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Author: David N Stephens (59)


Jan
2017

In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1-/-) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits.

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Dec
1969

Variations in genes encoding several GABAreceptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between, the gene encoding GABAreceptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric illnesses. In the present study, we hypothesized that thegenetically-associated increased risk for developing alcoholism may be associated with impaired behavioral control and altered sensitivity to reward, as a consequence of altered brain function.

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Oct
2016

Youths with family history (FH) of alcoholism are at greater risk of developing alcohol use disorder (AUD); heightened impulsive behavior may underlie such increased vulnerability. Here, we studied waiting impulsivity (previously suggested to predispose to alcohol drinking) in young moderate-to-heavy social drinkers (18 to 33 years old) characterized as family history positive (FHP) and negative (FHN) following an alcoholic or nonalcoholic (placebo) drink.
Two groups of young male and female social drinkers (n = 64) were administered an acute dose of alcohol (0.

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Dec
1969

Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains.

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Dec
1969

Variations in the GABRA2 gene, encoding α2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation.
We report human and mouse studies investigating a potential endophenotype underlying this association.

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Sep
2015

Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice.
We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy.
Thirty-six C57BL/6J mice were tested in a DID procedure.

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Apr
2015

Recent evidence has implicated the opioid system in exaggerated ethanol consumption and impulsivity deficits. The opioid receptor antagonist naltrexone (NTX) has proven efficient in reducing alcohol consumption; however, its role on impulsive behaviour is not fully characterised.
The aim of this study was to investigate the effects of NTX on two measures of impulsive behaviour in two inbred mouse strains that differ in ethanol preference and impulsive phenotype.

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Oct
2014

A strong association exists between impulsivity and binge drinking, and between adolescent alcohol exposure and alcohol abuse in humans. To understand the extent to which early-life alcohol exposure contributes to increased impulsivity, we developed an animal model of binge drinking using 2 strains of mice, C57BL/6J (B6) and DBA2/J (D2), that differ in both motor impulsivity and alcohol drinking.
Mice were treated with 2 g/kg ethanol (EtOH) during their early (intermittent ethanol exposure [IEE]_Early; postnatal day [PND]30 to 45) or late (IEE_Late; PND45 to 60) adolescence or with saline (control group [CON]) throughout the adolescence period.

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Dec
2014

There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18-25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task).

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Jan
2014

Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ(-/-) or α4(-/-) mice.

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Jun
2014

There is evidence to support the role of alpha-synuclein in motor impulsivity, but the extrapolation of this finding to other types of impulsivity remains to be elucidated.
This study aims to investigate the role of alpha-synuclein in choice impulsivity/risky decision-making by means of a mouse version of the Iowa Gambling Task (mIGT).
Two strains of mice that differ in the expression of the alpha-synuclein gene, the C57BL/6JOlaHsd (HA) and C57BL/6J (CR), were tested in the mIGT.

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Dec
1969

Alcohol dependence is a common, complex and debilitating disorder with genetic and environmental influences. Here we show that alcohol consumption increases following mutations to the γ-aminobutyric acidA receptor (GABAAR) β1 subunit gene (Gabrb1). Using N-ethyl-N-nitrosourea mutagenesis on an alcohol-averse background (F1 BALB/cAnN x C3H/HeH), we develop a mouse model exhibiting strong heritable preference for ethanol resulting from a dominant mutation (L285R) in Gabrb1.

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Nov
2013

Over the last decade there have been further developments in our knowledge of the risks and benefits of benzodiazepines, and of the risks and benefits of alternatives to benzodiazepines. Representatives drawn from the Psychopharmacology Special Interest Group of the Royal College of Psychiatrists and the British Association for Psychopharmacology together examined these developments, and have provided this joint statement with recommendations for clinical practice. The working group was mindful of widespread concerns about benzodiazepines and related anxiolytic and hypnotic drugs.

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Dec
1969

Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice.

