Publications by authors named "Michael Z Leonard"

13 Publications

  • Page 1 of 1

Hypoactive Thalamic Crh+ Cells in a Female Mouse Model of Alcohol Drinking After Social Trauma.

Biol Psychiatry 2021 Oct 1;90(8):563-574. Epub 2021 Jun 1.

Department of Psychology, Tufts University, Medford, Massachusetts; Department of Neuroscience, Tufts University, Boston, Massachusetts. Electronic address:

Background: Comorbid stress-induced mood and alcohol use disorders are increasingly prevalent among female patients. Stress exposure can disrupt salience processing and goal-directed decision making, contributing to persistent maladaptive behavioral patterns; these and other stress-sensitive cognitive and behavioral processes rely on dynamic and coordinated signaling by midline and intralaminar thalamic nuclei. Considering the role of social trauma in the trajectory of these debilitating psychopathologies, identifying vulnerable thalamic cells may provide guidance for targeting persistent stress-induced symptoms.

Methods: A novel behavioral protocol traced the progression from social trauma to the development of social defensiveness and chronically escalated alcohol consumption in female mice. Recent cell activation-measured as cFos-was quantified in thalamic cells after safe social interactions, revealing stress-sensitive corticotropin-releasing hormone-expressing (Crh+) anterior central medial thalamic (aCMT) cells. These cells were optogenetically stimulated during stress-induced social defensiveness and abstinence-escalated binge drinking.

Results: Crh+ aCMT neurons exhibited substantial activation after social interactions in stress-naïve but not in stressed female mice. Photoactivating Crh+ aCMT cells dampened stress-induced social deficits, whereas inhibiting these cells increased social defensiveness in stress-naïve mice. Optogenetically activating Crh+ aCMT cells diminished abstinence-escalated binge alcohol drinking in female mice, regardless of stress history.

Conclusions: This work uncovers a role for Crh+ aCMT neurons in maladaptive stress-induced social interactions and in binge drinking after forced abstinence in female mice. This molecularly defined thalamic cell population may serve as a critical stress-sensitive hub for social deficits caused by exposure to social trauma and for patterns of excessive alcohol drinking in female populations.
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http://dx.doi.org/10.1016/j.biopsych.2021.05.022DOI Listing
October 2021

Don't Ditch the Laptop Just Yet: A Direct Replication of Mueller and Oppenheimer's (2014) Study 1 Plus Mini Meta-Analyses Across Similar Studies.

Psychol Sci 2021 03 4;32(3):326-339. Epub 2021 Feb 4.

Department of Psychology, Tufts University.

In this direct replication of Mueller and Oppenheimer's (2014) Study 1, participants watched a lecture while taking notes with a laptop ( = 74) or longhand ( = 68). After a brief distraction and without the opportunity to study, they took a quiz. As in the original study, laptop participants took notes containing more words spoken verbatim by the lecturer and more words overall than did longhand participants. However, laptop participants did not perform better than longhand participants on the quiz. Exploratory meta-analyses of eight similar studies echoed this pattern. In addition, in both the original study and our replication, higher word count was associated with better quiz performance, and higher verbatim overlap was associated with worse quiz performance, but the latter finding was not robust in our replication. Overall, results do not support the idea that longhand note taking improves immediate learning via better encoding of information.
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http://dx.doi.org/10.1177/0956797620965541DOI Listing
March 2021

The Molecular-Container Calabadion-2 Prevents Methamphetamine-Induced Reinstatement in Rats: A Potential Approach to Relapse Prevention?

Int J Neuropsychopharmacol 2020 06;23(6):401-405

Department of Psychology, Tufts University, Medford, MA.

Background: Reexposure to methamphetamine with a single "priming dose" can trigger intense cravings and precipitate relapse in methamphetamine-dependent individuals. The acyclic cucurbit[n]uril "molecular container" calabadion-2 shows a high affinity to bind and sequester methamphetamine in vitro and attenuates its locomotor-stimulating effect in rats. The present study investigates whether pretreatment with calabadion-2 is sufficient to prevent the reinstatement of drug seeking by a priming dose of methamphetamine in rats.

Methods: Male Long-Evans rats were trained to self-administer i.v. methamphetamine (0.06 mg/kg/infusion). Following 10 days of stable self-administration, rats underwent extinction training and were subsequently tested on a multi-phase reinstatement procedure. Drug-primed reinstatement sessions (0.3 mg/kg methamphetamine, i.v.) were preceded by either saline or calabadion-2 (130 mg/kg). Additional reinstatement tests were conducted after administration of yohimbine (1.0 mg/kg, i.v.) to define the pharmacological specificity of calabadion-2.

Results: Pretreatment with calabadion-2 significantly attenuated methamphetamine-induced reinstatement of responding. Cal2 did not affect drug-seeking behavior stimulated by the pharmacological stressor yohimbine, indicating a mechanism of action specific to methamphetamine.

