Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction.

Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF1 receptors. Overactivation of the CRF-CRF1 system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.abstinence ͉ addiction ͉ amygdala ͉ deprivation ͉ stress

Several neuropsychological hypotheses have been formulated to explain the transition to addiction, including hedonic allostasis, incentive salience, and the development of habits. A key feature of addiction that remains to be explored is the important individual variability observed in the propensity to self-administer drugs, the sensitivity to drug-associated cues, the severity of the withdrawal state, and the ability to quit. In this review, we suggest that the concept of self-regulation, combined with the concept of modularity of cognitive function, may aid in the understanding of the neural basis of individual differences in the vulnerability to drugs and the transition to addiction. The thesis of this review is that drug addiction involves a failure of the different subcomponents of the executive systems controlling key cognitive modules that process reward, pain, stress, emotion, habits, and decision-making. A subhypothesis is that the different patterns of drug addiction and individual differences in the transition to addiction may emerge from differential vulnerability in one or more of the subcomponents.

No abstract

Chronic intermittent access to alcohol leads to the escalation of alcohol intake, similar to binge drinking in humans. Converging lines of evidence suggest that impairment of medial prefrontal cortex (mPFC) cognitive function and overactivation of the central nucleus of the amygdala (CeA) are key factors that lead to excessive drinking in dependence. However, the role of the mPFC and CeA in the escalation of alcohol intake in rats with a history of binge drinking without dependence is currently unknown. To address this issue, we examined FBJ murine osteosarcoma viral oncogene homolog (Fos) expression in the mPFC, CeA, hippocampus, and nucleus accumbens and evaluated working memory and anxiety-like behavior in rats given continuous (24 h/d for 7 d/wk) or intermittent (3 d/wk) access to alcohol (20% vol/vol) using a two-bottle choice paradigm. The results showed that abstinence from alcohol in rats with a history of escalation of alcohol intake specifically recruited GABA and corticotropin-releasing factor (CRF) neurons in the mPFC and produced working memory impairments associated with excessive alcohol drinking during acute (24-72 h) but not protracted (16 -68 d) abstinence. Moreover, abstinence from alcohol was associated with a functional disconnection of the mPFC and CeA but not mPFC and nucleus accumbens. These results show that recruitment of a subset of GABA and CRF neurons in the mPFC during withdrawal and disconnection of the PFC-CeA pathway may be critical for impaired executive control over motivated behavior, suggesting that dysregulation of mPFC interneurons may be an early index of neuroadaptation in alcohol dependence.A lcoholism is a chronic relapsing disorder associated with compulsive drinking, loss of control over intake, and emergence of a negative emotional state during abstinence from the drug (1). Although no known animal model of addiction fully emulates the condition in humans, some models are better suited for the investigation of specific elements of the addiction process in a clinically relevant manner. Recently, an animal model of alcohol binge drinking with good face and predictive validity for what may be considered a transition to alcoholism has been reintroduced (2, 3). Rats given extended (24 h/d) and intermittent (every other day) choice access to ethanol escalate their intake of alcohol over the course of 2-4 wk in a binge-like pattern (2-6), and alcohol drinking using this paradigm was reduced by two drugs approved by the US Food and Drug Administration for the treatment of alcoholism (i.e., naltrexone and acamprosate) (2). Moreover, escalation of alcohol drinking using this model is associated with decreased dopamine levels in the nucleus accumbens after 24 h of abstinence (7), decreased endocannabinoid signaling in the dorsolateral striatum (8), and activation of FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB) in the nucleus accumbens core, dorsolateral striatum, and orbitofrontal cortex.Converging lines of evidence from human and animal studies suggest that impairm...