Psychopharmacology (2010) 208:469–474 DOI 10.1007/s00213-009-1747-5 ORIGINAL INVESTIGATION Alcohol breaks down interhemispheric inhibition in females but not in males Alcohol and frontal connectivity Sylco S. Hoppenbrouwers & Dennis Hofman & Dennis J. L. G. Schutter Received: 8 October 2009 / Accepted: 25 November 2009 / Published online: 18 December 2009 # The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Introduction Alcohol has renowned behavioral disinhibi- tory properties which are suggested to involve reductions in frontal lobe functioning as a result of diminished inter- hemispheric connectivity. Methods To examine sex differences in frontal interhemi- spheric connectivity in response to alcohol, 12 female and ten male healthy volunteers received a single administration of 0.5‰ alcohol in a placebo-controlled counterbalanced crossover design. Paired-pulse transcranial magnetic stim- ulation was applied to measure transcallosal inhibition (TCI) between the left and right primary motor cortex (M1). Results Results showed significant reductions in TCI after alcohol administration in female participants exclusively. Discussion These findings provide the first evidence that moderate doses of alcohol differentially affect frontal interhemispheric connectivity in males and females. The present data may shed new light on the physiological mechanisms underlying sex differences in the susceptibility to alcohol. Keywords Alcohol . Frontal cortex . Interhemispheric connectivity . Transcallosal inhibition . Transcranial magnetic stimulation S. S. Hoppenbrouwers (*) : D. Hofman : D. J. L. G. Schutter Department of Experimental Psychology, Helmholtz Research Institute, Utrecht University, Heidelberglaan 2, 3584 CS Utrecht, The Netherlands e-mail: s.s.hoppenbrouwers@uu.nl Introduction In the last decades, alcohol consumption steadily increased culminating in 3.2 million yearly deaths either as a direct or indirect result of alcohol worldwide (World Health Organi- sation 2004). Moderate doses of alcohol (≤0.5‰) can produce feelings of relaxation and release of response inhibition, whereas higher doses of alcohol (1–1.5‰) cause impairments in motor coordination and vision. Extremely high alcohol levels (≥2.5‰) ultimately lead to coma and death (Hieda et al. 2005). Interestingly, the effects of alcohol seem to be more pronounced in females than in males (Mills and Bisgrove 1983; Niaura et al. 1987; Mumenthaler et al. 1999; Hommer 2003). Sex differences in response to alcohol intake can in part be explained by differences in the percentage of body fat (Addolorato et al. 1999) and the availability of the enzyme alcohol dehydro- genase which breaks down alcohol (Baraona et al. 2001). However, other research suggests that females differ from males on the innate physiological susceptibility to the central effects of alcohol (Hommer et al. 1996, 2001; Agartz et al. 2003; Sasaki et al. 2009). For instance, chronic misuse of alcohol leaves female alcoholics with more brain damage than their male counterparts (Hommer et al. 2001; Hommer 2003). Notably, however, moderate drinking habits also affect the female brain more strongly than the male brain (Sasaki et al. 2009). In addition to the general effects on the central and peripheral nervous system, alcohol typically affects frontal cortical functions such as response inhibition and cognitive regulation (Jentsch and Taylor 1999; Lyvers 2000). In fact, even though alcohol diffuses through all biological mem- branes and is distributed throughout the body, the anterior cortical regions of the brain have been shown to be especially vulnerable to the acute (Weitlauf and Woodward