David N Stephens

David N Stephens
University of Sussex · School of Psychology

PhD

About

294
Publications
13,082
Reads
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Introduction
David N Stephens currently works at the School of Psychology, University of Sussex. Dai does research in Biological Psychology, Experimental Psychology and Emotion. Their current project is 'GABAA receptors in accumbens and drugs of abuse'.
Additional affiliations
January 1995 - present
University of Sussex
Position
  • Professor Emeritus

Publications

Publications (294)
Article
Full-text available
Early-life stress (ELS) is known to exert long-term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding α2 subuni...
Article
Full-text available
Haplotypes of the Gabra2 gene encoding the α2 subunit of the GABAA receptor (GABAAR) are associated with drug abuse, suggesting that α2-GABAARs may play an important role in the circuitry underlying drug misuse. The genetic association of Gabra2 haplotypes with cocaine addiction appears to be evident primarily in individuals who had experienced chi...
Article
Full-text available
Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric ill...
Article
Variations in genes encoding several GABAA receptors have been associated with human drug and alcohol abuse. Among these, a number of human studies have suggested an association between GABRB1, the gene encoding GABAA receptor β1 subunits, with Alcohol dependence (AD), both on its own and comorbid with other substance dependence and psychiatric ill...
Article
Full-text available
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-ter...
Article
GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarise the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GAB...
Article
Background 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 33years old) c...
Preprint
Full-text available
Extrasynaptic GABA A receptors (GABA A Rs) composed of α4, β and δ subunits mediate GABAergic tonic inhibition and are pertinent molecular targets in the modulation of behavioural responses to drugs of abuse, including ethanol and cocaine. These GABAARs are highly expressed within the nucleus accumbens (NAc) where they influence the excitability of...
Article
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 behaviour in the 5...
Article
Full-text available
Background: 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 fa...
Article
Full-text available
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 t...
Article
Rationale: 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. Objective: The aim of this study was to investigate the...
Article
BackgroundA 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),...
Article
Full-text available
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...
Article
Full-text available
Alcohol abuse is frequently characterised by cycles of heavy drinking, detoxification, and relapse. We review evidence that multiple detoxifications are associated with impaired ability to control reward seeking, and with exaggerated responses to negative emotional stimuli. Under conditions of incentive conflict and in intra-extra dimensional shift...
Article
Full-text available
GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. We investigated the reinforcing properties...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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 t...
Article
Full-text available
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 t...
Article
Full-text available
Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in Attention Deficit Hyperactivity Disorder: namely, inattentiveness and impulsivity (indicated by their greater % omissions and premature responses in the 5-Choice Serial Reaction-Time Task (5-CSRTT) and locomotor hyperactivity. We...
Article
Full-text available
Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those al...
Article
Full-text available
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...
Article
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-ty...
Article
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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, mu...
Article
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 ide...
Article
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The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impu...
Article
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, wit...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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 t...
Article
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 differ...
Data
Statistical comparisons of behavior during the LITI: NI-2 versus vehicle-injected mice. (DOC)
Data
Statistical comparisons of behavior in vehicle- and d amphetamine (0.3 mg/kg or 1 mg/kg (i.p.)) treated mice in the VITI. (DOC)
Data
Statistical comparisons of behaviour in NK1R-/- and wildtype mice during training stages 1–6. (DOC)
Data
Number of training sessions needed to match the baseline criteria for testing. (DOC)
Data
Statistical comparisons of behavior in vehicle- and d amphetamine (0.3 mg/kg or 1 mg/kg (i.p.)) treated mice in the LITI. (DOC)
Data
Statistical comparisons of behavior during the VITI: NI-2 versus vehicle-injected mice. (DOC)
Data
Statistical analysis of the effect of genotype and time of day on behavior of uninjected mice, tested for the first time (NI-1), with a long ITI (LITI). (DOC)
Data
Statistical analysis of the effect of genotype and time of day on behavior of uninjected mice, tested for the first time (NI-1), with a variable ITI (VITI). (DOC)
Article
Full-text available
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-ampheta...
Conference Paper
Full-text available
Background / Purpose: The propensity to attribute incentive value to reward-paired stimuli has been associated with susceptibility to behavioural sensitization, a form of drug-induced plasticity implicated in addiction. The underlying neural correlates of these processes are not fully understood, so we examined the role of the metabotropic glutam...
Conference Paper
Background / Purpose: Alpha-synuclein plays a role in dopamine neurotransmission and has been associated with addiction, which in turn has been associated with impulsivity. The reason of the study was to investigate the potential relationship between alpha-synuclein and impulsivity.The main hypothesis was that alpha-synuclein contributes to the i...
Article
Full-text available
A fundamental function of the brain is to evaluate the emotional and motivational significance of stimuli and to adapt behaviour accordingly. The IMAGEN study is the first multicentre genetic-neuroimaging study aimed at identifying the genetic and neurobiological basis of individual variability in impulsivity, reinforcer sensitivity and emotional r...
Article
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. the necessity of craving and/or the involvement of drug-value representations), a number of commonalit...
Article
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...
Article
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. For example, a Pavlovian CS can serve to reinforce (novel) instrumental behavior (con...
Article
Full-text available
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 ro...
Article
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 broke...
Article
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 differ...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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 anxi...