Neurobehavioral effects of tetramisole in mice F.K. Mohammad * , G.A.-M. Faris, M.S.H. Rhayma, K. Ahmed Department of Physiology, College of Veterinary Medicine, University of Mosul, P.O. Box 11136, Mosul, Iraq Received 23 May 2005; accepted 7 August 2005 Available online 12 September 2005 Abstract Acute toxicity and neurobehavioral effects of the veterinary anthelmintic tetramisole were examined in male albino mice. The 24-h median lethal doses of tetramisole were determined by the up-and-down method in mice after oral, subcutaneous and intraperitoneal administrations, and they were 110, 57 and 34 mg/kg, respectively. The intoxicated mice manifested nervousness, crouching, piloerection and tremor. Subcutaneous injection of tetramisole at 0.5 and 1 mg/kg did not significantly affect general locomotor activity of the mice in 5-min open-field activity test or negative geotaxis performance and landing foot splay. However, the 1 mg/kg dose of tetramisole significantly increased the stereotyped behavior (grooming, sniffing, biting and licking and head bobbing) of the mice when compared to the control group. Daily treatment of mice with tetramisole at 0.5 and 1 mg/kg for six consecutive days did not significantly affect their general locomotor activity in the open-field activity test. Both doses of tetramisole significantly increased stereotyped behavior of the mice on days 3, 5 and 8 in comparison with respective control values. Repeated tetramisole treatments (0.5 and 1 mg/kg) also significantly decreased the time needed to complete the negative geotaxis task and reduced landing foot splay. All tetramisole-treated mice showed crouching behavior and were nervous and difficult to handle. The results suggest nervous involvement in the acute toxicity of tetramisole. Stereotyped behavior and changes in the negative geotaxis and landing foot splay are reported for the first time in mice treated with tetramisole. # 2005 Elsevier Inc. All rights reserved. Keywords: Tetramisole; Behavior; Mice; LD50; Stereotyped behavior; Open-field activity 1. Introduction DL-Tetramisole and its L-isomer levamisole are broad spectrum antinematodal drugs commonly used in veterinary practice (Marriner, 1986; Khan et al., 1999; Plumb, 2002). Levamisole is also known for its immunostimulant effects used in a variety of disease conditions in man and animals (Dalvi, 1990). The acute toxicity and pharmacological effects of tetramisole has been extensively studied previously without concerns to the potential neurobehavioral effects of the drug (Eyre, 1970; Van Nueten, 1972; Donev et al., 1982; Fayez et al., 1987). The suggested mode of action of tetramisole is nicotinic–cholinergic stimulation of the autonomic ganglia, skeletal muscles and the central nervous system (Eyre, 1970; Hsu, 1980, 1981; Dalvi, 1990). The therapeutic anthelmintic dose of tetramisole in ruminants is usually 15 mg/kg body weight given orally or subcutaneously (Marriner, 1986; Dalvi, 1990). Doses of tetramisole more than twice the therapeutic dose may cause salivation and muscular tremors in animals (Eyre, 1970; Dalvi, 1990). Domestic animals are more susceptible to tetramisole-induced toxicosis than rodents (Dalvi, 1990). Further, tetramisole was reported to cause catecholamine release from the adrenal medulla (Eyre, 1970). Tetramisole may also affect the central nervous system functions. The reported toxic effects of tetramisole in sheep and calves are nervousness characterized by locomotor excitement, tremor, salivation, increased respiration and pulse rate, frequent urination and defecation (Donev et al., 1982; Dalvi, 1990). However, these studies were mainly descriptive in nature and the potential neurotoxic effects of tetramisole have not been quantitated objectively. Dexamisole, the D-isomer of tetramisole, was reported to resemble tricylic antidepressants by antagonizing the reserpine-induced hypothermia and reduced the duration of immobility of rats in the despair test (Przegalinski et al., 1980). The studies cited above suggest central involvement of tetramisole in affecting the locomotor behaviors. However, no attempt has been made to quantitate behavioral effects of tetramisole, especially locomotor activ- ities and stereotyped behavior in rodents (Przegalinski et al., 1980; Donev et al., 1982). The reported acute oral, subcutaneous (s.c.) and intravenous (i.v.) median lethal doses NeuroToxicology 27 (2006) 153–157 * Corresponding author. Tel.: +964 770 160 5334 E-mail address: fouadmohammad@yahoo.com (F.K. Mohammad). 0161-813X/$ – see front matter # 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2005.08.003