Toxicology Letters 128 (2002) 107 – 115 Early spatial memory deficit induced by 2,5-hexanedione in the rat R. Carney a , C. Dardis a , W.K. Cullen a , V. Felipo c , R. Anwyl b , M.J. Rowan a, * a Department of Pharmacology and Therapeutics, Zoology Building, Trinity College, Uniersity of Dublin, Dublin 2, Ireland b Department of Physiology, Trinity College, Dublin 2, Ireland c Laboratory of Neurobiology, Instituto de Inestigaciones Citologicas, Fundacion Valenciana de Inestigaciones Biomedicas, Valencia, Spain Dedicated to the late Philip Chambers Abstract 2,5-Hexanedione (2,5-HD), the major common neurotoxic metabolite of n -hexane and methyl n -butyl ketone, causes a delayed neuropathy with associated sensorimotor impairments. The question arises as to whether specific cognitive deficits occur even prior to changes in sensorimotor ability. The present experiments examined the effects of 2,5-HD on spatial navigation of rats in a water maze at levels/times that did not affect spontaneous exploratory motor activity in an open field holeboard apparatus. Exposure to 1% 2,5-HD in the drinking water for 2 weeks did not significantly affect escape learning, as measured by latency to find a hidden platform. However, 2,5-HD treated animals were impaired in the use of a spatial strategy during a recall test. A similar impairment in spatial memory was observed after i.p. injection of 500 mg/kg/day 2,5-HD for 4 days, in the absence of significant changes in sensorimotor ability or weight loss. Thus 2,5-HD may mediate some of the cognitive effects of hexacarbons and these changes can occur prior to the development of motor symptoms. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 2,5-Hexanedione; Spatial navigation; Motor activity; n -Hexane metabolite; Cognition; Memory www.elsevier.com/locate/toxlet 1. Introduction Occupational and recreational exposure to hex- acarbons is characterised by clinical symptoms of sensory dysfunction, muscular weakness of the limb extremities and ataxia that are associated with the delayed development of a toxic central – peripheral distal axonopathy (Spencer et al., 1980; Couri and Milks, 1982; LoPachin, 2000). The delayed distal axonopathy that is caused by sub- chronic exposure to the hexacarbons, n -hexane and methyl n -butyl ketone is largely attributed to Abbreiations: 2,5-HD, 2,5-hexanedione. * Corresponding author. Tel.: +353-1-608-1567; fax: + 353-1-671-3507. E-mail address: mrowan@tcd.ie (M.J. Rowan). 0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0378-4274(01)00538-0