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As drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of<jats:styled-content style=\"fixed-case\">PRZ<\/jats:styled-content>and<jats:styled-content style=\"fixed-case\">NTX<\/jats:styled-content>administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence, and repeated withdrawals closely resembling human alcoholism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Male P rats became alcohol\u2010dependent during 1\u00a0year of ad\u00a0libitum 24\u00a0h\/d access to food, water, and 20% alcohol with repetitive temporary alcohol withdrawals. Four sequential studies then addressed effects of oral<jats:styled-content style=\"fixed-case\">PRZ<\/jats:styled-content>(2\u00a0mg\/kg) and<jats:styled-content style=\"fixed-case\">NTX<\/jats:styled-content>(10\u00a0mg\/kg), alone or together, on alcohol drinking during: (i) daily alcohol access with daily drug treatment, (ii) intermittent alcohol access with daily drug treatment, (iii) intermittent alcohol access with occasional drug treatment, and (iv) postdeprivation reinstatement of alcohol access.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The combination of<jats:styled-content style=\"fixed-case\">PRZ<\/jats:styled-content>\u00a0+\u00a0<jats:styled-content style=\"fixed-case\">NTX<\/jats:styled-content>consistently suppressed alcohol drinking during daily or intermittent alcohol access conditions and when drug treatment was either daily or occasional.<jats:styled-content style=\"fixed-case\">PRZ<\/jats:styled-content>\u00a0+\u00a0<jats:styled-content style=\"fixed-case\">NTX<\/jats:styled-content>was consistently more effective than either drug alone. The reduction in alcohol drinking was not due to sedation, motor effects, or malaise.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Both daily and \u201cas\u2010needed\u201d treatment with<jats:styled-content style=\"fixed-case\">PRZ<\/jats:styled-content>\u00a0+\u00a0<jats:styled-content style=\"fixed-case\">NTX<\/jats:styled-content>are highly effective in suppressing daily, intermittent, and postdeprivation alcohol drinking in male P rats with a protracted history of alcohol dependence and repeated withdrawals. This drug combination may be especially effective for treating individuals with long histories of heavy alcohol abuse, dependence, and repeated relapse, as commonly encountered in clinical practice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.12828","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T06:21:22Z","timestamp":1439274082000},"page":"1832-1841","source":"Crossref","is-referenced-by-count":19,"title":["Prazosin\u00a0+\u00a0Naltrexone Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone in P Rats with a Protracted History of Extensive Voluntary Alcohol Drinking, Dependence, and Multiple Withdrawals"],"prefix":"10.1111","volume":"39","author":[{"given":"Dennis D.","family":"Rasmussen","sequence":"first","affiliation":[{"name":"VISN 20 Mental Illness Research, Education and Clinical Center Seattle Washington"},{"name":"VA Puget Sound Health Care System Seattle Washington"},{"name":"Department of Psychiatry and Behavioral Sciences University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie L.","family":"Kincaid","sequence":"additional","affiliation":[{"name":"VA Puget Sound Health Care System Seattle Washington"},{"name":"Department of Psychiatry and Behavioral Sciences University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice C.","family":"Froehlich","sequence":"additional","affiliation":[{"name":"Department of Medicine Indiana University School of Medicine Indianapolis Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,8,11]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"65","article-title":"Noradrenergic mediation of the positive reinforcing properties of ethanol. 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