Chronic Moderate Hyperammonemia Impairs Active and Passive Avoidance Behavior and Conditional Discrimination Learning in Rats M. A. Aguilar,* J. Min ˜arro,* and V. Felipo† *Area de Psicobiologı´a, Facultad de Psicologı´a, Universitat de Valencia. Aptdo. 22109, 46071 Valencia, Spain; and †Instituto de Investigaciones Citolo ´ gicas de la Fundacio ´n Valenciana de Investigaciones Biome ´dicas, Amadeo de Saboya, 4, 46010 Valencia, Spain Received October 26, 1998; accepted October 19, 1999 The cerebral dysfunction associated with hepatic encephalopathy is generally considered to have hyper- ammonemia as one of its main causes. Hyperammone- mia impairs the neuronal glutamate–nitric oxide– cyclic GMP pathway and the induction of NMDA receptor-dependent long-term potentiation in the hip- pocampus. We studied the performance of pre/neona- tally and postnatally exposed rats to hyperammone- mia on active avoidance, passive avoidance, and conditional discrimination tasks. Pre/neonatal hyper- ammonemia slowed learning of active avoidance behav- iors and impaired memory for the passive avoidance task while postnatal hyperammonemia impaired learn- ing on the conditional discrimination task. Hyperam- monemia thus may produce cognitive disturbances that relate to the effects of ammonia on the neuronal glutamate–nitric oxide–cyclic GMP pathway.  2000 Academic Press Key Words: hyperammonemia; active avoidance; pas- sive avoidance; conditional discrimination learning; motor activity; rats. INTRODUCTION Chronic or acute liver diseases frequently lead to hepatic encephalopathy, a complex neuropsychiatric syndrome that covers a wide range of neuropsychiatric disturbances ranging from minimal changes in person- ality or altered sleep patterns to deep coma and death. Hepatic encephalopathy affects mainly the personality, intellectual and motor functions, neuromuscular coordi- nation, and consciousness. There are also subclinical forms of hepatic encephalopathy with subtle intellec- tual function impairment. Subclinical hepatic encepha- lopathy is defined by the presence of abnormalities on formal neuropsychological testing in subjects affected by liver cirrhosis who present normal neurological or mental status examination (33, 38). Although the pathogenesis of hepatic encephalopa- thy is not well understood, ammonia is considered the main cause in the mediation of hepatic encephalopathy (e.g., 7). When the liver fails or when blood is shunted past the liver, ammonia is not adequately detoxified and ammonia levels in blood and tissues increase. A 5- to 10-fold increase in ammonia levels is neurotoxic, leading to alterations in the function of the central nervous system. These effects are especially marked in newborn in- fants. Neonatal hyperammonemia can be due to con- genital deficiencies of any of the urea cycle enzymes and can also appear in critically ill newborns, particu- larly in those who are preterm or suffer asphyxia (4, 5, 8, 39). Affected neonates appear clinically normal at birth; however, within 24–48 h their situation deterio- rates quickly, leading to coma and death. Immediate and aggressive therapy is essential to prevent brain damage and death. Hyperammonemia in the neonatal period is usually associated with significant central nervous system damage and an inverse correlation of the IQ with the duration of hyperammonemia has been reported (10, 22). We are studying the molecular mechanisms by which chronic moderate hyperammonemia (similar to that present in patients with liver cirrhosis) leads to neuro- logical alterations. Chronic hyperammonemia impairs the response of NMDA receptors to its agonists (18) and this impairment is especially marked and long-lasting in rats pre- and neonatally exposed to ammonia (21). Chronic moderate hyperammonemia impairs the neuro- nal glutamate–nitric oxide–cyclic GMP pathway both in cultured neurons and in the rat in vivo (14). Hyper- ammonemia also impairs the induction of NMDA recep- tor-dependent long-term potentiation (LTP) in the CA1 region of the hippocampus (23). Both the glutamate–nitric oxide–cGMP pathway and the NMDA receptor-dependent LTP are involved in some forms of learning and memory formation (6, 11, 12, 19). For example, the nitric oxide synthase inhibi- tors impair learning of several spatial tasks such as the 14-unit T-maze (15, 16) and radial maze (41) and also impair object recognition memory (28) and the passive avoidance task (25). In the same way, pretraining administration of NMDA receptor antagonists impairs Experimental Neurology 161, 704–713 (2000) doi:10.1006/exnr.1999.7299, available online at http://www.idealibrary.com on 704 0014-4886/00 $35.00 Copyright  2000 by Academic Press All rights of reproduction in any form reserved.