{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:35:27Z","timestamp":1760243727862,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2012,9,20]],"date-time":"2012-09-20T00:00:00Z","timestamp":1348099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats. Here, we first compared the effects of several protocols for the induction of opiate dependence (morphine pellets, repeated morphine or heroin injections) on the subsequent response to heroin challenges (0.25 mg\/kg) at different time points during abstinence (3, 6, 9 and 18 weeks). In a second set of experiments, rats were exposed to increasing doses of heroin and subsequently monitored for general circadian activity up to 20 weeks of abstinence. Results show that heroin injections rather than the other methods of opiate administration have long-term consequences on rats\u2019 sensitivity to heroin with its psychostimulant effects persisting up to 18 weeks of abstinence. Moreover, intermittent episodes of heroin dependence rather than a single exposure produce enduring alteration of the basal circadian activity both upon heroin cessation and protracted abstinence. Altogether, these findings suggest that the induction of heroin dependence through intermittent increasing heroin injections is the optimal method to model long-term behavioral alterations during protracted abstinence in rats. This animal model would be useful in further characterizing long-lasting changes in post-dependent subjects to help understand the prolonged vulnerability to relapse.<\/jats:p>","DOI":"10.3390\/brainsci2030421","type":"journal-article","created":{"date-parts":[[2012,9,20]],"date-time":"2012-09-20T11:11:53Z","timestamp":1348139513000},"page":"421-433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Repeated Episodes of Heroin Cause Enduring Alterations of Circadian Activity in Protracted Abstinence"],"prefix":"10.3390","volume":"2","author":[{"given":"Luis","family":"Stinus","sequence":"first","affiliation":[{"name":"University of Bordeaux, INCIA, F-33076 Bordeaux, France"},{"name":"National Center of Scientific Research (CNRS), UMR 5287, INCIA, F-33076 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martine","family":"Cador","sequence":"additional","affiliation":[{"name":"University of Bordeaux, INCIA, F-33076 Bordeaux, France"},{"name":"National Center of Scientific Research (CNRS), UMR 5287, INCIA, F-33076 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Caille","sequence":"additional","affiliation":[{"name":"University of Bordeaux, INCIA, F-33076 Bordeaux, France"},{"name":"National Center of Scientific Research (CNRS), UMR 5287, INCIA, F-33076 Bordeaux, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1126\/science.1099020","article-title":"Evidence for addiction-like behavior in the rat","volume":"305","author":"Belin","year":"2004","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0893-133X(00)00195-0","article-title":"Drug addiction, dysregulation of reward, and allostasis","volume":"24","author":"Koob","year":"2001","journal-title":"Neuropsychopharmacology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1126\/science.1098975","article-title":"Drug seeking becomes compulsive after prolonged cocaine self-administration","volume":"305","author":"Vanderschuren","year":"2004","journal-title":"Science"},{"unstructured":"(1992). International Statistical Classification of Diseases and Related Problems.","key":"ref_4"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1176\/appi.ajp.162.8.1423","article-title":"Anticraving medications for relapse prevention: A possible new class of psychoactive medications","volume":"162","year":"2005","journal-title":"Am. J. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00213-002-1224-x","article-title":"The reinstatement model of drug relapse: History, methodology and major findings","volume":"168","author":"Shaham","year":"2003","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1192\/bjp.154.3.348","article-title":"Lapse, relapse and survival among opiate addicts after treatment. A prospective follow-up study","volume":"154","author":"Gossop","year":"1989","journal-title":"Br. J. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.biopsych.2008.11.025","article-title":"Circadian alteration in neurobiology during 30 days of abstinence in heroin users","volume":"65","author":"Li","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0022-3956(69)90007-7","article-title":"Physiological parameters of morphine dependence in man\u2014Tolerance, early abstinence, protracted abstinence","volume":"7","author":"Martin","year":"1969","journal-title":"J. Psychiatr. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0022-3565(25)28907-8","article-title":"Decline in the mean integrated electroencephalogram voltage during morphine abstinence in the rat","volume":"177","author":"Khazan","year":"1971","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/S0091-3057(02)00810-9","article-title":"Dorsal and median raphe serotonergic system lesion does not alter the opiate withdrawal syndrome","volume":"72","author":"Espejo","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0022-3565(24)34977-8","article-title":"Total neurochemical lesion of noradrenergic neurons of the locus coeruleus does not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does it influence ability of clonidine to reverse opiate withdrawal","volume":"290","author":"Espejo","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000026622","article-title":"Sleep impairments in the rats implanted with morphine pellets","volume":"40","author":"Robert","year":"1999","journal-title":"Neuropsychobiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0149-7634(89)80022-3","article-title":"Opponent process theory of motivation: Neurobiological evidence from studies of opiate dependence","volume":"13","author":"Koob","year":"1989","journal-title":"Neurosci. Biobehav. Rev."},{"unstructured":"O\u2019Brien, C.P., and Jaffe, J.H. (1992). Addictive States, Raven Press.","key":"ref_15"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1037\/h0036128","article-title":"An opponent-process theory of motivation: Temporal dynamics of effect","volume":"81","author":"Solomon","year":"1974","journal-title":"Psychol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/BF00401386","article-title":"Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and \u201cRelapse\u201din morphine-addicted rats","volume":"10","author":"Wikler","year":"1967","journal-title":"Psychopharmacologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5894","DOI":"10.1523\/JNEUROSCI.0740-06.2006","article-title":"Conditioned withdrawal drives heroin consumption and decreases reward sensitivity","volume":"26","author":"Kenny","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/sj.npp.1300037","article-title":"Enhanced morphine preference following prolonged abstinence: Association with increased Fos expression in the extended amygdala","volume":"28","author":"Harris","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s002130100748","article-title":"Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats","volume":"156","author":"Shalev","year":"2001","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s002130050273","article-title":"Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen","volume":"131","author":"Vanderschuren","year":"1997","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1523\/JNEUROSCI.16-05-01957.1996","article-title":"Relapse to heroin-seeking in rats under opioid maintenance: The effect of stress, heroin priming and withdrawal","volume":"16","author":"Shaham","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1037\/0735-7044.120.1.103","article-title":"Motivational control of heroin seeking by conditioned stimuli associated with withdrawal and heroin taking by rats","volume":"120","author":"Hellemans","year":"2006","journal-title":"Behav. