Individual differences in the neuropsychopathology of addiction.

Drug addiction or substance-use disorder is a chronically relapsing disorder that progresses through binge/intoxication, withdrawal/negative affect and preoccupation/anticipation stages. These stages represent diverse neurobiological mechanisms that are differentially involved in the transition from recreational to compulsive drug use and from positive to negative reinforcement. The progression from recreational to compulsive substance use is associated with downregulation of the brain reward systems and upregulation of the brain stress systems. Individual differences in the neurobiological systems that underlie the processing of reward, incentive salience, habits, stress, pain, and executive function may explain (i) the vulnerability to substance-use disorder; (ii) the diversity of emotional, motivational, and cognitive profiles of individuals with substance-use disorders; and (iii) heterogeneous responses to cognitive and pharmacological treatments. Characterization of the neuropsychological mechanisms that underlie individual differences in addiction-like behaviors is the key to understanding the mechanisms of addiction and development of personalized pharmacotherapy

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background 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. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Nicotine addiction : a review

Nicotine, the major psychoactive compound in tobacco, acts as a potent addictive drug in humans. The addictive nature of nicotine leads to more than 6 million deaths a year. Evidence indicates that nicotine and other drugs of abuse act on central dopaminergic pathways and modulate their neurophysiological mechanisms. Nicotine stimulates dopaminergic pathways and the prefrontal cortex (PFC), inducing enhanced reward perception and increased cognitive function, respectively. These findings are consistent with the fact that nicotine binds to different subtypes of nicotinic acetylcholine receptors present on the neurons found in the PFC and ventral tegmental area of the midbrain. The latter, being the area most involved in addictive behaviour, projects on the limbic system, particularly the nucleus accumbens, and receives afferents from the prefrontal cortex and brainstem. Although dopaminergic pathways and nicotinic acetylcholine receptors are the protagonists of nicotine addiction, several minor pathways and their constituent receptors have been indicated as being either directly or indirectly affected by nicotine. These include serotonergic pathways and central cannabinoid receptors. Despite the scarcity of approved drugs and partial efficacy of approved treatment, insight into nicotine neurophysiological modulation led to better appreciation of nicotine-seeking behaviour and subsequent improved design of pharmacological and behavioural approaches to smoking cessation. Tobacco is the single most preventable cause of death in the world today. Better understanding of the neurobiological mechanisms underlying nicotine addiction will ultimately lead to more effective treatments of both nicotine dependence and nicotine rewarding effects.peer-reviewe

Neuronal Distortions of Reward Probability without Choice

Reward probability crucially determines the value of outcomes. A basic phenomenon, defying explanation by traditional decision theories, is that people often overweigh small and underweigh large probabilities in choices under uncertainty. However, the neuronal basis of such reward probability distortions and their position in the decision process are largely unknown. We assessed individual probability distortions with behavioral pleasantness ratings and brain imaging in the absence of choice. Dorsolateral frontal cortex regions showed experience dependent overweighting of small, and underweighting of large, probabilities whereas ventral frontal regions showed the opposite pattern. These results demonstrate distorted neuronal coding of reward probabilities in the absence of choice, stress the importance of experience with probabilistic outcomes and contrast with linear probability coding in the striatum. Input of the distorted probability estimations to decision-making mechanisms are likely to contribute to well known inconsistencies in preferences formalized in theories of behavioral economics

Local and regional heterogeneity underlying hippocampal modulation of cognition and mood.

While the hippocampus has been classically studied for its role in learning and memory, there is significant support for a role of the HPC in regulating emotional behavior. Emerging research suggests these functions may be segregated along the dorsoventral axis of the HPC. In addition to this regional heterogeneity, within the HPC, the dentate gyrus is one of two areas in the adult brain where stem cells continuously give rise to new neurons. This process can influence and be modulated by the emotional state of the animal, suggesting that adult neurogenesis within the DG may contribute to psychiatric disorders and cognitive abilities. Yet, the exact mechanism by which these newborn neurons influence behavior remains unknown. Here, we will examine the contribution of hippocampal neurogenesis to the output of the HPC, and suggest that the role of neurogenesis may vary along the DV axis. Next, we will review literature indicating that anatomical connectivity varies along the DV axis of the HPC, and that this underlies the functional segregation along this axis. This analysis will allow us to synthesize novel hypotheses for the differential contribution of the HPC to cognition and mood

Stress and Decision Making: Effects on Valuation, Learning, and Risk-taking

A wide range of stressful experiences can influence human decision making in complex ways beyond the simple predictions of a fight-or-flight model. Recent advances may provide insight into this complicated interaction, potentially in directions that could result in translational applications. Early research suggests that stress exposure influences basic neural circuits involved in reward processing and learning, while also biasing decisions toward habit and modulating our propensity to engage in risk-taking. That said, a substantial array of theoretical and methodological considerations in research on the topic challenge strong cross study comparisons necessary for the field to move forward. In this review we examine the multifaceted stress construct in the context of human decision making, emphasizing stress’ effect on valuation, learning, and risk-taking

Behavioral and pharmacological characterization of a mouse model of palatable diet alternation

Obesity and eating disorders represent a severe problem in Western societies. Both the increased availability of highly palatable foods and dieting are major risk factors contributing to the epidemic disorders of feeding. The purpose of this study was to characterize an animal model of maladaptive feeding induced by intermittent access to a palatable diet alternation in mice. In this study, mice were either continuously provided with standard chow food (Chow/Chow), or provided with standard chow for 2 days, with 1 day of access to a high-sucrose, palatable food (Chow/Palatable). Following stability of intake within the cycling paradigm, we investigated the effects of several pharmacological treatments: Naltrexone, an opioid antagonist, SR141716A (rimonabant), a type 1 cannabinoid receptor antagonist, and BD-1063, a type 1 sigma receptor antagonist. Over successive cycles, Chow/Palatable mice showed an escalation of palatable food intake within the first-hour of renewed access to palatable diet, and displayed hypophagia upon its removal. Naltrexone, SR141716A, and BD-1063 reduced overconsumption of palatable food during this first hour. Here we provide evidence of strong face and convergence validities in a palatable diet alternation model in the mouse, confirming multiple shared underlying mechanisms of pathological eating across species, and thus making it a useful therapeutic development tool.2019-07-11T00:00:00