Publications by authors named "Henry Sershen"

34 Publications

Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls.

Biomark Neuropsychiatry 2021 Dec 24;5. Epub 2021 Jun 24.

Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.

Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC. No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.
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http://dx.doi.org/10.1016/j.bionps.2021.100038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341034PMC
December 2021

Translational neurophysiological biomarkers of N-methyl-d-aspartate receptor dysfunction in serine racemase knockout mice.

Biomark Neuropsychiatry 2020 Jun 18;2. Epub 2020 Jun 18.

Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, 10962, United States.

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-d-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. PCP led to significant increases of ASSR that were further increased in SRKO-/-, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.
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http://dx.doi.org/10.1016/j.bionps.2020.100019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301266PMC
June 2020

Cocaine Induces Sex-Associated Changes in Lipid Profiles of Brain Extracellular Vesicles.

Neurochem Res 2021 Nov 10;46(11):2909-2922. Epub 2021 Jul 10.

Division of Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA.

Cocaine is a highly addictive stimulant with diverse effects on physiology. Recent studies indicate the involvement of extracellular vesicles (EVs) secreted by neural cells in the cocaine addiction process. It is hypothesized that cocaine affects secretion levels of EVs and their cargos, resulting in modulation of synaptic transmission and plasticity related to addiction physiology and pathology. Lipids present in EVs are important for EV formation and for intercellular lipid exchange that may trigger physiological and pathological responses, including neuroplasticity, neurotoxicity, and neuroinflammation. Specific lipids are highly enriched in EVs compared to parent cells, and recent studies suggest the involvement of various lipids in drug-induced synaptic plasticity during the development and maintenance of addiction processes. Therefore, we examined interstitial small EVs isolated from the brain of mice treated with either saline or cocaine, focusing on the effects of cocaine on the lipid composition of EVs. We demonstrate that 12 days of noncontingent repeated cocaine (10 mg/kg) injections to mice, which induce locomotor sensitization, cause lipid composition changes in brain EVs of male mice as compared with saline-injected controls. The most prominent change is the elevation of GD1a ganglioside in brain EVs of males. However, cocaine does not affect the EV lipid profiles of the brain in female mice. Understanding the relationship between lipid composition in EVs and vulnerability to cocaine addiction may provide insight into novel targets for therapies for addiction.
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http://dx.doi.org/10.1007/s11064-021-03395-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490334PMC
November 2021

Concordance of Immune-Related Markers in Lymphocytes and Prefrontal Cortex in Schizophrenia.

Schizophr Bull Open 2021 Jan 6;2(1):sgab002. Epub 2021 Feb 6.

Center for Alcohol Research in Epigenetics, Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL.

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts ( < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes ( < .01 and |log FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.
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http://dx.doi.org/10.1093/schizbullopen/sgab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865130PMC
January 2021

Reduced Motivation in Perinatal Fluoxetine-Treated Mice: A Hypodopaminergic Phenotype.

J Neurosci 2021 03 3;41(12):2723-2732. Epub 2021 Feb 3.

Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process. The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.
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http://dx.doi.org/10.1523/JNEUROSCI.2608-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018732PMC
March 2021

Betahistine effects on weight-related measures in patients treated with antipsychotic medications: a double-blind placebo-controlled study.

Psychopharmacology (Berl) 2018 Dec 31;235(12):3545-3558. Epub 2018 Oct 31.

Psychiatric Institute University of Illinois, Chicago, Illinois and John Hopkins University Medical School, Baltimore, USA.

Rationale: Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics.

Method: We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales.

Results: In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients.

Conclusions: These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.
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http://dx.doi.org/10.1007/s00213-018-5079-1DOI Listing
December 2018

LSD Administered as a Single Dose Reduces Alcohol Consumption in C57BL/6J Mice.

Front Pharmacol 2018 31;9:994. Epub 2018 Aug 31.

Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States.

