psicológico/fisiopatologíaRESUMEN
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. We previously reported that ZJ43, a potent inhibitor of the enzymes that inactivate synaptically released NAAG, reduced motor and stereotypic effects of PCP in the rat. METHODS: To confirm the efficacy of NAAG peptidase inhibition in decreasing motor behaviors induced by PCP and MK-801, ZJ43 was tested in additional schizophrenia models. RESULTS: ZJ43 reduced MK-801-induced motor activation in a mouse model that has been used to characterize the efficacy of a wide range of pharmacotherapies for this human disorder. In a second mouse strain, the peptidase inhibitor reduced PCP-induced stereotypic movements. ZJ43 also reduced PCP-induced negative symptoms in a resident-intruder assay. The group II metabotropic glutamate receptor antagonist, LY341495, blocked the effect of NAAG peptidase inhibition in these mouse models of positive and negative PCP- and MK-801-induced behaviors. Additionally, LY341495 alone increased some PCP-induced behaviors suggesting that normal levels of NAAG act to moderate the effect of PCP via a group II mGluR. CONCLUSIONS: These data support the proposal that NAAG peptidase inhibition and elevation of synaptic NAAG levels represent a new therapeutic approach to treating the positive and negative symptoms of schizophrenia that are modeled by open channel NMDA receptor antagonists.
Asunto(s)
Conducta Animal/efectos de los fármacos , Maleato de Dizocilpina , Glutamato Carboxipeptidasa II/uso terapéutico , Fenciclidina , Receptores de Glutamato Metabotrópico/fisiología , Esquizofrenia , Conducta Agonística/efectos de los fármacos , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Masculino , Ratones , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/fisiopatología , Conducta Estereotipada/efectos de los fármacos , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
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. The results support the allosteric modulatory influence of galantamine on CDP-choline; however, individual doses of CDP-choline and galantamine must be carefully titrated in order to achieve optimal levels of alpha7 nAChR "agonism" that may be necessary for the desired therapeutic effect.
Asunto(s)
Inhibidores de la Colinesterasa/uso terapéutico , Citidina Difosfato Colina/uso terapéutico , Galantamina/uso terapéutico , Nootrópicos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , RatonesRESUMEN
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. The modulatory effect of guanosine on MK-801's ability to disrupt rotorod performance in unstressed mice or antagonize electrically-precipitated seizures in stressed mice was not seen. The inability to demonstrate modulation in the rotorod paradigm may reflect the sensitivity of this measure of motor incoordination to MK-801's disruptive effects. Whereas failure to see this effect in our incremental electroconvulsive shock paradigm in stressed mice may be due to the fact that stress and guanosine act in the same direction to reduce MK-801's antiseizure efficacy. Given the phencyclidine model of schizophrenia and its pharmacological actions as a noncompetitive NMDA receptor "open-channel" blocker and guanosine's antagonistic effect on MK-801's antiseizure efficacy in unstressed mice, the current data support development of guanine-based purines for the treatment of at least some aspects of schizophrenia.
Asunto(s)
Guanosina/farmacología , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Frío/efectos adversos , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Equilibrio Postural/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/fisiopatología , Estrés Psicológico/fisiopatología , Natación/psicologíaRESUMEN
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. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.
Asunto(s)
Maleato de Dizocilpina/uso terapéutico , Electrochoque/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Convulsiones/prevención & control , Serina/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Masculino , Ratones , Convulsiones/etiologíaRESUMEN
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. Half of the images were imitated with the use of a mirror and half were imitated without the use of a mirror. In addition, we examined whether practice in imitating and producing expressions improved the ability of participants to generate facial expressions on their own, without the aid of a model or mirror. Participants' facial expressions were photographed with a digital camera and each was rated for accuracy in producing characteristic facial expressions. Patients with schizophrenia were less accurate in imitating and producing facial expressions than controls, and real-time visual feedback did not improve accuracy in either group. Preliminary findings suggest that exposure to model expressions and practice in generating these expressions can improve the accuracy of certain posed expressions in schizophrenia.
