472 Fig. 1 Mean and standard error of the mean of frontal interhemi- spheric inhibition in the placebo and alcohol condition The observed sex difference in TCI after alcohol could not be explained by reductions in single-pulse TMS as demonstrated by a nonsignificant drug × sex interaction (F (1, 21) = 1.024; p = 0.324). However, a main effect of alcohol on single-pulse TMS (F(1, 21) = 4,517; p = 0.046; ηp2 = 0.184) was observed, replicating prior studies that found alcohol-related reductions in cortical excitability (Ziemann et al. 1995; Kähkönen et al. 2003). Finally, the sex-related effect of alcohol on TCI could not be explained by differences in baseline EMG activity as shown by the nonsignificant drug × sex interaction (F(1, 21) = 0.278; p = 0.604). No main effects of alcohol on baseline EMG was observed (F(1, 21) = 0.270; p = 0.609). For an impression of the raw data, please see Table 2. Discussion The aim of the present study was to examine alcohol- related sex differences in frontal interhemispheric connec- tivity and found reductions in frontal interhemispheric connectivity to a moderate dose of alcohol in healthy female but not male subjects. To the best of our knowledge, this is the first study to demonstrate evidence for sex differences in frontal interhemispheric connectivity in response to alcohol that cannot be explained by effects of Table 2 Sex-related effect of alcohol on TCI, single pulse, and EMG Psychopharmacology (2010) 208:469–474 alcohol on baseline EMG activity or single-pulse TMS. The global reduction in cortical excitability as evidenced by a decrease in MEP size in both sexes replicates earlier findings by Ziemann et al. (1995) and Kähkönen et al. (2003). This reduction in frontal cortical excitability has been explained in terms of increased binding of alcohol to GABA-a receptors and alcohol-related inhibition of NMDA currents (Kähkönen et al. 2003). In measuring TCI with paired-pulse TMS, the conditioning pulse administered over the motor cortex is thought to activate glutamatergic excitatory callosal fibers terminating on local GABAergic interneurons of the contralateral motor cortex (Daskalakis et al. 2002). Excitation of these GABAergic inhibitory interneurons results in inhibition of the pyramidal motor neurons which causes a reduction in the MEP size. Consequently, a decrease in frontal interhemispheric con- nectivity may relate to the influence of alcohol on either NMDA glutamate receptor functioning or GABAergic inhibitory interneurons. Previous TMS research has dem- onstrated that alcohol mainly influences GABAergic func- tioning leaving glutamatergic excitatory transmission relatively unaffected (Ziemann et al. 1995; Conte et al. 2008). In contrast, alcohol has also been shown to attenuate glutamate/NMDA receptor functioning (Lovinger et al. 1989; White et al. 1990; Masood et al. 1994; Weitlauf and Woodward 2008) leaving open the possibility that alcohol may have disrupted the excitatory callosal pathway that terminates on inhibitory interneurons. This would result in less excitation of inhibitory interneurons, subsequently leading to a relatively increased MEP size. However, the crucial point revolves around the question how to explain the alcohol-related sex difference on frontal interhemispheric connectivity, and at present, the precise physiological mechanisms through which alcohol reduces frontal inter- hemispheric connectivity in females remain to be elucidated. A possible role for steroid hormones in explaining the presently observed sex differences is evidenced by a study in which testosterone was found to counteracts some of the effects of alcohol (Khalil et al. 2005). In this study, testosterone was shown to diminish alcohol-induced defi- cits in spatial memory (Khalil et al. 2005). Interestingly, Placebo (mean ± SEM) Alcohol (mean ± SEM) TCI Males 57.1±5.9 59.4±7.2 Females 56.3±7.2 40.7±8.1 Single pulse Males 1,843.2±235.6 1,573.2±336 Females 1,880.8±653.8 1,119.8±396.7 EMG Males 4,769±704.9 6,351.9±1,118.2 Females 8,574.7±2,403.2 8,563.9±1,256.4 Single-pulse TMS is expressed in microvolt TCI transcallosal inhibition (expressed in percentage inhibition of single-pulse TMS), EMG electromyogram (expressed in microvolt), SEM standard error of the mean