Lack of Depression-Like Effects of Saccharin Deprivation in Rats: Forced Swim Test, Differential Reinforcement of Low Rates, and Intracranial Self-Stimulation Procedures Irina A. Sukhotina and Andrey A. Malyshkin Pavlov Medical University Athina Markou The Scripps Research Institute Anton Y. Bespalov Pavlov Medical University In humans and laboratory animals, drug withdrawal often is associated with depression-like behaviors. In the present study, rats had unlimited free-choice access to water and a saccharin-containing solution before being subjected to repeated episodes of saccharin deprivation. Saccharin deprivation (a) reduced immobility time in the forced swim test, (b) increased reinforcement rate in rats trained to lever-press under the differential reinforcement of a low-rate (72-s) schedule of food reinforcement, and (c) lowered intracranial self-stimulation thresholds in a discrete-trial current titration procedure. Taken together, these findings suggest that deprivation from a nondrug reinforcer, saccharin, is not associated with depression- like behaviors. In contrast, saccharin-deprived rats demonstrated improved performance in the behavioral paradigms used here. One of the most intriguing features of drug addiction is its recurrence. Successful detoxification and management of the early symptoms of drug withdrawal do not predict the duration of drug abstinence. Therefore, relapse to drug use is one of the most important aspects of addiction that needs to be targeted by both medical and social treatment strategies. There are many experi- mental procedures that are purported to assess drug-seeking be- havior, but to date few of them have been shown to have adequate predictive and construct validity. Commenting on one of the most popular reinstatement models of relapse behavior, Everitt and Wolf (2002) wrote that “although an effective and fruitful model of relapse, extinction of drug self-administration is not a means by which human addicts achieve abstinence, which is more likely to arise through an active decision to abstain or through forced abstinence” (p. 3314). It was recently suggested that experimental procedures based on the deprivation effect (DE), which do not involve an extinction phase, may be used for modeling relapse behavior and drug crav- ing (Spanagel & Holter, 1999, 2000). The DE phenomenon was originally described in alcohol-drinking rats as an increase in the amount of free-choice consumption of alcohol after a period of forced abstinence (e.g., Hyytia & Sinclair, 1991; Holter et al., 1998; Sinclair & Li, 1989; Sinclair & Senter, 1968; Spanagel & Holter, 1999). The DE has been observed in both animals and humans with several drugs of abuse, as well as nondrug reinforcers such as saccharin (e.g., Burish, Maisto, Cooper, & Sobell, 1981; Heyne & Wolffgramm, 1998; Neznanova, Zvartau, & Bespalov, 2002; Sinclair & Li, 1989; Wolffgramm, Galli, Thimm, & Heyne, 2000; Wolffgramm & Heyne, 1995). Nevertheless, it is not known whether the DE is a general phenomenon attributable to certain behavioral contingencies or to reinforcer-specific mechanisms (e.g., drug-specific). Both animals and humans are likely to experience aversive affective states that arise from the discontinuation of repeated administration of various abused drugs, including psychostimu- lants, opiates, and nicotine. Human drug abusers report dysphoric symptoms that include depression and psychomotor retardation associated with drug withdrawal (e.g., Gawin & Kleber, 1986). In laboratory animals, the decreased hedonic capacity is reflected in elevations of brain reward thresholds (i.e., decreased reward), as shown by means of the electrical brain stimulation reward proce- dure (Kokkinidis, Zacharko, & Anisman, 1986; Markou & Koob, 1991; Wise & Munn, 1995). Evidence also has indicated reduced motivation to obtain natural reinforcers (e.g., sucrose solution or access to a sexually receptive conspecific; Barr, Fiorino, & Phil- lips, 1999; Barr & Phillips, 1999), as well as reduced spontaneous Irina A. Sukhotina, Andrey A. Malyshkin, and Anton Y. Bespalov, Laboratory of Behavioral Pharmacology, Institute of Pharmacology, Pav- lov Medical University, St. Petersburg, Russia; Athina Markou, Depart- ment of Neuropharmacology, The Scripps Research Institute, La Jolla, California. This study and preparation of the manuscript were supported in part by the National Institutes of Health Fogarty International Research Collabo- ration Award R03TW00714 to Anton Y. Bespalov and National Institute of Mental Health Grant MH 62527 to Athina Markou. We would like to thank Ivan Medvedev for help with surgical techniques and Michael Arends for editorial assistance. This is Publication 14349-NP from The Scripps Re- search Institute. Correspondence concerning this article should be addressed to Anton Y. Bespalov, Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy Street, St. Petersburg 197089, Russia. E-mail: abespalov@ spmu.rssi.ru Behavioral Neuroscience Copyright 2003 by the American Psychological Association, Inc. 2003, Vol. 117, No. 5, 970 –977 0735-7044/03/$12.00 DOI: 10.1037/0735-7044.117.5.970 970 This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.