Asunto(s)
Expresión Facial , Conducta Imitativa , Esquizofrenia , Psicología del Esquizofrénico , Adulto , Emoción Expresada , Retroalimentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Percepción/diagnóstico , Trastornos de la Percepción/etiología , Trastornos de la Percepción/terapia , Educación Compensatoria/métodos , Esquizofrenia/complicaciones , Percepción VisualRESUMEN
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. Preclinical research with a mouse model that is used to study pharmacological modulation of endogenous NMDA receptor-mediated tone may clarify, at least in some instances, varied phenotypic presentations of sarcosinemia that are often clinically benign. Sarcosine's effectiveness as a glycinergic agonist intervention for NMDA receptor hypofunction depends on an interaction between genetic background and a stressful environmental insult. Thus, neurodevelopmental and neurological abnormalities may manifest rarely in sarcosinemia in the context of relatively unique genetic factors and fetal insult or stress.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Encéfalo , Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Sarcosina/metabolismo , Encéfalo/anomalías , Encéfalo/crecimiento & desarrollo , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/etiología , Glicina/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Humanos , Receptores de N-Metil-D-Aspartato/efectos de los fármacosRESUMEN
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. Inbred mouse strains differ in their sensitivity to some of the behavioral effects of MK-801 (dizocilpine), a PCP analogue. The NMDA receptor complex in the BALB/c strain could reflect a unique stoichiometric combination of receptor subunits resulting in a higher proportion of the channels in the open configuration, a higher affinity of MK-801 for its hydrophobic channel domain, and/or a combination of the above. The BALB/c mouse strain, "stressed" mice, and behavioral consequences of MK-801 administration represent models of altered glutamatergic neural transmission. We were interested in examining the effect of stress on the modulatory properties of d-serine and sarcosine. d-Serine is a naturally occurring glycine agonist that modulates the ability of l-glutamate to influence the opening of the NMDA receptor-associated ionophore, and sarcosine is a naturally occurring glycine reuptake inhibitor. The data suggest that 24h after stress, d-serine and sarcosine interact synergistically to reduce MK-801's ability to antagonize electrically precipitated tonic hindlimb extension. Under conditions of stress, modulatory effects of d-serine and sarcosine on the antiseizure effect of MK-801 are observed that are not apparent in the nonstress condition. The results could be relevant to the development of glycinergic interventions for the treatment of neuropsychiatric disorders.
Asunto(s)
Receptores de N-Metil-D-Aspartato/fisiología , Sarcosina/farmacología , Serina/farmacología , Estrés Fisiológico/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Análisis de Varianza , Animales , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electrochoque/efectos adversos , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Convulsiones/fisiopatología , Transmisión Sináptica/genéticaRESUMEN
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. Diminished expression or function of the alpha7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial alpha7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modulators of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine).
Asunto(s)
Receptores Nicotínicos/fisiología , Esquizofrenia/fisiopatología , Esquizofrenia/terapia , Movimientos Oculares/fisiología , HumanosRESUMEN
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. The neurologic manifestations may result, at least in part, from a mixture of neurodevelopmental (eg, a failure to "arborize" dopaminergic synaptic terminals) and neurotransmitter (eg, disruption of GABA and glutamate receptor-mediated neurotransmission) consequences. HPRT deficiency results in elevated extracellular levels of hypoxanthine, which can bind to the benzodiazepine agonist recognition site on the GABA(A) receptor complex, and the possibility of diminished levels of guanine-based purines in discrete "pools" involved in synaptic transmission. In addition to their critical roles in metabolism, gene replication and expression, and signal transduction, guanine-based purines may be important regulators of the synaptic availability of L-glutamate. Guanine-based purines may also have important trophic functions in the CNS. The investigation of the Lesch-Nyhan syndrome may serve to clarify these and other important neurotransmitter, neuromodulatory, and neurotrophic roles that guanine-based purines play in the central nervous system, especially the developing brain. A widespread and general deficiency of guanine-based purines would lead to impaired transduction of a variety of signals that depend on GTP-protein-coupled second messenger systems. This is less likely in view of a prominent localized pathologic effect of HPRT deficiency on presynaptic dopaminergic projections to the striatum. A possible more circumscribed effect of a deficiency of guanine-based purines could be interference with modulation of glutamatergic neurotransmission. Guanosine has been shown to be an important modulator of glutamatergic neurotransmission, promoting glial reuptake of L-glutamate. A deficiency of guanosine could lead to dysregulated glutamatergic neurotransmission, including possible excitotoxic damage. Unfortunately, although the biochemical lesion has been known for quite some time (ie, HPRT deficiency), therapeutically beneficial interventions for these affected children and adults have not yet emerged based on this elucidation. Conceivably, guanosine or its analogues and excitatory amino acid receptor antagonists could participate in the pharmacotherapy of this devastating disorder.
