Effects of olanzapine on ethanol withdrawal syndrome in rats Nasibe Unsalan a , Esra Saglam b , Hakan Kayir c , Tayfun Uzbay c, ⁎ a Department of Psychiatry, Faculty of Medicine, Maltepe University, Istanbul, Turkey b Department of Pharmacology, Faculty of Medicine, Maltepe University, Istanbul, Turkey c Department of Medical Pharmacology, Psychopharmacology Research Unit, Gulhane Military Medical Academy, Ankara, Turkey Received 5 June 2007; received in revised form 11 October 2007; accepted 16 October 2007 Available online 25 October 2007 Abstract The present study was designed to investigate the effects of olanzapine, a serotonin–dopamine antagonistic atypical antipsychotic agent, on ethanol withdrawal syndrome in rats. Adult male Wistar rats were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair fed with an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. After 2nd, 4th and 6th h of ethanol withdrawal, rats were observed for 5 min, afterwards withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behavior, tremor, wet dog shakes, abnormal posture and abnormal gait were recorded or rated. Olanzapine (0.5, 1 and 2 mg/kg) and saline were injected to the rats intraperitoneally 30 min before ethanol withdrawal assessment. A second series of injections was also given 30 min before the 6th-h- observation, and subjects were then tested for audiogenic seizures. Olanzapine (2 mg/kg) produced significant inhibitory effects on stereotyped behaviors and wet dog shakes at the 6th h of ethanol withdrawal. Contrary, the same dose caused some increases in the intensity of posture and gait impairments at the 2nd h of ethanol withdrawal. In addition, that dose was found to be ineffective on agitation, tremor, tail stiffness and audiogenic seizures. Our results suggest that acute olanzapine treatment has beneficial effects on stereotyped behavior and wet dog shakes, but it also has some adverse effects on posture and gait during ethanol withdrawal in rats. Overall, olanzapine does not seem to be an adequate and suitable drug in controlling of ethanol withdrawal syndrome. © 2007 Elsevier B.V. All rights reserved. Keywords: Olanzapine; Ethanol withdrawal syndrome; Ethanol dependence; (Rat) 1. Introduction Ethanol, as a rewarding substance, is associated with the release of dopamine in the pleasure center of the brain. Current research related to the neurobiology of substance abuse supports the role of dopaminergic involvement in motivation, reward and reinforcement (Volkow et al., 2004). A strong body of evidence indicates that ethanol activates dopamine release from the nucleus accumbens and extended amygdale (Di Chiara, 1995; Heimer et al., 1997). The action of ethanol on the mesolimbic pathway is considered to be strongly associated with suscep- tibility to alcoholism (Noble, 1996) and the development of craving and loss of control (Robinson and Berridge, 1993). As mentioned before, the ethanol-related increase in dopamine release contributes to the rewarding and reinforcing effects of ethanol consumption (i.e. pleasurable feelings) (Kenna et al., 2004). Serotonergic drugs are thought to have particular interaction in that point, especially because of the hypothesized links between mood disorders and ethanol consumption. Neuro- chemical findings from clinical (Roy et al., 1987; Le Marquand et al., 1994) and experimental (Murphy et al., 1987) studies suggested some significant chances in central serotonergic neurotransmission during ethanol consumption and/or with- drawal. It is also hypothesized that serotonin is also associated with the rewarding and reinforcing effects of ethanol consump- tion. During intoxication, there is an increase in serotonin functioning. Considerable experimental evidence suggests that serotonin plays a crucial role in the impulsivity and craving often seen in alcoholics (Ciccocioppo, 1999) and is at least Available online at www.sciencedirect.com European Journal of Pharmacology 579 (2008) 208 – 214 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Gulhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Psychopharmacology Re- search Unit, Etlik 06018 Ankara, Turkey. Tel.: +90 312 304 4764; fax: +90 312 304 2010. E-mail addresses: tuzbay@gata.edu.tr, uzbayt@yahoo.com (T. Uzbay). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.10.024