Conclusions: These results demonstrate the effectiveness of calabadion-2 in a preclinical model relapse-like behavior. With further structural optimization, molecular containers may provide a novel and efficacious pharmacokinetic approach to relapse prevention for methamphetamine-dependent individuals.
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http://dx.doi.org/10.1093/ijnp/pyz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311644PMC
June 2020

Effects of oxycodone and diazepam alone and in combination on operant nociception.

Behav Pharmacol 2020 04;31(2&3):168-173

Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA.

Developing effective analgesics with fewer unwanted side effects is a pressing concern. Due to a lack of effective nonopioid options currently available, an alternative approach termed opioid-sparing evaluates the ability of a coadministered drug to reduce the amount of opioid needed to produce an antinociceptive effect. Opioids and benzodiazepines are often coprescribed. Although this approach is theoretically rational given the prevalent comorbidity of chronic pain and anxiety, it also has inherent risks of respiratory depression, which is likely responsible for the substantial percentage of fatal opioid overdoses that have involved benzodiazepines. Moreover, there have been no clinical trials to support the effectiveness of this drug combination nor has there been corroborative preclinical evidence using traditional animal models of nociception. The present studies examined the prescription µ-opioid analgesic oxycodone (0.003-0.1 mg/kg) and the prototypical benzodiazepine anxiolytic diazepam (0.03-1.0 mg/kg), alone and in combination, using an animal model of pain that examines the restoration of conflict-related operant behavior as evidence of analgesia. Results documented significant dose-related increases in thermal threshold following oxycodone treatment. Diazepam treatment alone did not produce significant antinociception. In combination, diazepam pretreatment shifted oxycodone functions upward in a dose-dependent manner, but the additive effects were limited to a narrow dose range. In addition, combinations of diazepam and oxycodone at higher doses abolished responding. Taken together, though intriguing, these findings do not provide sufficient evidence that coadministration of an anxiolytic will result in clinically relevant opioid-sparing for pain management, especially when considering the inherent risks of this drug class combination.
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http://dx.doi.org/10.1097/FBP.0000000000000542DOI Listing
April 2020

Reward sensitivity deficits in a rat model of compulsive eating behavior.

Neuropsychopharmacology 2020 03 17;45(4):589-596. Epub 2019 Oct 17.

Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.

Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase"). We first tested the sensitivity to d-Amphetamine's stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative "no-net-flux" microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative "no-net-flux" microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.
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http://dx.doi.org/10.1038/s41386-019-0550-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021808PMC
March 2020

Translational models of adaptive and excessive fighting: an emerging role for neural circuits in pathological aggression.

F1000Res 2019 25;8. Epub 2019 Jun 25.

Department of Psychology, Tufts University, Medford, 530 Boston Ave, 02155, MA, USA.

Aggression is a phylogenetically stable behavior, and attacks on conspecifics are observed in most animal species. In this review, we discuss translational models as they relate to pathological forms of offensive aggression and the brain mechanisms that underlie these behaviors. Quantifiable escalations in attack or the development of an atypical sequence of attacks and threats is useful for characterizing abnormal variations in aggression across species. Aggression that serves as a reinforcer can be excessive, and certain schedules of reinforcement that allow aggression rewards also allow for examining brain and behavior during the anticipation of a fight. Ethological attempts to capture and measure offensive aggression point to two prominent hypotheses for the neural basis of violence. First, pathological aggression may be due to an exaggeration of activity in subcortical circuits that mediate adaptive aggressive behaviors as they are triggered by environmental or endogenous cues at vulnerable time points. Indeed, repeated fighting experiences occur with plasticity in brain areas once considered hardwired. Alternatively, a separate "violence network" may converge on aggression circuitry that disinhibits pathological aggression (for example, via disrupted cortical inhibition). Advancing animal models that capture the motivation to commit pathological aggression remains important to fully distinguish the neural architecture of violence as it differs from adaptive competition among conspecifics.
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http://dx.doi.org/10.12688/f1000research.18883.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593325PMC
June 2020

Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF.

Neurobiol Stress 2018 Nov 19;9:151-165. Epub 2018 Sep 19.

Psychology Dept., Tufts University, Medford, MA, 02155, USA.

Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug-taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress-escalated drug consumption. However, the specific mechanisms that drive CRF-mediated increases in dopamine require additional investigation as do the stress-induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking.
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http://dx.doi.org/10.1016/j.ynstr.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236516PMC
November 2018

The Urge to Fight: Persistent Escalation by Alcohol and Role of NMDA Receptors in Mice.

Front Behav Neurosci 2018 13;12:206. Epub 2018 Sep 13.

Department of Psychology, Tufts University, Medford, MA, United States.