Asunto(s)
Hipoxantina Fosforribosiltransferasa/deficiencia , Síndrome de Lesch-Nyhan/metabolismo , Síndrome de Lesch-Nyhan/fisiopatología , Transmisión Sináptica/fisiología , Animales , HumanosRESUMEN
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. This deficit has encouraged speculation about the possible therapeutic benefit of selective alpha7-nicotinic acetylcholine receptor agonist interventions in this disorder. In view of this, we sought to examine the effect of anabasine, a selective alpha7-nicotinic acetylcholine receptor agonist, on popping behavior in mice elicited by MK-801. MK-801, a high affinity analogue of phencyclidine (PCP), is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that binds to the hydrophobic domain of this ligand-gated channel. PCP is known to precipitate a schizophreniform psychosis in susceptible individuals, causing productive (e.g. hallucinations) deficit (e.g. affective blunting, amotivation, and social withdrawal), cognitive and motor symptoms similar to those seen in naturally-occurring schizophrenia. Behaviors elicited by MK-801 in mice reflect a pharmacologically-induced state of NMDA receptor hypofunction (NRH), which has been proposed to exist in schizophrenia. Compounds that attenuate MK-801-elicited behaviors, which are identified in this animal model, may have the potential to treat schizophrenia, including deficit and cognitive symptoms. In the current study, anabasine attenuated MK-801-elicited popping at a dose that did not cause clonic seizures. The development of alpha7-nicotinic acetylcholine receptor agonist interventions for schizophrenia must consider their potential liability to elicit seizure activity.
Asunto(s)
Anabasina/farmacología , Antipsicóticos/farmacología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/antagonistas & inhibidores , Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Actividad Motora/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores Nicotínicos/efectos de los fármacos , Esquizofrenia/fisiopatología , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Masculino , Ratones , Actividad Motora/fisiología , Nimodipina , Receptores de N-Metil-D-Aspartato/fisiología , Receptores Nicotínicos/fisiología , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Procesamiento de Señales Asistido por Computador , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
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 (1.0, 3.2 and 10.0 mg/kg) and its saline vehicle. Thereafter, individual mice were observed over a one-hour interval and the intensity of a variety of behaviors were rated on a 4-point scale. The observed behaviors included: gnawing/chewing, rearing, grooming, sniffing, climbing, Straub tail, locomotion and ataxia. MLA produced statistically significant changes in the following observed behaviors: rearing, sniffing, climbing, and locomotion. A profile of the behavioral changes related to MLA administration in mice could lead to the development of a screening paradigm for alpha(7) nicotinic acetylcholine receptor agonist interventions. Ideally, an effective alpha(7) nicotinic acetylcholine receptor agonist intervention would target domains of psychopathology, especially cognitive symptoms that contribute to the profound functional disability that is often associated with schizophrenia.
Asunto(s)
Aconitina/análogos & derivados , Aconitina/farmacología , Conducta Animal/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/deficiencia , Animales , Sitios de Unión , Encéfalo/fisiopatología , Inyecciones Intraperitoneales , Masculino , Ratones , Modelos Animales , Receptores Nicotínicos/fisiología , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
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. The extra gene dosage effect associated with trisomy 21 results in abnormalities of the processing of amyloid precursor protein in persons with Down syndrome. Abeta peptides, especially Abeta1-42, have been shown to form tight complexes with the alpha7 nicotinic acetylcholine receptor, interfering with transduction of the acetylcholine signal by this nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides by this nicotinic acetylcholine receptor subtype is associated with cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique electrophysiologic properties and plays a prominent role in normal psychophysiologic processes (eg, sensory inhibition) and cognition. In persons with Down syndrome there is a decrease in the ability to perform instrumental activities of daily living that worsen with aging. The progressive worsening of adaptive functions and cognition in persons with Down syndrome may be, at least in part, mediated by interference with this receptor by soluble Abeta peptides. In view of this complex formed by soluble Abeta peptides and the alpha7 nicotinic acetylcholine receptor, cholinergic interventions that have been developed for Alzheimer disease, including selective nicotinic ones, should be explored in Down syndrome. Ideally, selective cholinergic interventions would slow the progression of the worsening of adaptive function and emergence of dementia in persons with Down syndrome.