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Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha\u20102 adrenergic receptor agonist that decreases NE cell firing and release, on stress\u2010induced reinstatement of heroin seeking. Rats were trained to self\u2010administer heroin (0.1\u2003mg\/kg per infusion, IV, three 3\u2010h sessions per day) for 9\u201310\u2003days. Extinction sessions were given for up to 11\u2003days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30\u2003min, 0.5\u2003mA). During testing, clonidine was injected systemically (10\u201340\u2003\u03bcg\/kg, i.p.) or directly into the lateral or fourth ventricles (1\u20133\u2003\u03bcg). Clonidine (1\u20132\u2003\u03bcg per site) or its charged analogue, 2\u2010[2,6\u2010diethylphenylamino]\u20102\u2010imidazole (ST\u201091, 0.5\u20131\u2003\u03bcg per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress\u2010induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST\u201091 consistently altered stress\u2010induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress\u2010induced reinstatement. 6\u2010Hydroxydopamine (6\u2010OHDA) lesions performed after training for heroin self\u2010administration had no effect on extinction of heroin\u2010taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress\u2010induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress\u2010induced reinstatement of heroin seeking.<\/jats:p>","DOI":"10.1046\/j.1460-9568.2000.00899.x","type":"journal-article","created":{"date-parts":[[2003,3,6]],"date-time":"2003-03-06T14:26:37Z","timestamp":1046960797000},"page":"292-302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":170,"title":["Clonidine blocks stress\u2010induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons"],"prefix":"10.1111","volume":"12","author":[{"given":"Yavin","family":"Shaham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Highfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Delfs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,10,9]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6278591"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb09284.x"},{"key":"e_1_2_6_4_1","first-page":"183","volume-title":"The Rat Nervous System.","author":"Aston\u2010Jones G.","year":"1995"},{"key":"e_1_2_6_5_1","first-page":"642","article-title":"Discriminative stimuli produced by clonidine. 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