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Jan
2013

Mice with functional ablation of the substance P-preferring receptor gene ('Nk1r' in mice ('NK1R-/-'), 'TACR1' in humans) display deficits in cognitive performance that resemble those seen in patients with Attention Deficit Hyperactivity Disorder (ADHD): namely, inattentiveness, impulsivity and perseveration. A recent report suggested that the L-type Ca(v) channel blocker, nifedipine, can ameliorate behavioral abnormalities of this type in humans. In light of evidence that NK1R antagonists modulate the opening of these L-type channels, we investigated whether nifedipine modifies %premature responses (impulsivity), perseveration or %omissions (inattentiveness) in the 5-Choice Serial Reaction-Time Task (5-CSRTT) and whether the response differs in NK1R-/- and wildtype mice.

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Sep
2012

Alcoholic patients who have undergone multiple detoxifications/relapses show altered processing of emotional signals. We performed functional magnetic resonance imaging during performance of implicit and explicit versions of a task in which subjects were presented with morphs of fearful facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n=12) or singly detoxified patients (SDTx; n=17), and social drinker controls (n=31).

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Jun
2012

The impulsive behavior that is often characteristic of adolescence may reflect underlying neurodevelopmental processes. Moreover, impulsivity is a multi-dimensional construct, and it is plausible that distinct brain networks contribute to its different cognitive, clinical and behavioral aspects. As these networks have not yet been described, we identified distinct cortical and subcortical networks underlying successful inhibitions and inhibition failures in a large sample (n = 1,896) of 14-year-old adolescents.

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Jan
2012

Mice are useful tools for dissecting genetic and environmental factors in relation to the study of attention and impulsivity. The five-choice serial reaction time task (5CSRTT) paradigm has been well established in rats, but its transferability to mice is less well documented.
This study aims to summarise the main results of the 5CSRTT in mice, with special focus on impulsivity.

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Dec
1969

The use of animal models is essential in carrying out research into clinical phenomena such as addiction. However, the complexity of the clinical condition inevitably means that even the best animal models are inadequate representations of the condition they seek to mimic. Such mismatches may account for apparent inconsistencies between discoveries in animal models, including the identification of potential novel therapies, and the translation of such discoveries to the clinic.

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Sep
2011

The ability to abstain from drinking, despite incentives to imbibe, is essential to recovery from alcoholism.
We used an incentive conflict task to investigate ability to abstain from responding during presentations of incentive cues. Both alcoholic (n = 23) and healthy subjects (n = 22) were required to withhold responding during the simultaneous presentation of two visual stimuli in which the individual presentation allowed responding for monetary reward.

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Oct
2011

There is extensive evidence that alcoholism and impulsivity are related, but the direction of causality is unclear.
The aim of the present investigation was to study the effects of chronic ethanol treatment and withdrawal in measures of attention and impulse control in the five-choice serial reaction time task (5CSRTT) in mice.
C57BL/6J mice were trained in the 5CSRTT and then tested in a variable inter-trial interval (vITI) session, which promotes the emergence of premature responses, a measure of poor inhibitory control.

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Oct
2011

Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents.

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Mar
2011

The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon.

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Sep
2011

Several theoretical frameworks have been developed to understand putative processes and mechanisms involved in addiction. Whilst these 'theories of addiction' disagree about importance and/or nature of a number of key psychological processes (e.g.

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Feb
2011

A clear interrelationship between biological rhythms and addiction has emerged from recent preclinical and clinical studies. In particular, the manipulation of the so-called 'clock genes' interferes with the manifestation of drug-related responses. For instance, Period 1 (Per1(Brdm1)) mutant mice do not display behavioural sensitization in response to repeated cocaine administration and do not express cocaine conditioned place preference, in contrast to control littermates.

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Oct
2010

In appetitive Pavlovian associative learning, a stimulus (conditioned stimulus, CS) that has been associated with the delivery of a reinforcing event (unconditioned stimulus, US; e.g., food) can subsequently elicit or modulate goal-directed instrumental behaviors.

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Sep
2010

Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse.

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Jul
2010

An environmental stimulus paired with reward (a conditioned stimulus; CS) can acquire predictive properties that signal reward availability and may also acquire incentive motivational properties that enable the CS to influence appetitive behaviors. The neural mechanisms involved in the acquisition and expression of these CS properties are not fully understood. The metabotropic glutamate receptor, mGluR5, contributes to synaptic plasticity underlying learning and memory processes.

