~ Pergamon 0306-4522(95)00536-6 Neuroscience Vol. 72, No. 4, pp. 1141-1153, 1996 Elsevier Science Ltd Copyright © 1996 IBRO Printed in Great Britain. All rights reserved 0306-4522/96 $15.00 + 0.00 REDUCTION OF REGIONAL BRAIN GLUCOSE METABOLISM FOLLOWING DIFFERENT DURATIONS OF CHRONIC ETHANOL CONSUMPTION IN MICE: A SELECTIVE EFFECT ON DIENCEPHALIC STRUCTURES B. BONTEMPI, D. BERACOCHEA, R. JAFFARD and C. DESTRADE* Laboratoire de Neurosciences Comportementales et Cognitives, URACNRS 339, Universit6 de Bordeaux 1, Avenue des Facult6s, 33405 Talence Cedex, France Abstract The effects of chronic alcohol consumption on regional brain glucose metabolism were examined in Balb/c mice using the [~4C]2-deoxyglucose autoradiographic technique. Animals were given a solution of 12% v/v ethanol as their only source of fluid for either 6, 12 or 18 months and compared to control groups receiving either an isocaloric solution of saccharose or tap water. Alterations of cerebral brain glucose metabolism were assessed in mice who were returned to a non-alcoholic diet and allowed to freely explore a T-maze. The results showed that chronic ethanol consumption induced reductions of regional metabolic activity which were functions both of the duration of alcohol treatment and of the structure studied. Whereas a six month period of alcoholization did not induce any significant effects on metabolic activity, 12 months of treatment were necessary to induce the first observable and significant reductions in [~4C]2-deoxyglucose labelling. These effects were mainly limited to diencephalic structures such as the lateral mammillary nuclei and the anterodorsal thalamic nuclei. The cerebellum was also affected, but to a lesser degree. After 18 months of alcoholization, a generalized spread of the metabolic reduction to the entire mammillary complex (lateral, medial and posterior nuclei) and to the thalamic nuclei was observed. This same duration of treatment was necessary to induce the first detectable decrease of metabolic activity in the hippocampus. In agreement with data from human neuropathology, these findings confirm the particular vulnerability of diencephalic structures to ethanol and suggest that damage limited to diencephalic regions rather than to hippocampal or cortical areas could be primarily responsible for the memory disorders observed in Korsakoff's syndrome. Key words: alcohol, 2-deoxyglucose, mammillary bodies, thalamus, Korsakoff's syndrome, brain imaging. Clinical studies in humans aimed at examining the deleterious effects of chronic and excessive alcohol consumption on the CNS have revealed neuropatho- logical a l t e r a t i o n s , 112t'%'58"77"78"82 which are often associated with memory i m p a i r m e n t s . H'~2'4°'48"5° Amongst the neuronal damage related to the alco- holic Korsakoff's syndrome, lesions of the mammil- lary bodies of the hypothalamus have been the most frequently observed even though debate is still open about the necessity of combined damage to both mammillary bodies and thalamic nuclei to induce memory i m p a i r m e n t s . 9A°'4°'43457°'79 A recent exper- iment using magnetic resonance imaging was able to distinguish between diencephalic and medial tem- poral lobe amnesia in Korsakoff and non-Korsakoff amnesic patients. 7~ In this study, the Korsakoff subjects exhibited a reduction of the size of the mammillary nuclei whereas the hippocampal for- mation was of normal size, an opposite pattern of *To whom correspondence should be addressed. Abhrer&tion: 2-DG, [~4C]2-deoxyglucose. alterations being observed in the second group of patients with medial temporal lobe amnesia. However, the brain damage specifically provoked by ethanol in humans is difficult to evaluate precisely since several interfering factors such as malnutrition (especially thiamine deficiency), 7'3°'39aging or heredity frequently interact with alcoholism. In order to cir- cumvent these complications, several authors have studied the effects of either acute or chronic ethanol consumption on laboratory animals receiving care- fully controlled diets. 1'423'42'56'73'82 U s i n g such protocols, multiple effects of ethanol have been demonstrated which result in brain damage and morphological alterations, such as altered neuronal morphology or cell loss in several brain a r e a s , 5"3~'33"34'52"75 and also in learning and memory i m p a i r m e n t s . 3"4"6"26"s~ Concomitant modifications in whole-brain blood flow and oxygen consumption, 22 changes in electrophysiological a c t i v i t f -28"29 a n d neurotransmitter f u n c t i o n 6'16'25 have also been observed. Although certain of these studies have established a differential vulnerability of a number of specific brain areas as functions of both the duration 1141