Antidepressant-like effects of 3,4-methylenedioxy- methamphetamine in an animal model of depression Irina Majumder a,b , Jason M. White a and Rodney J. Irvine b Increased synaptic serotonin (5-hydroxytryptamine) levels may underlie antidepressant-like effects of 3,4- methylenedioxymethamphetamine (MDMA) that may be more prominent in subjects with mood disturbance. The Flinders Sensitive Line (FSL) strain is an important animal model of depression. These rats are more immobile in the forced swimming test (FST), and their immobility is reversed by known antidepressants after prolonged administration. The objective of this study was to determine whether MDMA administration has a dose- dependent antidepressant-like effect in this animal model of depression. The effects of MDMA at 5 and 10 mg/kg following single and repeated administration were assessed in FSL rats using the FST. Sprague-Dawley rats were used as a control. During both FST sessions, saline-treated FSL rats were significantly more immobile than Sprague-Dawley rats (P < 0.001). Acute MDMA administration had a dose-dependent antidepressant-like effect in FSL rats, which was most evident after 10 mg/kg. This effect was diminished after repeated administration. Methamphetamine 2 mg/kg, which was used as a positive control for locomotor activity induction, did not affect the depressive-like state in FSL rats. There were no changes in the cortical levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid after treatments. It is concluded that MDMA exhibited an antidepressant- like effect in FSL rats, which was most evident following acute administration. Behavioural Pharmacology 22:758–765  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2011, 22:758–765 Keywords: depression, depression model, depressive-like state, Flinders Sensitive Line, 3,4-methylenedioxymethamphetamine, predisposition to depression, rat a School of Pharmacy and Medical Sciences, University of South Australia and b School of Medical Sciences, Discipline of Pharmacology, University of Adelaide, Adelaide, South Australia, Australia Correspondence Irina Majumder, MD, PhD, Level 4, School of Pharmacy and Medical Sciences, Playford Building, City East Campus, University of South Australia, North Terrace, Adelaide, South Australia, 5000, Australia E-mail: irina.majumder@unisa.edu.au Received 7 December 2010 Accepted as revised 15 July 2011 Introduction 3,4-methylenedioxymethamphetamine (MDMA) is an amphetamine derivative, and is typically the active com- ponent of ecstasy, a popular illicit drug. The pharmaco- logical action of MDMA leads to a rapid and substantial increase in serotonin [5-hydroxytryptamine (5-HT)] levels in the intrasynaptic space (White et al., 1996). Similarities in some of the mechanisms of action between MDMA and the main classes of antidepressants, such as mono- amineoxidase inhibitors (Leonardi and Azmitia, 1994; Bortolato et al., 2008) and selective serotonin reuptake inhibitors (SSRIs) (Vaswani et al., 2003; Han and Gu, 2006), indicate that MDMA may have antidepressant-like effects. Such activity may be relevant to the so-called ‘self-medication’ hypothesis of drug use. According to this hypothesis, the use of a particular drug by individuals may be explained by their desire to control their emotional state in order to be able to cope with the negative aspects of a pre-existing psychiatric condition (Khantzian, 1977). Thus, any antidepressant-like effects of MDMA may be more appealing to individuals with pre-existing mood disturbance (Croft et al., 2001). This in turn may put them at risk of consuming the drug more frequently and subsequently expose them to a range of long-term negative effects of MDMA. A few studies have addressed the question of predisposition to depression and MDMA use (Lieb et al., 2002; Huizink et al., 2006; Alati et al., 2008), but to date no preclinical study has explored the antidepressant-like potential of MDMA. The accumula- tion of mechanistic data on the antidepressant-like activity of MDMA may allow a better understanding of the patterns and sequelae of drug use. The Flinders Sensitive Line (FSL) rat strain is an important animal model of depression with a considerable degree of face, construct and predictive validity (Over- street, 1993). In comparison with control Sprague-Dawley (SD) rats, these animals show reduced body weight, psy- chomotor retardation, altered sleep patterns, dysfunction in monoaminergic neurotransmitter systems and respon- siveness to antidepressants (Shiromani et al., 1988; Over- street, 1993; Bushnell et al., 1995; Zangen et al., 1997, 1999; Schwartz et al., 2003; Overstreet and Griebel, 2004; Overstreet et al., 2004a, 2004b). The depressive- like state of FSL rats can be reproduced as increased immobility in the forced swimming test (FST) compared with their genetic controls, Flinders Resistant Line (FRL) rats and SD rats (Pucilowski and Overstreet, 1993; Overstreet and Griebel, 2004; Overstreet et al., 2004a, 2004b). Some characteristics of the FSL model are consistent with the current hypotheses on the develop- ment of depressive symptoms (Overstreet et al., 758 Original article 0955-8810  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32834d0f05