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Apr
2010

Reward is a concept fundamental to discussions of drug abuse and addiction. The idea that altered sensitivity to either drug-reward, or to rewards in general, contributes to, or results from, drug-taking is a common theme in several theories of addiction. However, the concept of reward is problematic in that it is used to refer to apparently different behavioural phenomena, and even to diverse neurobiological processes (reward pathways).

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Apr
2010

There is only modest overlap in the most common alcohol consumption phenotypes measured in animal studies and those typically studied in humans. To address this issue, we identified a number of alcohol consumption phenotypes of importance to the field that have potential for consilience between human and animal models. These phenotypes can be broken down into three categories: (1) abstinence/the decision to drink or abstain; (2) the actual amount of alcohol consumed; and (3) heavy drinking.

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Jun
2010

Alpha-synuclein is implicated in the pathology of Parkinson disease (PD) and is involved in synaptic function, particularly in presynaptic events in dopamine (DA) synapses. Recently, a role for alpha-synuclein in reward and addiction, especially in alcoholism, has been reported. Since PD and alcohol dependence present a strong comorbidity with anxiety disorders, a role for alpha-synuclein in anxiety has been proposed.

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Feb
2010

Because GABA(A) receptors containing alpha2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization.

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Jul
2009

The effects of ethanol on attention and impulsivity have been contradictory.
The aim of the present investigation is to study the effects of acute ethanol administration in measures of attention and response control in the five-choice serial reaction time task (5-CSRTT) in two strains of mice, C57BL/6JOlaHsd and CD1.
Mice were trained in the 5-CSRTT and then were injected intraperitoneally (i.

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Oct
2008

Binge drinking is an increasingly recognized problem within the UK. We have studied the relationship of binge drinking to cognitive and emotional functioning in young adults, and have found evidence for increased impulsivity, impairments in spatial working memory and impaired emotional learning. Since in human studies it is difficult to understand whether such behavioural changes pre-date or are a consequence of binge drinking, we have also studied parallel behaviours in a rodent model, in which rats are exposed to intermittent episodes of alcohol consumption and withdrawal.

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Jul
2007

Data on the ability of Delta 9-tetrahydrocannabinol (THC) to modify reward processes in experimental animals are inconsistent. This study examined the effects of Delta 9-THC on brain reward function using the rate-frequency curve shift paradigm of intracranial self-stimulation (ICSS) and the conditioned place preference (CPP) paradigm. In ICSS tests, rats were implanted with electrodes into the medial forebrain bundle.

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Jul
2006

Repeated exposure of rats to withdrawal from chronic ethanol reduces hippocampal long-term potentiation and gives rise to epileptiform-like activity in hippocampus. We investigated whether such withdrawal experience also affects learning in tasks thought to be sensitive to hippocampal damage. Rats fed an ethanol-containing diet for 24 days with two intermediate 3-day withdrawal episodes, resulting in intakes of 13-14 g/kg ethanol per day, showed impaired negative patterning discrimination compared with controls and animals that had continuous 24-day ethanol treatment, but did not differ from these animals in the degree of contextual freezing 24 h after training or in spatial learning in the Barnes maze.

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Jul
2006

Repeated administration of abused drugs sensitizes their stimulant effects and results in a drug-paired environment eliciting conditioned activity. We tested whether food induces similar effects. Food-deprived male mice were given novel food during 30 min tests in a runway (FR group) that measured locomotor activity.

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Aug
2006

Studies analysing the effects of acute treatments on animal behaviour and brain biochemistry frequently use pairwise comparisons between sham-treated and -untreated animals. In this study, we analyse expression of tPA, Grik2, Smarca2 and the transcription factor, Sp1, in mouse cerebellum following acute ethanol treatment. Expression is compared to saline-injected and -untreated control animals.

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Feb
2007

The learning processes underlying the formation of drug-cue associations involve changes in synaptic transmission mediated by AMPA receptors. Here, we examine the consequences of targeted deletion of the gene encoding GluR1 subunits of AMPA receptors (gria1 knockouts (KO)) on cocaine self-administration and on the ability of cocaine-paired cues to affect cocaine-seeking in mice. Cocaine self-administration was unaffected by gria1 deletion, as was the ability of a cocaine-paired cue to reinstate responding following extinction, following either a 3 or a 66 day delay.

