Psychopharmacology (2010) 208:469–474 acute alcohol administration reduces testosterone produc- tion in both males and females (Ylikahri et al. 1980; Valimaki et al. 1984). Together with the notion that men have multiple times more testosterone than females, testoster- one may play a role in the currently observed reductions of TCI in females exclusively. In agreement, we recently found evidence that a single administration of testosterone signifi- cantly increases frontal interhemispheric connectivity in healthy female subjects (Hoppenbrouwers et al., submitted). In sum, even though sex differences in steroid hormones may provide for an explanation of our findings, it remains elusive whether these sex differences already surface after an acute administration of alcohol. It is suggested that the decrease in frontal interhemispheric connectivity observed in females will most likely involve complex interactions between steroid hormones and the combined action of alcohol on GABAergic interneurons and NMDA glutamate receptor functioning in the corpus callosum. Despite the observed female vulnerability to the effects of alcohol on frontal interhemispheric connectivity, several issues should be mentioned. First, the relationship between alcohol-related effects on frontal interhemispheric connec- tivity and behavior is of importance. Executive functions including behavioral inhibition and cognitive regulation are normally ascribed to the prefrontal cortex (PFC) rather than M1. Even though both M1 and PFC are part of the frontal cortex, our current findings on M1 interhemispheric connectivity cannot simply be extrapolated to the PFC. Defensibly, there is evidence from recent interleaved TMS– EEG studies showing that M1 and the PFC share similar physiological properties (Daskalakis et al. 2008). Second, the fact that we observed reductions in frontal interhemi- spheric to alcohol consumption in females only does not in any way imply that men are immune to the effects of alcohol. In other words, males will likely demonstrate similar reductions in frontal interhemispheric connectivity at higher BAC levels. Third, in our sample, all female participants were taking oral contraceptives to abolish fluctuations in steroid levels at the time of testing. However, oral contraceptives have been shown to reduce plasma levels of progesterone metabolites in female rats and women (Follesa et al. 2001). Some of these metabolites (e.g., allopregnanolone) are highly potent endogenous positive modulators of the GABA-a receptor (Mitchell et al. 2008). It has been suggested that the combined effects of endogenous steroids and alcohol modulate GABA-a recep- tor functioning (Follesa et al. 2004). In contrast, alcohol has also been shown to increase allopregnanolone levels in the cerebral cortex (VanDoren et al. 2000), an increase that has proven effective to potentiate GABA-a receptor-mediated inhibition in the brain (VanDoren et al. 2000) and explain some of the physiological and behavioral effects of alcohol (VanDoren et al. 2000; Izumi et al. 2007). Taken together, 473 these findings suggest that the contraceptive- and alcohol- related increases in allopregnanolone levels may have contributed to the presently observed reductions in TCI. As it stands, the present findings can only be generalized to males and females taking oral contraceptives. Finally, an additional line of evidence consisting of conventional TMS measures of GABA function such as short-interval intra- cortical inhibition and long-interval intracortical cortical inhibition could potentially has given more direct evidence for the exact mechanisms underlying the observed effect. In conclusion, the present study provides the first evidence for reductions in frontal interhemispheric connec- tivity in females but not in males following a moderate dose of alcohol. Future research may focus on alcohol dose– response patterns in males and the involvement of steroid hormones to further explain the observed sex differences in interhemispheric connectivity. In addition, to clarify the potential role of contraceptives, future research may also look into the effects of alcohol on interhemispheric inhibition in females not using contraceptives. Acknowledgments This work was supported by an Innovational Research Grant (VIDI 452-07-012) from the Netherlands Organization for Scientific Research (NWO). Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References Aboitiz F, Montiel J (2003) One hundred million years of interhemi- spheric communication: the history of the corpus callosum. Braz J Med Biol Res 36(4):409–420 Addolorato G, Capristo E et al (1999) Nutritional status and body fluid distribution in chronic alcoholics compared with controls. Alcohol Clin Exp Res 23(7):1232–1237 Agartz I, Shoaf S et al (2003) CSF monoamine metabolites and MRI brain volumes in alcohol dependence. Psychiatry Res 122(1):21–35 Baraona E, Abittan CS et al (2001) Gender differences in pharmaco- kinetics of alcohol. Alcohol Clin Exp Res 25(4):502–507 Berks J, McCormick R (2008) Screening for alcohol misuse in elderly primary care patients: a systematic literature review. Int Psycho- geriatr 20(6):1090–1103 Berner MM, Kriston L et al (2007) The alcohol use disorders identification test for detecting at-risk drinking: a systematic review and meta-analysis. J Stud Alcohol Drugs 68(3):461–473 Conte A, Attilia ML et al (2008) Acute and chronic effects of ethanol on cortical excitability. Clin Neurophysiol 119(3):667–674 Daskalakis ZJ, Christensen BK et al (2002) The mechanisms of interhemispheric inhibition in the human motor cortex. J Physiol 543(Pt 1):317–326 Daskalakis ZJ, Farzan F et al (2008) Long-interval cortical inhibition from the dorsolateral prefrontal cortex: a TMS–EEG study. Neuropsychopharmacology 33:2860–2869 Ferbert A, Priori A et al (1992) Interhemispheric inhibition of the human motor cortex. J Physiol 453:525–546