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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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.

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. 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).

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. 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.

Topiramate antagonizes MK-801 in an animal model of schizophrenia.

The phencyclidine (PCP) model of schizophrenia suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction and its consequences may play an important role in the pathophysiology of this psychiatric disorder. Moreover, the schizophreniform psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, especially negative symptoms and cognitive dysfunction. Because of interest in the PCP model and possible NMDA receptor hypofunction in schizophrenia, animal behaviors elicited by PCP and its analogues have been characterized. These preclinical models may serve to identify candidate compounds that possess therapeutic efficacy in schizophrenia. Ideally, negative symptoms and cognitive dysfunction would also serve as therapeutic targets for these novel medications. In the current study, the ability of topiramate to attenuate the severity of a specific behavior elicited by MK-801 (dizocilpine), a high affinity analogue of PCP was studied in mice. Topiramate was chosen because it addresses two of the predicted pathological consequences of NMDA receptor hypofunction. Specifically, topiramate potentiates GABAergic neurotransmission and antagonizes the excitotoxic actions of glutamate at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) classes of glutamate-gated channels. Topiramate was shown to inhibit MK-801-elicited "popping" behavior in a complex dose-dependent manner.

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 (1.0, 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.

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." MK-801-elicited mouse popping is an animal model of NMDA receptor hypofunction that has been used to screen novel candidate compounds for the treatment of schizophrenia. Recently, a selective abnormality in the transduction of the acetylcholine signal at the level of the alpha 7 nicotinic receptor has been described in schizophrenia. The existence of a nicotinic cholinergic abnormality in schizophrenia has stimulated interest in a potential therapeutic role for positive allosteric modulation of nicotinic receptors. Galantamine is a compound that possesses two interesting properties: inhibition of acetylcholinesterase and positive allosteric modulation of nicotinic neurotransmission. Theoretically, galantamine would be expected to increase the efficiency or likelihood that acetylcholine will promote channel opening and ionic conductance at nicotinic receptors. As expected, in the current investigation statistically significant popping behavior was elicited by MK-801 in mice (T(22) = 2.16, P < 0.05). This MK-801-elicited popping was significantly attenuated by 100 mg/kg of galantamine (T(22) = 2.24, P < 0.05). The data show that nicotinic interventions can influence NMDA receptor-mediated neurotransmission in the intact mouse.

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. 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.

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. Unfortunately, a major theoretic limitation to the development of alpha(7) nicotinic receptor agonist interventions for the pharmacotherapy of schizophrenia is the development of seizures. In the current study, intraperitoneally administered methyllycaconitine, a selective alpha(7) nicotinic receptor antagonist, was shown to be unable to antagonize electrically precipitated seizures in mice. These data suggest that the alpha(7) nicotinic receptor does not mediate this type of seizure activity in mice. Also, although the medication-induced emergence of seizure activity remains a real concern with the development of alpha(7) nicotinic receptor agonist strategies, the data suggest that there should be lessened concern about precipitating seizures related to electrically precipitated tonic hindlimb extension in mice.

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. Patients were selected on the basis of the presence of negative symptoms. An optimal dose of topiramate was determined for each patient during a slow 4-week titration process. Patients were maintained on topiramate and their stable antipsychotic medications for 8 weeks, after which topiramate was tapered and discontinued. Patients were followed for an additional 4 weeks on their stable antipsychotic medications. Clinical measures of efficacy (eg, Positive and Negative Syndrome Scale), cognitive measures (eg, verbal fluency, memory), and safety measures (eg, postural sway) were assessed throughout this study. Topiramate administration (average dose, 110.42 mg/day) decreased total scores on the Positive and Negative Syndrome Scale. Topiramate was also associated with a selective and reversible worsening of verbal fluency performance. These results encourage further testing of topiramate and kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonists in schizophrenia patients and support the heuristic model of NRH.

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. Inbred BALBc mice are more resistant to electrically precipitated seizures than the NIH Swiss strain, and are more sensitive to both MK-801's anticonvulsant effect and ability to elicit popping. In the current experiments, we examined the influence of stress and genetic mouse strain on both MK-801's ability to antagonize electrically precipitated seizures and elicit popping. Stress significantly reduced the threshold voltage for precipitation of seizures in BALBc mice and the anticonvulsant properties of MK-801 in both strains. These data show that factors relevant to schizophrenia and its exacerbation (i.e., acute stress and genetics) influence N-methyl-D-aspartic acid (NMDA) receptor-mediated neurotransmission in intact mice. The BALBc inbred strain of mouse may possess advantages in preclinical screening paradigms designed to assess NMDA receptor agonist interventions for disorders such as schizophrenia. Specifically, stressed BALBc mice showed the greatest behavioral sensitivity to MK-801 with regard to electrically precipitated seizures in the incremental electroconvulsive shock (IECS) paradigm, whereas unstressed BALBc showed the greatest behavioral sensitivity to MK-801 in the "popping" paradigm, relative to BALBc and NIH Swiss mice in the appropriate comparison conditions.

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. 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.