There is a substantive clinical literature on classical hallucinogens, most commonly lysergic acid diethylamide (LSD) for the treatment of alcohol use disorder. However, there has been no published research on the effect of LSD on alcohol consumption in animals. This study evaluated the effect of LSD in mice using a two-bottle choice alcohol drinking paradigm. Adult male C57BL/6J mice were exposed to ethanol to develop preference and divided into three groups of equal ethanol consumption, and then treated with single intraperitoneal injection of saline or 25 or 50 μg/kg LSD and offered water and 20% ethanol. The respective LSD-treated groups were compared to the control group utilizing a multilevel model for repeated measures. In mice treated with 50 μg/kg LSD ethanol consumption was reduced relative to controls ( = 0.0035), as was ethanol preference ( = 0.0024), with a group mean reduction of ethanol consumption of 17.9% sustained over an interval of 46 days following LSD administration. No significant effects on ethanol consumption or preference were observed in mice treated with 25 μg/kg LSD. Neither total fluid intake nor locomotor activity in the LSD-treated groups differed significantly from controls. These results suggest that classical hallucinogens in the animal model merit further study as a potential approach to the identification of targets for drug discovery and investigation of the neurobiology of addiction.
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http://dx.doi.org/10.3389/fphar.2018.00994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127266PMC
August 2018

Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors.

Transl Psychiatry 2018 08 24;8(1):167. Epub 2018 Aug 24.

Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, 10962, USA.

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL-/- deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/- mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.
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http://dx.doi.org/10.1038/s41398-018-0194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109052PMC
August 2018

Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling.

Neuropharmacology 2018 03 3;131:200-208. Epub 2017 Nov 3.

Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, NY, United States; Emotional Brain Institute, Orangeburg, New York, NY, United States; Department of Child and Adolescent Psychiatry, NYU Langone Medical Center, New York, NY, United States. Electronic address:

Binge alcohol (ethanol) drinking is associated with profound adverse effects on our health and society. Rimonabant (SR141716A), a CB1 receptor inverse agonist, was previously shown to be effective for nicotine cessation and obesity. However, studies using rimonabant were discontinued as it was associated with an increased risk of depression and anxiety. In the present study, we examined the pharmacokinetics and effects of AM4113, a novel CB1 receptor neutral antagonist on binge-like ethanol drinking in C57BL/6J mice using a two-bottle choice drinking-in-dark (DID) paradigm. The results indicated a slower elimination of AM4113 in the brain than in plasma. AM4113 suppressed ethanol consumption and preference without having significant effects on body weight, ambulatory activity, preference for tastants (saccharin and quinine) and ethanol metabolism. AM4113 pretreatment reduced ethanol-induced increase in dopamine release in nucleus accumbens. Collectively, these data suggest an important role of CB1 receptor-mediated regulation of binge-like ethanol consumption and mesolimbic dopaminergic signaling, and further points to the potential utility of CB1 neutral antagonists for the treatment of binge ethanol drinking.
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http://dx.doi.org/10.1016/j.neuropharm.2017.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820178PMC
March 2018

Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia.

Neuropsychopharmacology 2018 02 17;43(3):571-582. Epub 2017 Aug 17.

Division of Experimental Therapeutics, Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.

Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (θ)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and θ-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (α) and beta (β) frequency ranges. PCP treatment also significantly reduced α-frequency response to standard stimuli while increasing θ-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to θ-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.
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http://dx.doi.org/10.1038/npp.2017.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770758PMC
February 2018

Modulating NMDA Receptor Function with D-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model.

Neurochem Res 2016 Feb 8;41(1-2):398-408. Epub 2016 Feb 8.

Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY, 10962, USA.

Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol(®)) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor NaB (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be determined, overall it supports continued glutamatergic drug development.
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http://dx.doi.org/10.1007/s11064-016-1838-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775346PMC
February 2016

Varenicline Effects on Smoking, Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial.

PLoS One 2016 5;11(1):e0143490. Epub 2016 Jan 5.

Psychiatric Institute University of Illinois, Chicago, Illinois, United States of America.

Unlabelled: Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer.

Trial Registration: ClinicalTrials.gov 00802919.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143490PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701439PMC
July 2016

Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study.

Schizophr Res 2015 Oct 17;168(1-2):260-6. Epub 2015 Jul 17.

University of Illinois College of Medicine Psychiatric Institute, Chicago, Illinois, United States. Electronic address:

Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers. Thirty subjects provided evaluable data on the MATRICS Consensus Cognitive Battery (MCCB), with the primary outcome measure, the MCCB Composite score. Active compared to sham tDCS subjects showed significant improvements after the fifth tDCS session in MCCB Composite score (p=0.008) and on the MCCB Working Memory (p=0.002) and Attention-Vigilance (p=0.027) domain scores, with large effect sizes. MCCB Composite and Working Memory domain scores remained significant at Benjamini-Hochberg corrected significance levels (α=0.05). There were no statistically significant effects on secondary outcome measures of psychiatric symptoms (PANSS scores), hallucinations, cigarette craving, or cigarettes smoked. The positive effects of tDCS on cognitive performance suggest a potential efficacious treatment for cognitive deficits in partially recovered chronic schizophrenia outpatients that should be further investigated.
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http://dx.doi.org/10.1016/j.schres.2015.06.011DOI Listing
October 2015

Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice.