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Apr
2006

Increased anxiety is a characteristic of the acute ethanol withdrawal syndrome. Repeated exposure of rats to withdrawal from chronic ethanol increases sensitivity to seizures.
We investigated whether repeated withdrawal experience increases withdrawal-induced anxiety and stress, and if it changes withdrawal-induced activation of related brain areas.

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Dec
2005

GABA(A) receptors containing alpha5 subunits have been suggested to mediate the rewarding effects of ethanol. We tested this hypothesis in mice with deletion of alpha5 subunits. alpha5 knockout mice did not differ from wildtypes in operant responding for 10% ethanol/10% sucrose, but responded less for 10% sucrose.

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Sep
2005

In rats, repeated episodes of alcohol consumption and withdrawal (RWD) impair fear conditioning to discrete cues.
Fear conditioning was measured in human binge drinkers as the increased startle response in the presence of a CS+ conditioned to aversive white noise. Secondly, the ability of tone CSs, paired with footshock, to induce c-fos expression, a marker of neuronal activity, in limbic structures subserving emotion was studied in rats.

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Mar
2005

This review contains the proceedings from a symposium held at the RSA conference in 2003 on "Alcohol Withdrawal and Conditioning." The presentations covered a range of interactions between conditioning and alcohol withdrawal, in both animal behavior and the clinic. Dr.

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Apr
2005

The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effects of a number of stimuli. Critically, this classical conditioning procedure requires the formation of associations between a rewarding stimulus and environmental cues, and the ability of these cues to direct subsequent behaviour.
The purpose of the current experiments was to examine the role of glutamatergic transmission via subunit-specific populations of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the formation of stimulus--reward associations involving contextual stimuli.

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Apr
2004

Tissue plasminogen activator (tPA), a serine protease immediate-early gene product expressed in brain areas important in learning and memory, has been shown to cleave the NR1 subunit of the NMDA receptor leading to a potentiated Ca(2+) influx. Mice lacking tPA (tPA-/- mice) have disrupted late phase-LTP in the hippocampus, possibly as a consequence of reduced Ca(2+) flux through NMDA receptors. In the present experiments, we investigated whether the NMDA antagonist dizocilpine might alter performance in tPA-/- mice in behavioural tasks shown to be sensitive to hippocampal lesions.

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Oct
2003

Repeated experience of withdrawal from alcohol results in a kindling-like process leading to increased likelihood and severity of convulsions during detoxification. The aim of this study was to determine whether repeated withdrawals affect cognitive function.
We investigated alcoholic patients undergoing detoxification in an inpatient setting, using tasks sensitive to dysfunction of prefrontal areas.

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Oct
2003

Presence of the glutamate receptor 2 (GluR2) subunit prevents calcium influx through AMPA-receptor complexes; deletion of this subunit results in enhanced hippocampal long-term potentiation. We investigated whether mice lacking the GluR2 subunit [gria2 knock-out (KO) mice] displayed impairments in learning stimulus-reward associations, and the subsequent ability of reward-paired cues to control motivated behavior. Both gria2 KO and wild-type (WT) mice learned to associate a light/tone stimulus with food delivery, as evidenced by approach toward the food magazine after the presentation of the cues (pavlovian conditioning).

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Sep
2003

Systemic injections of alcohol have previously been reported to 'prime' or to reinstate self-administration of alcohol in rats, and it has been suggested that the priming effects of drugs are related to their stimulus properties. We tested this hypothesis by investigating the effects of lorazepam, which cross-generalizes with alcohol in animal drug-discrimination studies, in rats trained to self-administer 7% alcohol in an operant paradigm. Once animals were trained, extinction tests were carried out twice weekly, before which rats were injected with either vehicle, alcohol (0.

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Apr
2003

Repeated withdrawal from ethanol, a procedure which resembles amygdala kindling in increasing seizure sensitivity, impairs the acquisition of fear conditioning (Stephens et al., 2001, Eur. J.

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