Choroid Plexus Dysfunction: The Initial Event in the Pathogenesis of Wernicke’s Encephalopathy and Ethanol Intoxication Peter F. Nixon, Lindsay Jordan*, Craig Zimitat , Stephen E. Rose, and Fernando Zelayaà Background: In both acute ethanol intoxication and in thiamin deficient glucose metabolism, previous studies have detected blood-brain barrier (BBB) and ⁄ or blood-CSF-barrier (BCSFB) impairment but were unable to assess their significance in relation to other changes in the brain. Methods: Contrast-enhanced, magnetic resonance imaging (MRI) was used to detect and time any impairment of the BBB or BCSFB in rats given an acute ethanol load or in rats made thia- min deficient to the point of mild ataxia and then given an acute glucose load. Results: The BCSFB at the choroid plexus (CP) was impaired within 10 minutes by either (i) a single i.p. dose of glucose in thiamin-deficiency, an effect that was attenuated by prior MK801 and preceded the published onset of exacerbation of motor incoordination and elevation of brain glutamate derivatives; or (ii) a single i.p. dose of ethanol in thiamin-sufficiency, an effect that was proportional to the blood alcohol concentration and preceded the published onset of signs of intoxication. In contrast to the BCSFB, the BBB remained intact throughout the 90 minutes per- iod of these experiments. Conclusions: In both ethanol intoxication and thiamin-deficient glucose metabolism, BCSFB impairment exposes the CSF and hence the brain extracellular fluid to neuroactive substances from the blood. CP impairment is the earliest detected event in both these animal models; and explains the paraventricular location of WE neuropathology and why WE is associated with, but not dependent on, alcoholism. Key Words: Choroid Plexus, Ethanol Intoxication, Thiamin Deficiency, Wernicke’s Encepha- lopathy, Contrast-Enhanced MRI, Rat. R EPEATED ACUTE ETHANOL exposure causes chronic neurotoxicity and neuropathology, but the chronic consequences are not all explained by our current understanding of the acute effects of ethanol on the brain. Direct application of ethanol to an animal brain does not cause detectable pathology (Phillips et al., 1981), suggesting that some of the effects of ethanol on the brain are mediated indirectly. Two possible sites of ethanol action, with indirect but global consequences for the remainder of the brain, are the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB). Evidence of BCSFB impairment by ethanol has been reported without comment (Phatouros et al., 1999) or interpreted as an alteration of the BBB secondary to effects on neuronal metabolism (Gulati et al., 1985; Lee, 1962). In healthy rats, we have used magnetic resonance imaging (MRI) with contrast medium, gadolinium-diethylenetriamine- pentaacetate (Gd-DTPA), to re-examine whether ethanol affects the BBB and ⁄ or BCSFB and to measure the time to onset of any barrier dysfunction, enabling comparison with the time to onset of intoxication. Since ethanol rapidly permeates all tissues and has many, diverse effects it can be difficult to assign sequence or cause and effect to any set of observations resulting from ethanol exposure. Hence we have also re-examined the BBB and BCSFB in Wernicke’s encephalopathy (WE) without expo- sure to ethanol. WE is a subset of alcohol-related neuro- pathology that also shows evidence of BBB or BCSFB impairment (see below). While the occurrence of WE does not require ethanol, there is debate as to whether brain damage due to ethanol abuse can occur without WE (Butterworth, 1995; Charness, 1993; Joyce, 1994). WE is an acute, well-defined disease syndrome character- ized by ataxia, ophthalmoplegia, apathy and confusion due to bilateral, symmetric brain lesions in paraventricular grey matter, a distinctive but unexplained distribution. Without From the Department of Biochemistry and Molecular Biology (PFN, LJ, CZ) and Centre for Magnetic Resonance (SER, FZ), The University of Queensland, St Lucia, Queensland, Australia. Received for publication January 13, 2008; accepted April 10, 2008. Reprint requests: Peter Nixon, Department of Biochemistry & Molecular Biology, The University of Queensland, St Lucia, Queensland 4072, Australia; Fax: +61-7-3365-4699; E-mail: p.nixon@ uq.edu.au *Present address: Brisbane City Council, Brisbane, Queensland, Australia.  Present address: Medical Education Unit, University of Tasmania, Hobart, Tasmania, Australia. àPresent address: Centre for Neuroimaging Sciences, Institute of Psychiatry, De Crespigny Park, London, UK. Copyright Ó 2008 by the Research Society on Alcoholism. DOI: 10.1111/j.1530-0277.2008.00723.x Alcoholism: Clinical and Experimental Research Vol. 32, No. 8 August 2008 Alcohol Clin Exp Res, Vol 32, No 8, 2008: pp 1513–1523 1513