J Neurosci 2014 Jul;34(28):9222-34

Center for Dementia Research and Departments of Psychiatry and Cell Biology, New York University Langone Medical Center, New York, New York 10016, and.

Tau pathogenicity in Alzheimer's disease and other tauopathies is thought to involve the generation of hyperphosphorylated, truncated, and oligomeric tau species with enhanced neurotoxicity, although the generative mechanisms and the implications for disease therapy are not well understood. Here, we report a striking rescue from mutant tau toxicity in the JNPL3 mouse model of tauopathy. We show that pathological activation of calpains gives rise to a range of potentially toxic forms of tau, directly, and by activating cdk5. Calpain overactivation in brains of these mice is accelerated as a result of the marked depletion of the endogenous calpain inhibitor, calpastatin. When levels of this inhibitor are restored in neurons of JNPL3 mice by overexpressing calpastatin, tauopathy is prevented, including calpain-mediated breakdown of cytoskeletal proteins, cdk5 activation, tau hyperphosphorylation, formation of potentially neurotoxic tau fragments by either calpain or caspase-3, and tau oligomerization. Calpastatin overexpression also prevents loss of motor axons, delays disease onset, and extends survival of JNPL3 mice by 3 months to within the range of normal lifespan. Our findings support the therapeutic promise of highly specific calpain inhibition in the treatment of tauopathies and other neurodegenerative states.
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http://dx.doi.org/10.1523/JNEUROSCI.1132-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087203PMC
July 2014

Functional connectivity fMRI in mouse brain at 7T using isoflurane.

J Neurosci Methods 2013 Apr 31;214(2):144-8. Epub 2013 Jan 31.

Center for Advanced Brain Imaging, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.

Although many resting state fMRI human studies have been published, the number of such rodent studies is considerably less. The reason for this is the severe technical challenge of high magnetic field small rodent imaging. Local magnetic field susceptibility changes at air tissue boundaries cause image distortion and signal losses. The current study reports measures of functional connectivity in mice using only isoflurane for the anesthetic. Because all anesthetic agents will alter cerebral blood flow and cerebral metabolism, the impact these changes have on neuronal connectivity has yet to be fully understood, however this work reports for the first time that reliable functional connectivity measures in mouse brain can be obtained with isoflurane.
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http://dx.doi.org/10.1016/j.jneumeth.2013.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644382PMC
April 2013

Novel C-1 substituted cocaine analogs unlike cocaine or benztropine.

J Pharmacol Exp Ther 2012 Nov 15;343(2):413-25. Epub 2012 Aug 15.

Department of Psychiatry, New York University School of Medicine, 450 E 29th Street, Alexandria Building Room 803, New York, NY 10016, USA.

Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.
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http://dx.doi.org/10.1124/jpet.112.193771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477221PMC
November 2012

Astrocyte origin of activity-dependent release of ATP and glutamate in hippocampal slices: real-time measurement utilizing microelectrode biosensors.

Authors:
Henry Sershen

Br J Pharmacol 2012 Nov;167(5):1000-2

Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.

It is well known that astrocytic and neuronal transmitter release processes are important for signalling, and that activity-dependent release of adenosine nucleotides and transmitters occurs after stimulation. Neurons and astrocytes can account for the source of ATP efflux. In this issue of the BJP, Heinrich et al. characterized K(+) depolarization-evoked release of ATP, adenosine and glutamate in hippocampal slices, utilizing microelectrode biosensors for simultaneous real-time recordings of multiple transmitter effluxes. They demonstrated efflux of ATP, adenosine and glutamate from hippocampus slices, in response to K(+) -depolarization, with distinct kinetics and mechanisms, suggesting a coordinated pattern of transmitter release. Surprisingly, it turned out that a considerable amount of the transmitter efflux measured under these conditions had a glial origin. For a long time, it was believed that the glial cell did not play a major role in neurotransmission, but the latter results somewhat change this view. The release of ATP and glutamate from glial cells under these conditions involved P2X7 receptors, and a source of adenosine accumulation independent of the metabolism of extracellular ATP was identified. This study also highlighted a novel use of multi-enzymatic microelectrode biosensors, which enabled a better characterization of transmitter release processes with higher temporal and spatial resolution than obtained previously. This technique was originally developed and used for the detection of purine release. In the present study, it was modified to identify the interplay between different transmitters, measured simultaneously in hippocampal slices.
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http://dx.doi.org/10.1111/j.1476-5381.2012.02072.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492982PMC
November 2012

Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia.

