doi: 10.1111/j.1472-8206.2004.00281.x ORIGINAL ARTICLE Effects of venlafaxine on ethanol withdrawal syndrome in rats Esra Sag ˘lam a , I. Tayfun Uzbay b *, Hakan Kayir b , Turgay C ¸ elik b , Mansur Beyazyu ¨ rek c a Department of Pharmacology, Maltepe University 81530, Istanbul, Turkey b Department of Medical Pharmacology, Psychopharmacology Research Unit, Faculty of Medicine, Gu ¨lhane Military Medical Academy, Etlik 06018, Ankara, Turkey c Department of Psychiatry, Faculty of Medicine, Maltepe University 81530, Istanbul, Turkey INTRODUCTION Several studies indicate a marked relationship between ethanol intake, ethanol dependence and central seroton- ergic system [1–4]. It has been known that many 5-hydroxytriptamine (5-HT) reuptake-blocking agents reduced voluntary ethanol consumption and inhibited ethanol craving or re-inforcement in human beings and animals [5–10]. It could be expected to influence the occurrence of mood symptoms in ethanol dependents, especially during withdrawal. This hypothesis was tested in ethanol-dependent rats, suggesting that deficits in accumbal 5-HT release may contribute to the negative affective consequences of ethanol withdrawal [11]. In human beings, a significant reduction in the availability of 5-HT transporters was found in the raphe nuclei of recently detoxified alcoholics, which was strongly correlated with increased levels of anxiety and depres- sion during early abstinence. Furthermore, reduced transcriptional efficiency of 5-HT transporter may underlie another set of symptoms during ethanol with- drawal [4,12]. In a previous study from our laboratory [13], we reported some significant reductions in striatal 5-HT levels of ethanol-dependent Wistar rats during the first 6 h of ethanol withdrawal. We also observed that the signs of ethanol withdrawal such as increased locomotor activity and stereotyped behaviours, wet dog shakes, agitation and audiogenic seizures appeared in a parallel group of the ethanol-dependent rats. Taking together, all these findings indicate a relationship between reduced brain 5-HT levels and some of the behavioural signs of ethanol withdrawal. In addition, a recent study from our laboratory indicated that acute fluoxetine treatment, a selective serotonin reuptake Keywords ethanol dependence, ethanol withdrawal syndrome, rat(s), venlafaxine Received 10 June 2004; accepted 2 July 2004 *Correspondence and reprints: tuzbay@gata.edu.tr ABSTRACT The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187–319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way ANOVA of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats. Ó 2004 Blackwell Publishing Fundamental & Clinical Pharmacology 18 (2004) 693–698 693