Neuroscience Letters 439 (2008) 84–88 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Withdrawal-like behavior in planarians is dependent on drug exposure duration Steve Sacavage a , Hiren Patel a , Mike Zielinski a , Jeneane Acker a , Austin G. Phillips a , Robert B. Raffa a,b , Scott M. Rawls a,b,∗ a Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA, USA b Center for Substance Abuse Research, Temple University School of Pharmacy, Philadelphia, PA, USA article info Article history: Received 5 March 2008 Received in revised form 17 April 2008 Accepted 18 April 2008 Keywords: Withdrawal Methamphetamine Planarians Cocaine Caffeine Dependence abstract Planarians display a concentration-related reduction in locomotor activity following their spontaneous withdrawal from opioids, cannabinoids, stimulants and benzodiazepines. This suggests that planarians display a withdrawal-like behavior that can be quantified as a reduction in locomotor activity. Because withdrawal-like behavior in previous studies has been quantified only following the cessation of a 60- min drug exposure, it is unclear whether the withdrawal response varies with drug exposure duration. Therefore, the goal of this study is to determine if the duration of drug exposure (0, 5, 15, 30, 45, 60min and 24 h) to three different drugs – methamphetamine, cocaine and caffeine – affects the magnitude of withdrawal-like behavior (i.e., reduced locomotor activity) in planarians. Experiments revealed that methamphetamine (10 M) produced significant withdrawal-like behavior regardless of the exposure time (P < 0.05). An exposure time of only 5 min resulted in a significant reduction in locomotor activ- ity. The peak effect, although occurring following a 24-h exposure, was only slightly greater than that caused by a 30-min exposure. For cocaine (10 M), a longer exposure time (15min) was required for the manifestation of significant withdrawal-like behavior. The peak cocaine effect was observed following a 24-h exposure. Caffeine (10 M) did not produce significant changes in locomotor activity during with- drawal or alter locomotor activity during acute exposure. The present results suggest that the magnitude of withdrawal-like behavior in planarians is dependent on both the duration and type of drug exposure, and that planarians do not display withdrawal to caffeine. © 2008 Elsevier Ireland Ltd. All rights reserved. Abstinence-induced withdrawal phenomena are behavioral man- ifestations of the physical dependence that develops to drugs of abuse and a common experimental paradigm used to assess and study dependence in mammals. A type of withdrawal phenomenon (hyperresponsiveness to vibration) has also been demonstrated in crickets, and tolerance and behavioral responses, like addiction, have been reported in mollusks and land snails [6,17,18,47]. Our laboratory has previously developed and reported the use of a new metric to identify and quantify an abstinence-induced withdrawal- like behavior in planarians [27]. Planarians are free-living, fresh-water flatworms that are considered to be the most primi- tive extant animals having bilateral symmetrical nerve processes consisting of cephalic ganglia and peripheral nerve cords. Planari- ans provide a useful and convenient model for the study of nervous ∗ Corresponding author at: Department of Pharmaceutical Sciences, Temple Uni- versity School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA. Tel.: +1 215 707 4942; fax: +1 215 707 3678. E-mail address: scott.rawls@temple.edu (S.M. Rawls). system function and drug-induced effects because they uti- lize mammalian-like neurotransmitters; express catecholamines and monoamine-containing neurons; display biochemical changes following exposure to direct- and indirect-acting sympath- omimetics; increase cyclic AMP formation following exposure to dopamine agonists; and respond with characteristic behaviors to selective ligands [1–3,7,8,10,11,20,21,24–25,35,40,41,39,44]. The withdrawal-like behavior in planarians is quantified as a reduc- tion in locomotor activity following the cessation of drug exposure [27]. Planarians display withdrawal-like behavior to a number of addictive drugs, including opioids, cannabinoids, benzodiazepines, cocaine and amphetamines, and the effect is not due to factors such as pH and osmolarity [31,32,34,36,38]. One unresolved question is whether withdrawal-like behavior in planarians is dependent on drug exposure duration. It is docu- mented in mammals that the intensity of a withdrawal syndrome, as well as the specific behaviors which accompany withdrawal, vary with the type of drug administered, duration of drug expo- sure and frequency of drug administration [5,26]. For example, in morphine-dependent rats, a characteristic behavior following the 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.04.086