Eur Neuropsychopharmacol 2012 Dec 5;22(12):902-10. Epub 2012 May 5.

Translational Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.

Dopaminergic hyperactivity within frontostriatal brain systems is a key feature of schizophrenia, and an objective neural correlate of positive schizophrenia symptoms. N-methyl-d-aspartate (NMDA) receptors are known to play a prominent role in regulation of frontostriatal dopamine release. Furthermore, disturbances in glutamatergic function are increasingly being linked to pathophysiology of both positive and negative symptoms of schizophrenia. Prior studies have demonstrated that subchronic continuous administration of the NMDA antagonist phencyclidine (PCP) induces schizophrenia-like hyper-reactivity of frontostriatal dopamine release to amphetamine (AMPH) in rodents, and that effects were reversed by glycine and the prototypic glycine transport inhibitor (GTI) NFPS. The present study investigates effectiveness of the novel, high affinity and well tolerated GTIs, R231857, R231860 and Org29335, to reverse schizophrenia-like enhancement of AMPH-induced DA release, along with effects of the partial glycine-site agonist d-cycloserine. As previously, PCP had no significant effect on basal DA levels, but significantly enhanced AMPH-induced DA release in prefrontal cortex. All GTIs tested, as well as d-cycloserine, significantly reduced PCP-induced enhancement of DA release in prefrontal cortex. Neither PCP nor GTIs significantly affected striatal DA release. Overall, these findings suggest that treatments which target the glycine modulatory site of the NMDA receptor may significantly reverse NMDA receptor antagonist-induced dysregulation of frontal DA systems, consistent with potential beneficial effects on positive-, in addition to negative-, symptoms of schizophrenia.
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http://dx.doi.org/10.1016/j.euroneuro.2012.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882073PMC
December 2012

Ibogaine and the inhibition of acetylcholinesterase.

J Ethnopharmacol 2012 Feb 19;139(3):879-82. Epub 2011 Dec 19.

Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA.

Ethnopharmacological Relevance: Ibogaine is a psychoactive monoterpine indole alkaloid extracted from the root bark of Tabernanthe iboga Baill. that is used globally in medical and nonmedical settings to treat drug and alcohol addiction, and is of interest as an ethnopharmacological prototype for experimental investigation and pharmaceutical development. The question of whether ibogaine inhibits acetylcholinesterase (AChE) is of pharmacological and toxicological significance.

Materials And Methods: AChE activity was evaluated utilizing reaction with Ellman's reagent with physostigmine as a control.

Results: Ibogaine inhibited AChE with an IC(50) of 520±40 μM.

Conclusions: Ibogaine's inhibition of AChE is physiologically negligible, and does not appear to account for observations of functional effects in animals and humans that might otherwise suggest the possible involvement of pathways linked to muscarinic acetylcholine transmission.
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http://dx.doi.org/10.1016/j.jep.2011.12.006DOI Listing
February 2012

Differential regulation of catechol-O-methyltransferase expression in a mouse model of aggression.

Brain Struct Funct 2011 Nov 22;216(4):347-56. Epub 2011 Apr 22.

Center for Dementia Research, Nathan Kline Institute, New York University Langone Medical Center, New York, NY, USA.

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression.
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http://dx.doi.org/10.1007/s00429-011-0315-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199365PMC
November 2011

Special issue in honor of Dr. Abel Lajitha. Preface.

Authors:
Henry Sershen

Neurochem Res 2010 Dec;35(12):1857-8

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http://dx.doi.org/10.1007/s11064-010-0333-xDOI Listing
December 2010

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum.

Neuropharmacology 2009 Apr 6;56(5):915-21. Epub 2009 Feb 6.

Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.