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s00213-005-2207-5","article-title":"Role of withdrawal in reinstatement of morphine-conditioned place preference","volume":"181","author":"Lu","year":"2005","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neuropharm.2004.06.020","article-title":"Brain substrates for increased drug seeking during protracted withdrawal","volume":"47","author":"Harris","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s002139900358","article-title":"Opiate withdrawal induced place aversion lasts for up to 16 weeks","volume":"149","author":"Stinus","year":"2000","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s002130050162","article-title":"Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: Potentiation with repeated morphine treatment","volume":"129","author":"Schulteis","year":"1997","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF02245446","article-title":"Opioid physical dependence development: Effects of single versus repeated pretreatments and of subjects opioid exposure history","volume":"114","author":"Azorlosa","year":"1994","journal-title":"Psychopharmacology (Berl.)"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1038\/npp.2012.67","article-title":"Robust escalation of nicotine intake with extended access to nicotine self-administration and intermittent periods of abstinence","volume":"37","author":"Cohen","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/S0022-3565(24)39271-7","article-title":"Changes in catecholaminergic pathways innervating paraventricular nucleus and pituitary-adrenal axis response during morphine dependence: Implication of alpha(1)- and alpha(2)-adrenoceptors","volume":"293","author":"Laorden","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/S0022-3565(24)37420-8","article-title":"Alterations in corticotropin-releasing factor and vasopressin content in rat brain during morphine withdrawal: Correlation with hypothalamic noradrenergic activity and pituitary-adrenal response","volume":"285","author":"Milanes","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1046\/j.1365-2826.2001.00714.x","article-title":"Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid negative-feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: Possible mechanisms involved in facilitated and attenuated stress responses","volume":"13","author":"Houshyar","year":"2001","journal-title":"J. Neuroendocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1038\/sj.npp.1300271","article-title":"Intermittent morphine administration induces dependence and is a chronic stressor in rats","volume":"28","author":"Houshyar","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0024-3205(78)90342-9","article-title":"Self-administration of heroin, acetylmethadol, morphine, and methadone in rhesus monkeys","volume":"22","author":"Harrigan","year":"1978","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/S0022-3565(25)11333-5","article-title":"Heroin, 6-acetylmorphine and morphine effects on threshold for rewarding and aversive brain stimulation","volume":"260","author":"Hubner","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S0022-3565(25)31172-9","article-title":"Intravenous self-administration of drugs in rats","volume":"204","author":"Slangen","year":"1978","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/35079077","article-title":"Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons","volume":"411","author":"Ungless","year":"2001","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nn1219","article-title":"Stimuli associated with a single cocaine experience elicit long-lasting cocaine-seeking","volume":"7","author":"Ciccocioppo","year":"2004","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1001\/jama.284.13.1689","article-title":"Drug dependence, a chronic medical illness: Implications for treatment, insurance, and outcomes evaluation","volume":"284","author":"McLellan","year":"2000","journal-title":"JAMA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1038\/sj.npp.1301008","article-title":"Unlimited access to heroin self-administration: Independent motivational markers of opiate dependence","volume":"31","author":"Chen","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.pbb.2008.08.023","article-title":"Diurnal variation in cue-induced responses among protracted abstinent heroin users","volume":"91","author":"Ren","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.brainres.2009.11.054","article-title":"The role of hypocretin in driving arousal and goal-oriented behaviors","volume":"1314","author":"Boutrel","year":"2010","journal-title":"Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/B978-0-444-59489-1.00007-0","article-title":"Multiple roles for orexin\/hypocretin in addiction","volume":"198","author":"Mahler","year":"2012","journal-title":"Prog. Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1001\/archpsyc.1986.01800020013003","article-title":"Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations","volume":"43","author":"Gawin","year":"1986","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/35084134","article-title":"Neuroadaptation: Incubation of cocaine craving after withdrawal","volume":"412","author":"Grimm","year":"2001","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0014-2999(94)90755-2","article-title":"Prolonged tolerance, dependence and abstinence following subcutaneous morphine pellet implantation in the rat","volume":"253","author":"Gold","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1196\/annals.1441.020","article-title":"Drug addiction and the memory systems of the brain","volume":"1141","author":"Robbins","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/2\/3\/421\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:52:29Z","timestamp":1760219549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/2\/3\/421"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,20]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2012,9]]}},"alternative-id":["brainsci2030421"],"URL":"https:\/\/doi.org\/10.3390\/brainsci2030421","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2012,9,20]]}}}