A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration Costanza Burattini 1 *, Andrew J. Mcgeehan 1 , William C. Griffin III 2 , Justin T. Gass 2 , Jennifer R. Kinder 1 , Patricia H. Janak 1 & M. Foster Olive 2 University of California, San Francisco, USA 1 and Medical University of South Carolina, USA 2 ABSTRACT Acamprosate and naltrexone are widely used in the treatment of alcoholism. However, numerous studies in rodents have shown differential effects of these compounds on alcohol consumption and/or relapse-like behavior following acute versus repeated administration. In order to determine if these differential behavioral effects could be attributable to changes in extracellular levels of these compounds, we used in vivo microdialysis to monitor extracellular levels of acamprosate and naltrexone in the rat medial prefrontal cortex following acute and repeated intraperitoneal admin- istration. For acute treatment, animals received a single administration of acamprosate (100 or 300 mg/kg) or naltrexone (1 or 3 mg/kg). For repeated treatment, animals received once daily treatment with saline, acamprosate (300 mg/kg) or naltrexone (3 mg/kg) for 10 days before a subsequent challenge with the compound according to their respective pretreatment group. Dialysate levels of acamprosate and naltrexone were analyzed by liquid chromatography–tandem mass spectrometry and high performance liquid chromatography, respectively. Following acute administration, peak dialysate concentrations of each compound were dose-dependent, observed within 1 hour of administration, and were found to be in the low micromolar range for acamprosate and in the low to mid-nanomolar range for naltrexone. Pretreatment with acamprosate, but not naltrexone, for 10 days resulted in higher dialysate concentrations of the compound relative to saline-pretreated controls. Thus, repeated administration of acamprosate, but not naltrexone, results in augmented extracellular levels of the compound in the brain relative to saline-pretreated controls, which may explain the need for repeated administration of acamprosate in order to observe effects on alcohol consumption and/or relapse. Keywords Acamprosate, extracellular fluid, microdialysis, naltrexone, prefrontal cortex, rat. Correspondence to: M. Foster Olive, Center for Drug and Alcohol Programs, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, PO Box 250861, Charleston, SC 29425, USA. E-mail: olive@musc.edu INTRODUCTION Acamprosate and naltrexone are widely used as pharma- cological agents in the treatment of alcoholism (for recent reviews, see Heilig & Egli 2006; Roozen et al. 2006; Rosenthal 2006; Soyka & Roesner 2006). Naltrexone is a long-acting opioid antagonist with preferential affinity for m and k opioid receptors (Raynor et al. 1994), and primarily reduces alcohol consumption in the context of behavioral therapy. Acamprosate, on the other hand, is effective in helping alcoholic patients maintain abstinence, but its precise pharmacological mech- anism of action has remained elusive for over two decades, although most evidence suggests it modulates glutamatergic neurotransmission (Littleton & Zieglgan- sberger 2003; De Witte et al. 2005; Littleton 2007). Studies with radiolabeled analogues of acamprosate and naltrexone have shown that both drugs penetrate the blood-brain barrier (BBB) in rodents after systemic administration (Misra et al. 1976; Durbin & Belleville 1995; Durbin, Belleville & Chabac 1995; Courtyn et al. 2004). However, these studies measured total brain levels *Current address: Department of Human and General Physiology, University of Bologna, 40127 Bologna, Italy. PRECLINICAL STUDY doi:10.1111/j.1369-1600.2008.00097.x © 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction Biology, 13, 70–79