Deficits in N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA(B) receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation. Since glycine (GLY) has been found to ameliorate treatment resistant negative symptoms in schizophrenia, we treated a group of rats with 16% GLY food for 2 weeks. DA levels in prefrontal cortex (PFC) and striatum (STR) were assessed by dual-probe microdialysis and HPLC-EC in freely moving rats. Infusion of the GABA(B) receptor agonists SKF97541 and baclofen into PFC and STR significantly reduced basal DA, an effect that was reversed by the antagonist, CGP52432. In PFC, GABA(B) agonists also reduced AMPH-induced DA release following treatment with either 1 or 5 mg/kg AMPH. Similar effects were seen following subchronic glycine treatment in the absence, but not presence of CGP52432 during 5 mg/kg AMPH treatment. In STR SKF97541 decreased only the 1 mg/kg AMPH-induced DA release. Subchronic GLY treatment in STR leads to a significant reduction in basal DA levels, but did not affect AMPH (5 mg/kg)-induced release. Our findings support a model in which NMDA/glycine-site agonists modulate DA release in part through presynaptic GABA(B) receptors on DA terminals, with both GABA(B) ligands and GLY significantly modulating AMPH-induced DA release. Both sites, therefore, may represent appropriate targets for drug development in schizophrenia and substance abuse disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2009.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681299PMC
April 2009

Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder.

Schizophr Res 2009 May 28;110(1-3):149-55. Epub 2009 Feb 28.

Department of Psychiatry, New York University Medical School, NY 11557-0316, United States.

Objective: Varenicline has been shown to be an effective anti-smoking treatment in smokers without identified psychiatric illness, and the drug's pharmacology suggests possibilities of pro-cognitive effects. However, recent reports suggest varenicline may have the potential for important psychiatric side-effects in some people. We present the first prospective quantitative data on the effects of varenicline on cognitive function, cigarette smoking, and psychopathology in a small sample of schizophrenic patients.

Method: Fourteen schizophrenic smokers were enrolled in an open-label study of varenicline with a pre-post design. Measures of cognitive function (RBANS, Virtual Water-Maze Task), cigarette smoking (cotinine levels, CO levels, self-reported smoking and smoking urges), and psychopathology (PANSS) were evaluated prior to and during treatment with varenicline. Data on psychopathology changes among schizophrenic smokers in another drug study, in which patients were not receiving varenicline, were used for comparison.

Results: 12 patients completed the study, and 2 patients terminated in the first two weeks of active varenicline because of complaints of nausea or shaking. Varenicline produced significant improvements in some cognitive test scores, primarily associated with verbal learning and memory, but not in scores on visual-spatial learning or memory, or attention. Varenicline significantly decreased all indices of smoking, but did not produce complete smoking abstinence in most patients. During treatment with varenicline there were no significant increases in psychopathology scores and no patient developed signs of clinical depression or suicidal ideation.

Conclusions: Our small prospective study suggests that treatment with varenicline appears to have some beneficial cognitive effects which need to be confirmed in larger studies with additional neuropsychological tests. Varenicline appears to have some anti-smoking efficacy in schizophrenia but longer studies are needed to determine whether it will produce rates of smoking abstinence similar to those found in control smokers. Treatment with varenicline may not increase psychopathology or depression in most patients with schizophrenia, but we cannot accurately estimate the absolute risk of a potentially rare side-effect from this small sample.
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http://dx.doi.org/10.1016/j.schres.2009.02.001DOI Listing
May 2009

Increased dopaminergic neuron sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in transgenic mice expressing mutant A53T alpha-synuclein.

Neurochem Res 2008 May 13;33(5):902-11. Epub 2007 Nov 13.

Taub Institute on Alzheimer's Disease and Aging, Department of Pathology, Columbia University, Black Bldg 513, 650 W 168th St, New York, NY 10032, USA.

Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the alpha-synuclein gene and mutant alpha-synuclein expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T alpha-synuclein (alpha-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if mutant human alpha-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single, sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the alpha-syn tg and ntg mice. In the olfactory bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the alpha-syn tg mice. In addition, we identified a significant increase in dopamine metabolism in the alpha-syn transgenic, but not ntg mice. Finally, MPTP treatment of alpha-syn tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with alpha-synuclein. Cumulatively, the data support the hypothesis that mutant alpha-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress. The alpha-syn tg line is therefore useful to study the genetic and environmental inter-relationship in PD.
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http://dx.doi.org/10.1007/s11064-007-9533-4DOI Listing
May 2008

Food reward-induced neurotransmitter changes in cognitive brain regions.

