Benzodiazepines such as diazepam are widely prescribed as anxiolytics and sleep aids. Continued use of benzodiazepines, however, can lead to addiction in vulnerable individuals. Here, we investigate the neural mechanisms of the behavioral effects of benzodiazepines using the intracranial self-stimulation (ICSS) test, a procedure with which the reward-enhancing effects of these drugs can be measured. Benzodiazepines bind nonselectively to several different GABA A receptor subtypes. To elucidate the a subunit(s) responsible for the reward-enhancing effects of benzodiazepines, we examined mice carrying a histidine-to-arginine point mutation in the a1, a2, or a3 subunit, which renders the targeted subunit nonresponsive to diazepam, other benzodiazepines and zolpidem. In wild-type and a1-pointmutated mice, diazepam caused a dose-dependent reduction in ICSS thresholds (reflecting a reward-enhancing effect) that is comparable to the reduction observed following cocaine administration. This effect was abolished in a2-and a3-point-mutant mice, suggesting that these subunits are necessary for the reward-enhancing action of diazepam. a2 Subunits appear to be particularly important, since diazepam increased ICSS thresholds (reflecting an aversive-like effect) in a2-point-mutant animals. Zolpidem, an a1-preferring benzodiazepine-site agonist, had no reward-enhancing effects in any genotype. Our findings implicate a2 and a3 subunit containing GABA A receptors as key mediators of the reward-related effects of benzodiazepines. This finding has important implications for the development of new medications that retain the therapeutic effects of benzodiazepines but lack abuse liability.

BACKGROUND AND PURPOSE Examining how left-hemisphere brain tumors might impact both the microstructure of the corpus callosum (CC) as measured by fractional anisotropy (FA) values in diffusion tensor imaging (DTI) as well as cortical language lateralization measured with functional MRI (fMRI). METHODS fMRI tasks (phonemic fluency and verb generation) were performed in order to detect activation in Broca’s and Wernicke’s area. Twenty patients with left-hemisphere brain tumors were investigated. fMRI results were divided into left dominant (LD), right dominant (RD), or codominant (CD) for language function. DTI was performed to generate FA maps in the anterior and posterior CC. FA values were correlated with the degree of language dominance. RESULTS Patients who were LD or RD for language in Broca’s area had lower FA in the anterior CC than those who were CD for language (median for CD = .72, LD = .66, RD = .65, P < .09). Lateralized versus CD group level analysis also showed that CD patients had higher FA in the anterior CC than patients who displayed strong lateralization in either hemisphere (median for CD = .72, lateralized = .65, P < .05). CONCLUSION Our preliminary observations indicate that the greater FA in CD patients may reflect a more directional microstructure for the CC in this region, suggesting a greater need for interhemispheric transfer of information. Because brain tumors can cause compensatory codominance, our findings may suggest a mechanism by which interhemispheric transfer is facilitated during plasticity in the presence of a tumor.