Neurobiological mechanisms in addictive and psychiatric disorders

Drug dependence is a psychiatric disorder characterized by compulsive drug use [1] and the appearance of negative affective symptoms when the drug is no longer self-administered [2]. The positive reinforcing effects of drugs of abuse are important for establishing self-administration behavior and habit formation [3]. In addition, it has been suggested that self-medication of symptoms associated with psychiatric disorders provides another source of motivation for the initiation of self-administration of drugs of abuse [4]. Habitual drug use induces adaptations in brain systems associated with the acute rewarding effects of drugs such as the mesolimbic dopaminergic system. Cessation of drug self-administration induces changes in monoamine levels in brain reward circuits opposite to those after the administration of drugs of abuse [5-7]. For example, the acute administration of drugs of abuse elevates accumbal dopamine and scrotonin levels, and dopamine and serotonin levels decrease below baseline levels after the termination of drug use [8,9]. Drugs of abuse also induce adaptations in different neuronal substrates than those involved in the acute reinforcing effects of drugs of abuse. There is evidence that cessation of drug use leads to the recruitment of the brain stress systems associated with behavioral and physiological responses to stressors [10,11]. Corticotropin-releasing factor (CRF) is a neuropeptide that induces behavioral and physiological responses resembling those observed during exposure to stress. Withdrawal from drugs of abuse such as cocaine, amphetamine, alcohol, and cannabinolds induces a strong activation of brain CRF systems, and antagonism of brain CRF receptors alleviates the negative affective symptoms associated with drug withdrawal [11]. It has been hypothesized that the negative affective state associated with the cessation of drug use provides a powerful motivational force for the continuation of drug self-administration [2].