Neurochem Res 2007 Oct 25;32(10):1772-82. Epub 2007 Aug 25.

Nathan Kline Institute, Orangeburg, New York 10962, USA.

Recent evidence indicates that mechanisms involved in reward and mechanisms involved in learning interact, in that reward includes learning processes and learning includes reward processes. In spite of such interactions, reward and learning represent distinct functions. In the present study, as part of an examination of the differences in learning and reward mechanisms, it was assumed that food principally affects reward mechanisms. After a brief period of fasting, we assayed the release of three neurotransmitters and their associated metabolites in eight brain areas associated with learning and memory as a response to feeding. Using microdialysis for the assay, we found changes in the hippocampus, cortex, amygdala, and the thalamic nucleus, (considered cognitive areas), in addition to those in the nucleus accumbens and ventral tegmental area (considered reward areas). Extracellular dopamine levels increased in the nucleus accumbens, ventral tegmental area, amygdala, and thalamic nucleus, while they decreased in the hippocampus and prefrontal cortex. Dopamine metabolites increased in all areas tested (except the dorsal hippocampus); changes in norepinephrine varied with decreases in the accumbens, dorsal hippocampus, amygdala, and thalamic nucleus, and increases in the prefrontal cortex; serotonin levels decreased in all the areas tested; although its metabolite 5HIAA increased in two regions (the medial temporal cortex, and thalamic nucleus). Our assays indicate that in reward activities such as feeding, in addition to areas usually associated with reward such as the mesolimbic dopamine system, other areas associated with cognition also participate. Results also indicate that several transmitter systems play a part, with several neurotransmitters and several receptors involved in the response to food in a number of brain structures, and the changes in transmitter levels may be affected by metabolism and transport in addition to changes in release in a regionally heterogeneous manner. Food reward represents a complex pattern of changes in the brain that involve cognitive processes. Although food reward elements overlap with other reward systems sharing some neurotransmitter compounds, it significantly differs indicating a specific reward to process for food consumption. Like in other rewards, both learning and cognitive areas play a significant part in food reward.
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http://dx.doi.org/10.1007/s11064-007-9343-8DOI Listing
October 2007

Characterization of interactions between phencyclidine and amphetamine in rodent prefrontal cortex and striatum: implications in NMDA/glycine-site-mediated dopaminergic dysregulation and dopamine transporter function.

Neurochem Int 2008 Jan 20;52(1-2):119-29. Epub 2007 Jul 20.

Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, United States.

N-Methyl-D-aspartate (NMDA) antagonists induced behavioral and neurochemical changes in rodents that serve as animal models of schizophrenia. Chronic phencyclidine (PCP, 15 mg/(kg day) for 3 weeks via Alzet osmotic pump) administration enhances the amphetamine (AMPH)-induced dopamine (DA) efflux in prefrontal cortex (PFC), similar to that observed in schizophrenia. NMDA/glycine-site agonists, such as glycine (GLY), administered via dietary supplementation, reverse the enhanced effect. The present study investigated mechanisms of glycine-induced reversal of PCP-induced stimulation of AMPH-induced DA release, using simultaneous measurement of DA and AMPH in brain microdialysate, as well as peripheral and tissue AMPH levels. PCP treatment, by itself, increased peripheral and central AMPH levels, presumably via interaction with hepatic enzymes (e.g. cytochrome P450 CYP2C11). GLY (16% diet) had no effect on peripheral AMPH levels in the presence of PCP. Nevertheless, GLY significantly reduced extracellular/tissue AMPH ratios in both PFC and striatum (STR), especially following PCP administration, suggesting a feedback mediated effect on the dopamine transporter. GLY also inhibited acute AMPH (5 mg/kg)-induced DA release in PFC, but not STR. These findings suggest that GLY may modulate DA release in brain by producing feedback regulation of dopamine transporter function, possibly via potentiation of NMDA-stimulated GABA release and presynaptic GABAB receptor activation. The present studies also demonstrate pharmacokinetic interaction between AMPH and PCP, which may be of both clinical and research relevance.
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http://dx.doi.org/10.1016/j.neuint.2007.07.011DOI Listing
January 2008

Modulation of striatal dopamine release by glycine transport inhibitors.

Neuropsychopharmacology 2005 Apr;30(4):649-56

Department of Neurochemistry, Nathan S Kline Institute for Psychiatric Research/NYU School of Medicine, Orangeburg, NY, USA.

