Ischemia-induced glutamate release in rat frontoparietal cortex after chronic alcohol and withdrawal Luigia Favalli a , Annalinda Rozza a , Pietro Frattini a , Elisabetta Masoero a , Roberto Scelsi b , Alessia Pascale a , Stefano Govoni a, * a Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy b Department of Human and Hereditary Pathology, University of Pavia, Via Forlanini 14, 27100 Pavia, Italy Received 15 January 2002; received in revised form 19 March 2002; accepted 5 April 2002 Abstract High doses of ethanol increase stroke risk: in this context, a role for excitatory amino acids has been proposed. The present results show that, in frontoparietal cerebral cortex, chronic ethanol treatment (10% v/v in drinking water for 28 days) was able to slightly reduce glutamate release (evaluated through transdialysis coupled with high-pressure liquid chromatography) following focal ischemia as regards non-treated ischemic rats. This reduction was, however, not associated with decreased cerebral damage. In 24-h withdrawing rats, histological and morphometric analyzes showed an exacerbated cerebral damage coupled with higher glutamate and aspartate release compared to controls. These results suggest that adaptive changes following chronic ethanol consumption lead to an increased excitotoxicity that is particularly evident during the withdrawal condition. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chronic alcohol; Withdrawal; Cerebral focal ischemia; Glutamate; Aspartate; Microdialysis; Frontoparietal cortex A growing number of epidemiologic studies have docu- mented an association between light-to-moderate alcohol intake and lower risk for Coronary Heart Disease [3,8,9]. The relationship between alcohol intake and cerebrovascu- lar disease is much less clear. Cerebrovascular disease can lead to a sudden, severe disruption of blood supply to the brain generating a stroke episode: the relationship between stroke and ethanol consumption has not yet been fully eluci- dated. Heavy drinking has been associated with increased stroke risk, particularly evident in women, while it is not clear whether lower doses may be protective [2]. The bene- ficial effects observed in some cases, have been mostly related to a regular pattern of light-to-moderate alcohol intake [15]. In this view, ethanol seems to be able to decrease the risk of ischemic (blockage of a blood vessel) stroke by reducing the damage to blood vessels due to lipid deposits and blood clotting. However, these anticlotting properties may increase the risk of hemorrhagic (rupture of a blood vessel) stroke [10]. Moreover, cerebral ischemia profoundly affects signal transmission pathways making it more difficult to predict the overall effect of ethanol. Within this context, in a previous work, we showed that acute administration of ethanol was able to reduce glutamate release, the major excitatory neurotransmitter in the brain, in a model of focal cerebral ischemia [13]. However, this decrease was not accompanied by a significant reduction of the extension of the cerebral damage [13]. It should be additionally considered that long-term alcohol exposure also induces adaptive changes within neuronal systems [6]. These neuroadaptations seem more prominent when ethanol is removed, resulting in neuronal hyperexcitability and in the characteristic withdrawal syndrome, thus making this entire picture even more complex. The present study was aimed to investigate the effect of chronic ethanol treatment on excitatory amino acid release after focal cerebral ischemia and the presence of possible adaptive changes associated with the withdrawal condition. Male Wistar rats weighting 250–300 g received food in pellets ad libitum and were kept in standard housing condi- tions with a 12-h light/dark cycle. Anesthesia was induced by intraperitoneal injection of Equitensine (penthobarbital 29 mg/kg; chloral hydrate 127.5 mg/kg; MgSO 4 71.4 mg/kg; dihydroxypropane 40%; ethanol 10%). Equitensine anesthe- sia was chosen because, in our experience, it was the anes- thetic mixture displaying the least interference with the measurement of excitatory amino acid release [16]. A Neuroscience Letters 326 (2002) 183–186 0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(02)00352-X www.elsevier.com/locate/neulet * Corresponding author. Tel.: 139-382-507-394; fax: 139-382- 507-405. E-mail address: govonis@unipv.it (S. Govoni).