Alcohol drinking, in some individuals, culminates in pathologically aggressive and violent behaviors. Alcohol can escalate the urge to fight, despite causing disruptions in fighting performance. When orally administered under several dosing conditions the current study examined in a mouse model if repeated alcohol escalates the motivation to fight, the execution of fighting performance, or both. Specifically, seven daily administrations of alcohol (0, 1.8, or 2.2 g/kg) determined if changes in the motivation to initiate aggressive acts occur with, or without, shifts in the severity of fighting behavior. Responding under the control of a fixed interval (FI) schedule for aggression reinforcements across the initial daily sessions indicated the development of tolerance to alcohol's sedative effect. By day 7, alcohol augmented FI response rates for aggression rewards. While alcohol escalated the motivation to fight, fighting performance remained suppressed across the entire 7 days. Augmented FI responding for aggression rewards in response to a low dose of alcohol (1.0 g/kg) proved to be persistent, as we observed sensitized rates of responding for more than a month after alcohol pretreatment. In addition, this sensitization of motivated aggression did not occur with a general enhancement of motor activity. Antagonism of NMDA or AMPA receptors with ketamine, dizocilpine, or NBQX during later challenges with alcohol were largely serenic without having any notable impact on the expression of alcohol-escalated rates of FI responding. The current dissociation of appetitive and performance measures indicates that discrete neural mechanisms controlling aggressive arousal can be distinctly sensitized by alcohol.
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http://dx.doi.org/10.3389/fnbeh.2018.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146040PMC
September 2018

Cannabinoid CB Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors.

J Pharmacol Exp Ther 2017 12 25;363(3):314-323. Epub 2017 Sep 25.

Harvard Medical School, Department of Psychiatry, Boston, Massachusetts (J.B., B.D.K.); McLean Hospital, Preclinical Pharmacology Laboratory, Belmont, Massachusetts (M.Z.L., J.B., B.D.K.); MakScientific LLC, Burlington, Massachusetts (S.O.A.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (L.J., V.G.S., Y.L., S.P.N., A.M.).

An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB) receptor agonists such as Δ-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids -arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB agonist-like subjective effects, as reflected in CB-related discriminative stimulus effects in laboratory subjects. Squirrel monkeys ( = 8) that discriminated the CB full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB-related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB-like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB receptor-mediated subjective effects.
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http://dx.doi.org/10.1124/jpet.117.244392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683067PMC
December 2017

Escalated cocaine "binges" in rats: enduring effects of social defeat stress or intra-VTA CRF.

Psychopharmacology (Berl) 2017 Sep 18;234(18):2823-2836. Epub 2017 Jul 18.

Department of Psychology, Tufts University, Medford, MA, USA.

Rationale: Exposure to intermittent social defeat stress elicits corticotropin releasing factor (CRF) release into the VTA and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists.

Objective: The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake.

Methods: Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-h extended access "binge."

Results: Rats that experienced social defeat or received intra-VTA CRF microinfusions (50 ng) both took significantly more cocaine than controls over the 24-h binge but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B.

Conclusions: Repeated infusion of CRF into the VTA persistently alters cocaine valuation and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.
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http://dx.doi.org/10.1007/s00213-017-4677-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709163PMC
September 2017

Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues.

J Med Chem 2016 07 13;59(14):6903-19. Epub 2016 Jul 13.

Center for Drug Discovery, Department of Chemistry and Chemical Biology, and Department of Pharmaceutical Sciences, Northeastern University , Boston, Massachusetts 02115, United States.

In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1'-substituents, carries a metabolically labile 2',3'-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532543PMC
July 2016

Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates.

J Pharmacol Exp Ther 2016 Apr 29;357(1):125-33. Epub 2016 Jan 29.

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (B.D.K., J.B.); Preclinical Pharmacology Laboratory, McLean Hospital, Belmont, Massachusetts (B.D.K., M.Z.L., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (V.G.S., S.O.A., S.P.N., A.M.).

The primary psychoactive ingredient of marijuana, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ(9)-THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide]. The effects of Δ(9)-THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) Δ(9)-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability < learning < flexibility < short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matching-to-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than Δ(9)-THC, possibly offering a therapeutic advantage in clinical settings.
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http://dx.doi.org/10.1124/jpet.115.228189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809315PMC
April 2016

GAD67-GFP knock-in mice have normal sleep-wake patterns and sleep homeostasis.

Neuroreport 2010 Feb;21(3):216-20

Laboratory of Neuroscience, VA Boston Healthcare System and Department of Psychiatry, Harvard Medical School, Brockton, Massachusetts, USA.

Gamma-aminobutyric acid (GABA) ergic neurons are important for controlling sleep and wakefulness but are difficult to identify, limiting their study. Knock-in mice with GABAergic neurons labeled by expression of green fluorescent protein (GFP) under control of the glutamate decarboxylase 67 (GAD67) promoter are now extensively used in neuroscience. However, it is unknown whether these mice have a normal sleep phenotype. Compared with wild-type control mice, GAD67-GFP knock-in mice had the same amount of non-rapid eye movement (NREM) sleep and rapid-eye movement (REM) sleep, a similar diurnal distribution of sleep, no NREM or REM sleep differences in electroencephalogram power, and normal sleep rebound following 6-h sleep deprivation. Our results suggest GAD67-GFP knock-in mice are an excellent tool for study of GABAergic neurons involved in sleep-wake regulation.
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http://dx.doi.org/10.1097/WNR.0b013e32833655c4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201775PMC
February 2010
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