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

Neurobiological mechanisms of control in alcohol use disorder – Moving towards mechanism-based non-invasive brain stimulation treatments

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour

Opiate-Induced Neuroplastic Alterations to Dopamine Signaling in the Basolateral Amygdala-Prefrontal Cortical Pathway

Opiate addiction is a chronic disorder with high rates of relapse. The failure to maintain sobriety after prolonged abstinence is believed to be due in part to the persistence of potent memories associated with the drug-taking experience. Activation of these memories by re-exposure to drug-related cues can trigger craving in many individuals. Thus, understanding the neurobiological processes underlying the formation of these memories may provide insight into the persistence of addiction. The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. There is some evidence that chronic opiate exposure results in alterations to the function of dopamine (DA) D1 and D2 receptors and their intracellular targets within the BLA, but critical questions remain in regards to these effects within the BLA-mPFC circuit. For instance, opiate-induced alterations to intra-mPFC DA signaling in the context of associative opiate memories has not yet been explored. Furthermore, the role of the DA D3 receptor has not yet been investigated. Finally, there is little understanding of the temporal dynamics underlying these changes in DAergic signaling. Using behavioural models of associative memory formation (conditioned place preference and conditioned place aversion) paired with analyses of protein expression, we further characterized how chronic opiate exposure results in neuroplastic changes to DA receptor expression and signaling in the BLA-mPFC pathway. Here, we report that chronic opiate exposure results in a series of alterations to D1, D2 and D3 signaling within the BLA-mPFC circuit in the context of both opiate reward and withdrawal aversion memories. Specifically, we highlighted the importance of D2 and CaMKIIα signaling within the mPFC, identified the role of intra-BLA D3-Cdk5-calcineurin signaling in reward and aversion memory formation, and temporally mapped opiate-induced alterations to intra-BLA memory molecules. Together, these results provide a more complete understanding of how opiate exposure profoundly alters DA signaling between the dependent and non-dependent states. Interestingly, we found that many of the changes induced by chronic opiate exposure are not only transient, but may be functionally reversible, thus providing an avenue for future development of pharmacological interventions for opiate addiction

Bioligands Acting on the Cannabinoid Receptor CB1 for the Treatment of Withdrawal Syndrome Caused by Cannabis sativa

Every day, the questions about Cannabis sativa ability to cause chemical dependence are closed with the considerable increase in the demand for treatment of addicts to this plant. Most drug addicts submitted to treatment have difficulty in achieving and maintaining abstinence from Cannabis due to the appearance of symptoms as irritability, anxiety, desire to consume marijuana, decreased quality and quantity of sleep, and change in appetite, weight loss, and physical discomfort, besides emotional and behavioral symptoms. The neurobiological basis for the withdrawal syndrome, that is, withdrawal of Cannabis, was established after the discovery of the endogenous cannabinoid system, identification of CB1 and CB2 cannabinoid receptors, and demonstrations of precipitated removal with antagonists of these receptors. The chapter discusses the main studies currently conducted for the treatment of withdrawal syndrome based on bioligands that act directly on the CB1 cannabinoid receptor

The Effect Of Abstinence From Smoking On Stress Reactivity

Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by the reliability of current available measures of stress. Functional magnetic reasoning imaging (fMRI) could provide a much-needed objective measure of stress reactivity. The goal of this dissertation is to contribute to the understanding of abstinence-induced changes in stress reactivity by examining neural, neuroendocrine (cortisol), and subjective measures of stress response during abstinence. In addition, this study investigated the influence of individual variation in nicotine metabolism rates on these measures of stress reactivity. Seventy-five treatment-seeking smokers underwent blood oxygen level dependent (BOLD) fMRI during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counter-balanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST. Neural stress reactivity during abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus (IFG), a brain region previously associated with inhibitory control. Greater abstinence-induced change in brain response to stress was associated with greater abstinence-induced change in subjective stress. However, there was no association with abstinence-induced change in cortisol response. In addition, higher rates of nicotine metabolism were associated with increased abstinence-induced change in self-reported stress, but not with brain or cortisol response. This study provides novel evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety. These results underscore the importance of stress response during abstinence, and suggest that neuroimaging may provide a useful biomarker of stress response during the early smoking cessation, a period when smokers are most vulnerable to relapse

Addictions NeuroImaging Assessment (ANIA): Towards an integrative framework for alcohol use disorder.

Alcohol misuse and addiction are major international public health issues. Addiction can be characterized as a disorder of aberrant neurocircuitry interacting with environmental, genetic and social factors. Neuroimaging in alcohol misuse can thus provide a critical window into underlying neural mechanisms, highlighting possible treatment targets and acting as clinical biomarkers for predicting risk and treatment outcomes. This neuroimaging review on alcohol misuse in humans follows the Addictions Neuroclinical Assessment (ANA) that proposes incorporating three functional neuroscience domains integral to the neurocircuitry of addiction: incentive salience and habits, negative emotional states, and executive function within the context of the addiction cycle. Here we review and integrate multiple imaging modalities focusing on underlying cognitive processes such as reward anticipation, negative emotionality, cue reactivity, impulsivity, compulsivity and executive function. We highlight limitations in the literature and propose a model forward in the use of neuroimaging as a tool to understanding underlying mechanisms and potential clinical applicability for phenotyping of heterogeneity and predicting risk and treatment outcomes

The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms

In drug addiction, cues previously associated with drug use can produce craving and frequently trigger the resumption of drug taking in individuals vulnerable to relapse. Environmental stimuli associated with drugs or natural reinforcers can become reliably conditioned to increase behavior that was previously reinforced. In preclinical models of addiction, these cues enhance both drug self-administration and reinstatement of drug seeking. In this review, we will dissociate the roles of conditioned stimuli as reinforcers from their modulatory or discriminative functions in producing drug-seeking behavior. As well, we will examine possible differences in neurobiological encoding underlying these functional differences. Specifically, we will discuss how models of drug addiction and relapse should more systematically evaluate these different types of stimuli to better understand the neurobiology underlying craving and relapse. In this way, behavioral and pharmacotherapeutic interventions may be better tailored to promote drug use cessation outcomes and long-term abstinence