Ft ft

Individual differences & genetics


Negative emotional state ttt

Environmental stressors daTT

GlucocorticoidsTT GR Sensitivity! CRFTT

DAW GlucocorticoidsTTT GR SensitivityT? CRFTTT

Protracted abstinence

Negative emotional Reward state experiences t

Environmental stressors

Individual differences & genetics

Environmental stressors & cues

Glucocorticoids^ GR SensitivityTT CRFT

Allostasis -ยป Allostatic -^ A)lost1atic load state (pathology)

Figure 5 The transition from drug taking to addiction and protracted abstinence. (Reprinted from Koob, G. F.; Le Moal, M. Neuropsychopharmacology 2001, 24, 97-129, with permission from Elsevier.)

take drugs (Figure 5).22 This is known as the 'opponent motivational process.' According to this model, the emergence of dysphoria, anxiety, and a general negative emotional state promotes the transition from drug use to addiction. The most recent concept in this hypothesis is that of 'allostasis' which is a state that is proposed to develop from chronic drug use that sets a new and higher 'hedonic' threshold and has been linked to dysregulation of molecular systems.23

The primary criticism of this hypothesis is that in the absence of withdrawal symptoms and despite long periods of drug abstinence, relapse still occurs.14 Nevertheless, long-term neurochemical and cellular changes may account for relapse, despite the absence of overt symptoms. Aberrant Learning Hypothesis

The role of learning in addiction has been explored, in part based on the fact that repeated exposure to drugs of abuse causes neuroadaptations in this reward learning circuitry that have been termed 'aberrant learning' as it differs from learning associated with natural rewards.14 The neuroadaptations or neuroplasticity within the brain networks that involve motivation and emotion form the basis for the hypothesis that aberrant learning can lead to habit and automatic behaviors associated with addiction.24 Critics of this hypothesis suggest that it is too simplistic to think that knowledge can, by itself, cause the behavior of drug taking that leads to addiction. On the other hand, recent data that cue-induced drug seeking behavior can be attenuated by the administration of pharmacological agents strongly suggests that this research area may provide new therapeutic agents for treating addiction.25'26 Incentive Sensitization Hypothesis

Repeated administration of psychostimulants produces greater increases in motor activity with each administration, a phenomenon termed locomotor sensitization. The incentive-sensitization theory of addiction and relapse, proposed by Robinson and Berridge,14 extends this observation to psychostimulant reward, positing that sensitization of a neural system that attributes incentive salience causes compulsive motivation or 'wanting' to take addictive drugs. According to this hypothesis, as reviewed by Hyman,27 drug-induced increases in DA do not produce drug-liking (i.e., the 'high') but rather shape behavioral responses so as to maximize the attainment of future rewards. Repeated exposure to the drug of abuse sensitizes this process, increasing the motivational significance of cues that predict the delivery of drug. Counterindications to this theory are the limited data that support its occurrence in human addicts and other data, reviewed by Di Chiara,28 that psychomotor-induced increases in brain DA in humans correlates with the subjective experience of a 'high.' Craving, Relapse, and the Role of Stress

The phenomenon of relapse is part of the definition of addiction and understanding its neurobiological basis has been the focus of recent investigation. Two major precipitating factors for relapse have been identified as craving and stress. These risk factors are further exacerbated by prolonged withdrawal symptoms, comorbidity of other psychiatric disorders, socioeconomic status, and perceived drug availability.29 Understanding the long-term brain changes that serve to maintain craving and promote relapse and resumption of chronic drug use, even after years of drug abstinence, is at the forefront of addiction research. For example, signaling factors activated by brain-derived neurotrophic factor (BDNF) may be one type of cellular and molecular neuroadaptation that is associated with craving and relapse.29,30 Differential activation of BDNF-induced signaling is suggested to contribute to the differences between behaviors associated with natural versus drug reward.31 Another area of increasing interest is the involvement of stress on craving and relapse, which has been related to increases in central noradrenergic and corticotrophin releasing factor.32 Thus, there is considerable interest in developing a corticotrophin releasing hormone (CRH) receptor antagonist as a potential treatment agent for drug dependence.

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