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Puhl M.D.,Harvard University | Puhl M.D.,Laboratory for Psychiatric and Molecular Neuroscience | Berg A.R.,Harvard University | Berg A.R.,Behavioral Genetics Laboratory | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015

Schizophrenia is associated with high prevalence of substance abuse. Recent research suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR) function may play a role in the pathophysiology of both schizophrenia and drug addiction, and thus, may account for this high comorbidity. Our laboratory has developed two transgenic mouse lines that exhibit contrasting NMDAR activity based on the availability of the glycine modulatory site (GMS) agonists D-serine and glycine. Glycine transporter 1 knockdowns (GlyT1+/-) exhibit NMDAR hyperfunction, whereas serine racemase knockouts (SR-/-) exhibit NMDAR hypofunction. We characterized the behavior of these lines in a cocaine-induced (20 mg/kg) conditioned place preference (CPP) and locomotor sensitization paradigm. Compared with wild-type mice, GlyT1+/- mice displayed hastened extinction of CPP and robust cocaine-induced reinstatement. SR-/- mice appeared to immediately "forget" the learned preference, because they did not exhibit cocaine-induced reinstatement and also displayed attenuated locomotor sensitization. Treatment of GlyT1+/- mice with gavestinel (10 mg/kg on day 1; 5 mg/kg on days 2-17), a GMS antagonist, attenuated cocaine-induced CPP and caused them to immediately "forget" the learned preference. Treatment of SR-/- mice with D-serine (300 mg/kg on day 1; 150 mg/kg on days 2-17) to normalize brain levels caused them to avoid the cocaine-paired side of the chamber during extinction. These results highlight NMDAR dysfunction as a possible neural mechanism underlying comorbid schizophrenia and substance abuse. Also, these findings suggest drugs that directly or indirectly activate the NMDAR GMS could be an effective treatment of cocaine abuse. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source

Reynolds L.M.,Harvard University | Engin E.,Harvard University | Tantillo G.,Harvard University | Lau H.M.,Harvard University | And 5 more authors.
Neuropsychopharmacology | Year: 2012

Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA A receptor subtypes. To elucidate the α subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the α1, α2, or α3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and α1-point-mutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in α2-and α3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. α2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in α2-point-mutant animals. Zolpidem, an α1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate α2 and α3 subunit containing GABA A receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

Myers K.M.,Behavioral Genetics Laboratory | Myers K.M.,Harvard University | Carlezon Jr. W.A.,Behavioral Genetics Laboratory | Carlezon Jr. W.A.,Harvard University | Davis M.,Emory University
Neuropsychopharmacology | Year: 2011

Some psychiatric illnesses involve a learned component. For example, in posttraumatic stress disorder, memories triggered by trauma-associated cues trigger fear and anxiety, and in addiction, drug-associated cues elicit drug craving and withdrawal. Clinical interventions to reduce the impact of conditioned cues in eliciting these maladaptive conditioned responses are likely to be beneficial. Extinction is a method of lessening conditioned responses and involves repeated exposures to a cue in the absence of the event it once predicted. We believe that an improved understanding of the behavioral and neurobiological mechanisms of extinction will allow extinction-like procedures in the clinic to become more effective. Research on the role of glutamateFthe major excitatory neurotransmitter in the mammalian brainFin extinction has led to the development of pharmacotherapeutics to enhance the efficacy of extinction-based protocols in clinical populations. In this review, we describe what has been learned about glutamate actions at its three major receptor types (N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors, and metabotropic glutamate receptors) in the extinction of conditioned fear, drug craving, and withdrawal. We then discuss how these findings have been applied in clinical research. © 2011 Nature Publishing Group All rights reserved. Source

Vahabzadeh A.,Massachusetts General Hospital | Vahabzadeh A.,Harvard University | Landino S.M.,Behavioral Genetics Laboratory | Finger B.C.,Harvard University | And 6 more authors.
Handbook of Experimental Pharmacology | Year: 2015

The purpose of this chapter is to present results from recent research on social cognition in autism spectrum disorder (ASD). The clinical phenomenology and neuroanatomical circuitry of ASD are first briefly described. The neuropharmacology of social cognition in animal models of ASD and humans is then addressed. Next, preclinical and clinical research on the neurohormone oxytocin is reviewed. This is followed by a presentation of results from preclinical and clinical studies on the excitatory amino acid glutamate. Finally, the role of neuroinflammation in ASD is addressed from the perspectives of preclinical neuroscience and research involving humans with ASD. © 2015 Springer International Publishing Switzerland. Source

Paine T.A.,Behavioral Genetics Laboratory | Paine T.A.,Oberlin College | Slipp L.E.,Behavioral Genetics Laboratory | Carlezon Jr. W.A.,Behavioral Genetics Laboratory
Neuropsychopharmacology | Year: 2011

Attentional deficits are a core symptom of schizophrenia. Post-mortem analyses of the brains of schizophrenics reveal consistent abnormalities in γ-aminobutyric acid (GABA) interneurons indicative of reduced cortical GABA transmission, raising the possibility that this pathology contributes to attentional deficits. We examined whether blockade of prefrontal cortex (PFC) GABA A receptors with bicuculline (BMI) impairs attention in rats using the 5-choice serial reaction time task (5CSRTT). For comparison, we also examined whether administration of the GABA A receptor agonist muscimol (MUS) would improve attention. In parallel, we examined the effects of both manipulations on activity in an open field and on motivation using the intracranial self-stimulation (ICSS) test. BMI increased PFC neuronal activity, as reflected by increased Fos immunolabeling, and impaired attention, as reflected by decreased accuracy and increased omissions. Although increased omissions also may reflect reductions in locomotor activity or motivation, the overall pattern of effects does not support either of these interpretations: BMI did not affect locomotor activity, and it enhanced motivation in the ICSS test. MUS did not affect attention, although it increased impulsive behavior at a dose that suppressed PFC neuronal activity, as reflected by decreased Fos immunolabeling. These impulsivity effects are not due to altered locomotor activity (which was decreased) or motivation (which was not affected). Our data support the hypothesis that cortical GABA neurons have an important role in regulating attention and may have direct implications for the treatment of schizophrenia. © 2011 American College of Neuropsychopharmacology. All rights reserved. Source

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