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BNST: bed nucleus of the stria terminalis; CRF: corticotropin releasing factor; VTA: ventral tegmental area Recommended journal section: Neuropharmacology This article has not been copyedited and formatted. The final version may differ from this version. ABSTRACT Stress can trigger relapse of drug use in recovering cocaine addicts and reinstatement in rodent models through mechanisms that appear to involve norepinephrine release and beta adrenergic receptor activation. The present study examined the role of beta adrenergic receptor subtypes in the stressor-induced reinstatement of extinguished cocaine-induced (15 mg/kg, ip) conditioned place preference in mice. Forced swim (6 min at 22ºC) stress or activation of central noradrenergic neurotransmission by administration the selective alpha-2 adrenergic receptor antagonist, BRL-44,408 (10 mg/kg, ip) induced reinstatement in wild-type but not beta adrenergic receptor-deficient Adrb1/Adrb2 double-knockout mice. By contrast, cocaine administration (15 mg/kg, ip) resulted in reinstatement in both wild-type and beta adrenergic receptor knockout mice. Stress-induced reinstatement likely involved beta-2 adrenergic receptors. The beta-2 adrenergic receptor antagonist ICI-118,551 (1 or 2 mg/kg, ip) blocked reinstatement by forced swim or BRL-44,408, while administration of the non-selective beta adrenergic receptor agonist, isoproterenol (2 or 4 mg/kg, ip), or the beta-2 adrenergic receptor-selective agonist, clenbuterol (2 or 4 mg/kg, ip), induced reinstatement. Forced swim, but not BRL-44,408,-induced reinstatement was also blocked by a high (20 mg/kg) but not low (10 mg/kg) dose of the beta-1 adrenergic receptor antagonist betaxolol and isoproterenol-induced reinstatement was blocked by pretreatment with either ICI-118,551 or betaxolol, suggesting a potential cooperative role for beta-1 and beta-2 adrenergic receptors in stress-induced reinstatement. Overall, these findings suggest that targeting beta adrenergic receptors may represent a promising pharmacotherapeutic strategy for preventing drug relapse, particularly in cocaine addicts whose drug use is stress-related.