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Animal Model Drug Treatment
Naltrexone Acamprosate Corticotropin-Releasing Factor Antagonist
Baseline drinking [44] No effect[23] No effect[29,30,49]
Dependence-induced drinking [45] [21,47] [29,30,49]
Cue-induced reinstatement [46] [48] No effect[46]
Stress-induced reinstatement No effect[46] Not tested [50]
Alcohol deprivation effect / Protracted abstinence [45] [23] [49]

Effects of Drugs in Animal Models of Different Components of the Alcohol Addiction Cycle Relevant for Medications Development

Alcohol Dependence: The Importance of Neurobiology to Treatment

Authors: George F. Koob, PhDFaculty and Disclosures


Introduction -- Definitions, Conceptual Framework, and Animal Models

Substance dependence on alcohol can be defined as a maladaptive pattern of alcohol use leading to at least 3 of a set of 7 possible symptoms, including tolerance, withdrawal, loss of control in limiting intake, desire to reduce alcohol intake, compulsion to seek and take the drug, loss of other activities because of alcohol use, and continued use despite knowledge of its negative effects.[1] In addition, there may be emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when access to the drug is prevented).[2]Reward can be defined as a reinforcing stimulus with positive hedonic valence and anti-reward. Anti-reward is a concept based on the hypothesis that there are brain mechanisms to limit reward and is represented at the neurocircuitry level by both within- and between-system neuroadaptations to activation of the reward system.[3] One important goal of current neurobiological research relevant to addiction treatment is to understand the neuropharmacologic and neuroadaptive mechanisms within specific neurocircuits that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug seeking and drug taking that defines alcoholism.

Alcoholism has been conceptualized as a chronic relapsing disorder that progresses from impulsivity to compulsivity in a 3-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.[2] Neurobiological mechanisms change as the subject moves from one domain to another. As individuals move from an impulsive to a compulsive disorder, the drive for the drug-taking behavior shifts from positive to negative reinforcement.

Much of the recent progress in understanding the mechanisms of alcoholism has derived from the study of animal models.[4-6] While no animal model of addiction fully emulates the human condition, animal models do permit investigation of specific elements of the process of alcoholism. Such elements can be defined in various ways, but models of different stages of the addiction cycle have provided heuristic value not only for understanding the neurobiology of addiction but also for the development of medications for the treatment of alcoholism. Much focus in animal studies has been on the synaptic sites and molecular mechanisms in the nervous system on which drugs with dependence potential act initially to produce their positive reinforcing effects, and much emphasis now is placed on the neurobiological mechanisms of addiction that are involved in the various stages of the addiction cycle. Particularly important is the focus on certain brain circuits and the neurochemical changes associated with those circuits during the transition from drug taking to drug addiction; these are key components for understanding the importance of the neurobiology of addiction for treatment.

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