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Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.<\/jats:p>","DOI":"10.1098\/rstb.2008.0094","type":"journal-article","created":{"date-parts":[[2008,7,24]],"date-time":"2008-07-24T21:01:44Z","timestamp":1216933304000},"page":"3113-3123","update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":527,"title":["Neurobiological mechanisms for opponent motivational processes in addiction"],"prefix":"10.1098","volume":"363","author":[{"given":"George F","family":"Koob","sequence":"first","affiliation":[{"name":"Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Le Moal","sequence":"additional","affiliation":[{"name":"Physiopathologie du Comportement, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Institut Fran\u00e7ois Magendie, Universit\u00e9 Victor S\u00e9galen Bordeaux 233076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2008,7,24]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5387.298"},{"key":"e_1_3_2_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0893-133X(99)00133-5"},{"key":"e_1_3_2_4_1","first-page":"495","volume-title":"The rat nervous system","author":"Alheid G.F","year":"1995"},{"key":"e_1_3_2_5_1","unstructured":"American Psychiatric Association Diagnostic and statistical manual of mental disorders. 4th edn. 1994 Washington DC:American Psychiatric Press."},{"key":"e_1_3_2_6_1","doi-asserted-by":"crossref","unstructured":"Aston-Jones G. 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