Traditional models of schizophrenia have focused primarily upon dopaminergic (DA) dysregulation. In contrast, more recent models focus on dysfunction of glutamatergic systems, acting particularly through N-methyl-D-aspartate (NMDA) receptors. NMDA receptors in brain are regulated by glycine, acting via a strychnine-insensitive regulatory site, and by glycine (GlyT1) transporters that maintain low glycine levels in the immediate vicinity of the NMDA receptor complex. The present study investigates the role of NMDA receptors in the modulation of striatal dopamine release in vitro, and of glycine transport inhibitors (GTIs) as potential psychotherapeutic agents in schizophrenia. In striatum, NMDA receptors exert dual excitatory/inhibitory effects, with inhibition reflecting activity of local GABAergic feedback regulation. We have previously demonstrated effectiveness of glycine in regulating [3H]DA release both in vivo and in vitro, consistent with its beneficial clinical effects. In the present study, similar effects were observed for the high-affinity GTI (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy-)propyl]sarcosine (NFPS), and for a range of high-affinity GTIs with appropriate rank order of potency. In addition, (+)NFPS significantly stimulated NMDA-induced [3H]GABA release. Effects, of GTIs, were blocked by the glycine-site antagonists L689,560 and HA-966, and the GABA(B) antagonists phaclofen and CGP 52432, confirming the roles of both the NMDA-associated glycine-site and presynaptic GABA(B) receptors in NMDA receptor-mediated regulation of striatal DA release in vitro. Endogenous DA hyperactivity is associated with prominent positive symptoms in schizophrenia. The present results are consistent with recent clinical studies showing significant effectiveness of glycine-site agonists and GTIs in reduction of persistent positive, as well as negative, symptoms in schizophrenia.
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http://dx.doi.org/10.1038/sj.npp.1300589DOI Listing
April 2005

Effects of acute lorazepam administration on aminergic activity in normal elderly subjects: relationship to performance effects and apolipoprotein genotype.

Neurochem Res 2004 Jul;29(7):1391-8

Geriatric Psychiatry Program, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.

The effects of acute lorazepam challenges on plasma (p) HVA, MHPG, and 5-HIAA, and their relationship to drug-induced cognitive and motor deficits and the apolipoprotein (APOE)-epsilon4 allele were examined. Eighteen healthy elderly (8 epsilon4 carriers) received placebo or acute oral lorazepam doses (0.5 mg or 1 mg) in random sequence, 1-week apart. Cognitive assessment and plasma levels of pHVA, pMHPG, and p5-HIAA were determined at baseline and at 1, 2.5, and 5 h postchallenge. There was no drug-to-placebo difference in monoamine levels and no consistent relationship between changes in monoamine levels and cognitive performance, regardless of epsilon4 status. However, the 1.0 mg dose increased p5-HIAA in epsilon4 carriers, whereas it caused a reduction in noncarriers. Higher baseline pMHPG and p5-HIAA levels were associated with better baseline memory. The epsilon4 allele may modulate the effect of lorazepam on p5-HIAA, but further studies are needed to confirm this finding and elucidate its possible significance.
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http://dx.doi.org/10.1023/b:nere.0000026402.09466.54DOI Listing
July 2004

Sensitive and simple gas chromatographic-mass spectrometric determination for amphetamine in microdialysate and ultrafiltrate samples.

J Chromatogr B Analyt Technol Biomed Life Sci 2004 Jun;805(1):27-31

Analytical Psychopharmacology Laboratory, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.

A gas chromatographic-mass spectrometric (GC-MS) method is described for the measurement of amphetamine (AMP) using negative chemical ionization (NCI) mode. Without prior extraction AMP was derivatized with 2,3,4,5,6-pentafluorobenzoyl chloride (PFBC) and simultaneously extracted into toluene. The toluene extract was injected directly into GC-MS equipped with a HP-1 capillary column. The method is simple and more sensitive than most of the previously published methods. The limit of quantification of amphetamine is 25pg (1.4pg on column) with a very limited sample volume (25microl). The within-day precision was from 1.7 to 5.1% and between-day precision was from 2.2 to 7.3%. The method has been used for the measurement of several thousand microdialysate and ultrafiltrate samples and proven reliable.
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http://dx.doi.org/10.1016/j.jchromb.2004.02.001DOI Listing
June 2004
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