The Neuropsychopharmacological Effects of Catha edulis in Mice Offspring Born to Mothers Exposed during Pregnancy and Lactation Worku Bedada and Ephrem Engidawork* Department of Pharmacology, School of Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia Chewing fresh leaves of the khat plant (Catha edulis Forsk) is a deep rooted and widespread habit in East Africa and the Middle East. Although a body of knowledge exists about the adverse effects of khat during pregnancy, data are sparse with regard to the consequences of long-term exposure during pregnancy and lacta- tion. The present work, therefore, was initiated to evaluate the neuropsychopharmacological effects of Catha edulis exposure during pregnancy and lactation in mice at postnatal day 28. To this effect, a lyophilized extract of khat (100 mg/kg, K100 and 200 mg/kg, K200), amphetamine (1 mg/kg, positive control, AMP), and a similar volume of 2% v/v Tween-80 in distilled water (negative control, CONT) were administered daily to pregnant mice from gestational day 6 until weaning. Neuropsychopharmacological measurements were done by making use of a battery of neurobehavioural and cognitive tests. Moreover, toxicity to liver and kidney was also evalu- ated by determining biochemical markers for possible tissue damage. K200 produced significant motor in-coordination and emotional instability; as revealed by impairment in both cliff avoidance (p < 0.01) and forelimb grip strength (p < 0.001), as well as by an increase in stereotyped behaviour such as grooming (p < 0.05), and in the percent of time spent in open arms (p < 0.05). On the other hand, K100 had an effect only on grip strength where a decrement was noted (p < 0.01). A different pattern emerged with AMP whilst it increased duration of sniffing (p < 0.05), neither grip strength nor the time spent in the open arm was affected compared with CONT. Increased latency to reach the goal box and the number of wrong decisions (p < 0.05) in both the learning and the recall tests was observed with K200 and AMP. By contrast, both doses of khat and AMP equally affected performance in the Y-maze (p < 0.05). Alterations in the biochemical indices of liver and kidney function were also noted with AMP and K200. These findings indicate that khat exposure produces dose-related central and peripheral effects during pregnancy and lactation which might pose a serious impediment to the physical and mental development of the offspring. Copyright © 2009 John Wiley & Sons, Ltd. Keywords: khat; pregnancy; lactation; neuropsychopharmacological effects; mice; amphetamine. INTRODUCTION Catha edulis Forsk, popularly known as khat, is an ever- green perennial shrub plant that belongs to the Celestra- ceae family. It is cultivated primarily in East Africa and the Arabian Peninsula, harvested and then chewed to obtain a stimulant effect. Khat contains a number of pharmacologically active compounds (Kite et al., 2003). S-(-)-Cathinone is a major alkaloid component in fresh Catha leaves, but is relatively unstable and rapidly metabolized to norpseudoephedrine (cathine) and nor- ephedrine. S-(-)-cathinone has the same absolute con- figuration as d-(+)-amphetamine (Connor et al., 2002; Banjaw and Schmidt, 2005). Other alkaloids, such as the phenylpentenylamines and cathedulines, could also contribute to the pharmacological effects of khat (Kalix, 1992; Al-Motarreb et al., 2002). Although most of the pharmacological effects of the active principles are suggested to be mediated by the release of biogenic amines through preferential binding to the norepineph- rine receptor/transporter, binding to dopamine and 5-hydroxytryptamine receptors could also partly con- tribute to the observed effect (Rothman et al., 2003). Published reports show that there is a significant increase in the number of Ethiopians chewing khat and this habit has become popular among all segments of the population, including pregnant women (Selassie and Gebre, 1996). Indeed, there is a growing concern about the expanded use of this psychostimulant over the past 10 years and it has been dubbed as an increasingly and commonly used plant of abuse (WHO, 2006). A body of knowledge exists on the significant khat- induced adverse effects during pregnancy. Khat is asso- ciated with cardiovascular complication in pregnant women (Kuczkowski, 2005) and is known to cause reduced average birth weight (Abdul Ghani et al., 1987; Eriksson et al., 1991; Mwenda et al., 2003) as well as retarded fetal growth (Jansson et al., 1988a, 1988b) in animals. It is also reported to be genotoxic in humans (Tariq et al., 1986) and teratogenic in animals (Islam et al., 1994). Moreover, khat dose-dependently pro- duces antiimplantation and abortifacient effects in rodents (Tariq et al., 1987). Cathine, one of the active constituents of khat, is reported to pass into breast milk * Correspondence to: Dr Ephrem Engidawork, Department of Pharma- cology, School of Pharmacy, Addis Ababa University, P.O. Box 1176, Addis Ababa, Ethiopia. E-mail: ephrem@phar.aau.edu.et Received 15 October 2008 Revised 02 May 2009 Copyright © 2009 John Wiley & Sons, Ltd. Accepted 08 May 2009 PHYTOTHERAPY RESEARCH Phytother. Res. 24: 268–276 (2010) Published online 7 July 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/ptr.2925