Amygdala Serotonin Transporters in Alcoholics Measured by Whole Hemisphere Autoradiography MARKUS STORVIK, 1,2 * JARI TIIHONEN, 1 TUIJA HAUKIJA ¨ RVI, 3 AND ERKKI TUPALA 1,2{ 1 Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Kuopio, Kuopio, Finland 2 Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland 3 Department of Psychiatry, University of Kuopio, Kuopio, Finland KEY WORDS serotonin; amygdala; limbic system; autoradiography; alcoholism ABSTRACT Background: A dysfunction in brain serotonin turnover is a well- established factor associated with the impulsive and sociopathic behavior in alcoholics. The conjuncted alterations in functioning of serotonin transporter (SERT) may play a role in the regulation of emotional balance, judgement, and the adverse behavioral effects of ethanol misuse. These traits may be related to serotonergic regulation in the amygdala and prefrontal cortex. Methods: The binding of [ 3 H]citalopram to SERT was evaluated in the amygdala of Cloninger type 1 and 2 alcoholics (n ¼ 17), and non- alcoholic control subjects (n ¼ 10) by postmortem whole-hemisphere autoradiography. Results: The SERT binding was substantially lower in the dorsal amygdala in alco- holic subjects when compared with the controls (28%, effect size 1.26, P ¼ 0.016). In secondary analysis, this reduction was observed in both alcoholic subgroups (26% in type 1 alcoholics, and 33% in type 2 alcoholics). In ventral amygdala, no alteration was observed. There were significant correlations between the SERT binding in dorsal amygdala and in previous results from frontal cortical areas in alcoholics, depending on the type of alcoholic. Conclusions: These results suggest that SERT binding in the amygdala, as well as the differential regulation of the SERT in amygdala and frontal cortex in alcoholics may help to explain the dysfunctional regulation of emo- tions in alcoholics. Synapse 61:629–636, 2007. V V C 2007 Wiley-Liss, Inc. INTRODUCTION Alcoholics are a heterogeneous group of people who present a wide spectrum of problems in their regula- tion of emotions. The Cloninger type 1 alcoholism is characterized by an anxiety-prone temperament (Cloninger, 1995; Cloninger et al., 1988). The dopami- nergic system is deficient in this group, as reviewed in Tupala and Tiihonen (2004). In contrast, type 2 alco- holism (20% of alcoholics) is more strongly corre- lated with heredity and is characterized by teenage- onset of antisocial behavior. The character of type 2 alcoholics is socially hostile, and such patients tend to be unusually impulsive and risk-taking. The neuro- chemical typology of alcoholism, as proposed by Clo- ninger, suggests that type 2 alcoholics have serotoner- gic defects (Cloninger, 1995). In addition, the violent behavior presented by alcoholics has been linked with an alteration in the serotonergic system (Cloninger, 1995; Frankle et al., 2005; Hallikainen et al., 1999; Mantere et al., 2002; Tiihonen et al., 1997; Virkkunen et al., 1994). We have previously reported the occurrence of decreased serotonin transporter (SERT) binding in the frontal cortical areas of alcoholics (Mantere et al., 2002), where the serotonin system modulates the ac- tivity of inhibitory areas in the prefrontal cortex and related areas such as the anterior cingulate cortex (Hariri et al., 2002; Heinz et al., 2005). The amygdala controls neuronal activity in the prefrontal cortex (Garcia et al., 1999) and plays a crucial role in the function of selective attention through the anterior cingulate cortex (Franken, 2003), and it is connected to prefrontal cortical areas that have an important role in the expression of emotion (Davis and Whalen, 2001; Swanson and Petrovich, 1998). The function of { Deceased. *Correspondence to: Markus Storvik, Ph.D., Department of Pharmacology and Toxicology, University of Kuopio, FI-70211 Kuopio, Finland.. E-mail: markus.storvik@uku.fi Received 29 December 2006; Accepted 20 March 2007 DOI 10.1002/syn.20420 Published online in Wiley InterScience (www.interscience.wiley.com). V V C 2007 WILEY-LISS, INC. SYNAPSE 61:629–636 (2007)