Prenatal exposure to methylphenidate hydrochloride decreases anxiety and increases exploration in mice Melanie P. McFadyen-Leussis a , Stephen P. Lewis a , Tamara L.Y. Bond a , Normand Carrey b , Richard E. Brown a, * a Department of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J1 b Department of Outpatient Psychiatry, IWK-Grace Hospital, Halifax, Nova Scotia, Canada B3H 4A1 Received 8 July 2003; received in revised form 3 December 2003; accepted 5 December 2003 Abstract The administration of methylphenidate (MPH) to girls and adults has increased in the last decade. Given the similarity of MPH to cocaine and the increasing possibility of embryonic exposure, the gestational effects of this stimulant on development must be considered. We administered MPH (5 mg/kg) or saline to female CD-1 mice at three different periods during pregnancy [embryonic (E) days 8 – 10, 12 – 14, and 16 –18]. MPH-exposed pups were compared with the saline-treated pups for changes in physical, motor, and behavioral development at postnatal day (PND) 3 –11. In adulthood (>60 days of age) these mice were tested in the open field, elevated plus maze, and water maze, and given an acute MPH challenge. We observed limited effects of MPH exposure on early developmental variables. In adulthood, mice exposed to MPH on E8– 10 exhibited a general decrease in anxiety-related behaviors and a concomitant increase in exploratory behavior. Prenatal MPH exposure did not alter water maze performance or the response to an acute MPH challenge. Our data provide an initial overview of the possible effects occurring as a result of prenatal exposure to MPH, and strongly suggest that further studies of the in utero and developmental effects of psychostimulants are needed. D 2004 Elsevier Inc. All rights reserved. Keywords: Anxiety; Behavior; Development; Methylphenidate; Mice; Prenatal; Rodent 1. Introduction Methylphenidate hydrochloride (MPH; Ritalin) is rou- tinely prescribed for the treatment of attention deficit hyper- activity disorder (ADHD; Diller, 1998; Greenhill, 1995, 1998; Kimko et al., 1999). Between 1990 and 1998, there was a 2.8-fold increase in MPH prescriptions for girls (Robison et al., 2002). It is estimated that in up to 70% of ADHD cases, symptoms persist into adulthood (Biederman, 1998). ADHD, although less prevalent in females (Anderson et al., 1987), may actually be more severe in females; as they are more likely to seek treatment (Wender, 1987), they display greater disturbances in cerebral glucose metabolism than males (Ernst et al., 1994), and they exhibit a higher genetic loading for the disorder than males do (Pauls, 1991). For these and other reasons, it has been suggested that ADHD may be more likely to persist beyond adolescence in females (Andersen and Teicher, 2000). In addition, a sevenfold increase in MPH abuse among 10–19 year olds was reported between 1993 and 1999 (Klein-Schwartz and McGrath, 2003). In other words, since MPH is being increasingly prescribed to women of childbearing age, the incidence of prenatal MPH exposure should also be increas- ing. It is therefore imperative that we examine the effects of MPH on the developing fetus. Only one study has investigated the potential effects of intrauterine exposure to MPH in humans. Infants were identified with retrospective measures to assess the occur- rence of maternal MPH or pentazocine abuse during preg- nancy, and were followed for two years. The results suggested that prenatal MPH exposure is associated with premature birth, growth retardation, and signs of neonatal withdrawal, but not with any teratogenic anomaly or severe developmental delay (Debooy et al., 1993). However, the study did not distinguish between the effects of prenatal MPH or pentazocine and did not include sufficient controls. 0091-3057/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2003.12.011 * Corresponding author. Tel.: +1-902-494-3647; fax: +1-902-494- 6585. E-mail address: REBROWN@dal.ca (R.E. Brown). www.elsevier.com/locate/pharmbiochembeh Pharmacology, Biochemistry and Behavior 77 (2004) 491–500