We have collected full, volumetric T-1 weighted MR images using a 1.5 T scanner to measure intracranial volumes in 350 alcoholics (248 males and 112 females) and 163 healthy, non-alcoholic comparison subjects (82 males and 81 females). An automated segmentation program was used to divide the intracranial contents into CSF, gray and white matter (Human Brain Mapping, 5:194-205, 1997). When we measure brain volume we are measuring the combined effect of two processes: growth and degeneration. Growth determines maximum brain size achieved during life. Maximal brain growth can be estimated by intracranial volume (ICV) and since ICV remains constant throughout life, measuring ICV anytime after adolescence provides reliable data on maximal brain growth. In addition, degeneration can be measured by the ratio of cerebral volume or gray matter or white matter volume to the remainder of the intracranial contents. Alcoholics show greater brain degeneration than non-alcoholics. Alcoholic women are more affected than alcoholic men. Alcoholics also show significantly greater brain shrinkage than controls by their mid to late twenties. In addition, alcoholics have smaller intracranial volumes than controls suggesting that pre-morbid differences in brain size may contribute to the risk for alcoholism. Despite the significant difference in intracranial volume brain, degeneration accounts for a greater amount of the difference in brain volume between alcoholics and controls than brain growth does. Similarly, presence or absence of co-morbid psychiatric disorder or other substance abuse does not affect brain shrinkage among alcoholics. Over the past few years we have made several methodological advances in the automated measurement of brain volumes. An automated method for dividing the brain into right and left hemispheres was developed and validated. In addition, we have developed an automated method for measuring the volume of mesial and orbital frontal cortex, as well as the entire striatum. These regions are known to be involved in motivation and social behavior. We have begun to investigate the normal and pathological development of the striatum. It appears that children and adolescents at risk for the development of alcoholism have significantly smaller striatums, including nucleus accumbens, than child not at high risk for the development of alcoholism. We have examined how a family history (FH) of heavy drinking affects both brain shrinkage as measured by the ratio of brain volumes to intracranial volume as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. FH positive alcoholic patients have significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth among alcoholics with a heavy drinking motr or father. Brain shrinkage was not affected by FH. Late-onset alcoholics show a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. Late-onset FH positive patients also have significantly lower IQ scores than late-onset FH negative patients, and IQ scores are correlated with ICV. These data provide evidence that heavy parental alcohol use may increase risk for alcoholism in offspring in part by a genetic and/or environmental effect resulting in reduced brain growth. We have also completed specific investigations of frontal lobe volume in alcoholics and controls. Alcoholics appear to have smaller frontal lobe volumes than controls. This reduction in frontal volume is restricted to the mesial surface of the right frontal lobe. We have also found that among healthy subjects that the tendency to devalue delayed rewards (delay discounting), which is considered an excellent laboratory measure of impulsivity, is associated with shrinkage of the lateral surface of the frontal lobes. The lateral frontal lobe is the same region that has been shown to be activated during delayed discounting tasks during functional imaging. Thus our results are consistent with the functional neuroanatomy of human impulsivity and may be important in understanding brain differences associated with risk for the development of substance abuse. We are in the process of using voxel-based morphometry to confirm the reductions in frontal lobe vollume we have observed among alcoholics. We expect that this study we be one of the largest comparisons between the two methods of measuring differences in human brain size ever undertaken. During the past year we have completed two studies of brain imaging genetics. The first examined the genes for a mitochondrial superoxide dismutase 2 (SOD2) enzyme, critical in the metabolism of free radicals. An Ala16Val polymorphism putatively affects SOD2 enzyme activity in vivo. Brain volumes of 76 treatment-seeking alcohol-dependent individuals were measured with a 1.5T MRI. Intracranial tissue margins were manually outlined on coronal sections. Gray matter, white matter, sulcal, and ventricular CSF volumes were estimated using intensity-based K-means clustering. Ala16Val (rs4880) and a second haplotype tagging SNP, rs10370, were genotyped. The q-value package was used to correct for multiple comparisons. In the alcoholics, cerebrospinal fluid and intra-cranial volumes showed significant differences across the six diplotype categories. The homozygous Ala16-containing diplotype rs10370TT-rs4880GG was associated with lowest gray matter ratio (greater shrinkage;p=0.005). Presence of one or two copies of the low activity Ala16 allele was a risk factor for lower gray matter volume in alcoholics below the median alcohol consumption (p=0.03) but not in alcoholics above this level. White matter ratio was associated with sex (p=0.002) and lifetime total alcohol consumption (p=0.01) but not with diplotypes. In this exploratory analysis, a putative functional missense variant of SOD2 appears to influence gray matter loss in alcoholics. This may be due to impaired clearance of reactive oxygen species formed as a result of alcohol exposure. The risk/protective effect was observed in alcoholics with lower levels of lifetime alcohol consumption. Highest levels of exposure may overwhelm the protective action of the SOD2 enzyme. Finally we have used the PET methods of racloride displacement to investigate the genetics of dopamine release induced by intravenous alcohol administration. We found that a functional polymorphism of a gene coding for a type of brain opiate receptor (OPRM1 A118G) is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and (11)C-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. Carries of the more common allele of OPRM1 did not show measurable dopamine release following intravenous alcohol. These results are consistent with the idea that the 118G allele of the human opiate receptor may be a risk factor for the development of alcoholism or a marker for the utility of opiate receptor blockade as a treatment for alcoholism.