A relationship between the aldosterone-mineralocorticoid receptor pathway and alcohol drinking: preliminary translational findings across rats, monkeys and humans.

Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

Effects of selection for ethanol preference on gene expression in the nucleus accumbens of HS-CC mice.

Previous studies on changes in murine brain gene expression associated with the selection for ethanol preference have used F2 intercross or heterogeneous stock (HS) founders, derived from standard laboratory strains. However, these populations represent only a small proportion of the genetic variance available in Mus musculus. To investigate a wider range of genetic diversity, we selected mice for ethanol preference using an HS derived from the eight strains of the collaborative cross. These HS mice were selectively bred (four generations) for high and low ethanol preference. The nucleus accumbens shell of naive S4 mice was interrogated using RNA sequencing (RNA-Seq). Gene networks were constructed using the weighted gene coexpression network analysis assessing both coexpression and cosplicing. Selection targeted one of the network coexpression modules (greenyellow) that was significantly enriched in genes associated with receptor signaling activity including Chrna7, Grin2a, Htr2a and Oprd1. Connectivity in the module as measured by changes in the hub nodes was significantly reduced in the low preference line. Of particular interest was the observation that selection had marked effects on a large number of cell adhesion molecules, including cadherins and protocadherins. In addition, the coexpression data showed that selection had marked effects on long non-coding RNA hub nodes. Analysis of the cosplicing network data showed a significant effect of selection on a large cluster of Ras GTPase-binding genes including Cdkl5, Cyfip1, Ndrg1, Sod1 and Stxbp5. These data in part support the earlier observation that preference is linked to Ras/Mapk pathways.

Genes, behavior and next-generation RNA sequencing.

Advances in next-generation sequencing suggest that RNA-Seq is poised to supplant microarray-based approaches for transcriptome analysis. This article briefly reviews the use of microarrays in the brain-behavior context and then illustrates why RNA-Seq is a superior strategy. Compared with microarrays, RNA-Seq has a greater dynamic range, detects both coding and noncoding RNAs, is superior for gene network construction, detects alternative spliced transcripts, detects allele specific expression and can be used to extract genotype information, e.g. nonsynonymous coding single nucleotide polymorphisms. Examples of where RNA-Seq has been used to assess brain gene expression are provided. Despite the advantages of RNA-Seq, some disadvantages remain. These include the high cost of RNA-Seq and the computational complexities associated with data analysis. RNA-Seq embraces the complexity of the transcriptome and provides a mechanism to understand the underlying regulatory code; the potential to inform the brain-behavior relationship is substantial.

Gene networks and haloperidol-induced catalepsy.

The current study examined the changes in striatal gene network structure induced by short-term selective breeding from a heterogeneous stock for haloperidol response. Brain (striatum) gene expression data were obtained using the Illumina WG 8.2 array, and the datasets from responding and non-responding selected lines were independently interrogated using a weighted gene coexpression network analysis (WGCNA). We detected several gene modules (groups of coexpressed genes) in each dataset; the membership of the modules was found to be largely concordant, and a consensus network was constructed. Further validation of the network topology showed that using approximately 35 samples is sufficient to reliably infer the transcriptome network. An in-depth analysis showed significant changes in network structure and gene connectivity associated with the selected lines; these changes were validated using a bootstrapping procedure. The most dramatic changes were associated with a gene module richly annotated with neurobehavioral traits. The changes in network connectivity were concentrated in the links between this module and the rest of the network, in addition to changes within the module; this observation is consistent with recent results in protein and metabolic networks. These results suggest that a network-based strategy will help identify the genetic factors associated with haloperidol response.

Detection of reciprocal quantitative trait loci for acute ethanol withdrawal and ethanol consumption in heterogeneous stock mice.

RATIONALE: Previous studies have suggested that there is an inverse genetic relationship between ethanol consumption (two-bottle choice, continuous access) and ethanol withdrawal (e.g., Metten et al., Behav Brain Res 95:113-122, 1998a). OBJECTIVES: The current study used short-term selective breeding from heterogeneous stock (HS) animals to examine this relationship. The primary goal of the current study was to determine if reciprocal quantitative trait loci (QTLs) could be found in the selectively bred lines. The advantage of detecting QTLs in HS animals is that it is possible to extract a haplotype signature for the QTL, which in turn can be used to narrow the number of candidate genes generated from gene expression and sequence databases (see, e.g., Hitzemann et al., Mamm Genome 14:733-747, 2003). RESULTS: Seven reciprocal QTLs were detected on chromosomes (Chr) 1 (two), 3, 6, 11, 16, and 17 that exceeded the nominal LOD threshold of 10; genetic drift, which occurs during selection, dramatically increases the LOD threshold. The proximal Chr 1 QTL was examined in some detail. The haplotype structure of the QTL was such that the LP/J allele was associated with low withdrawal and high consumption. The QTL appears to be located in a gene-poor region between 170 and 173 Mbp. Based on available sequence data, two plausible candidate genes emerge-Nos1ap and Atf6alpha. CONCLUSIONS: The data presented here confirm some aspects of the negative genetic relationship between acute ethanol withdrawal and ethanol consumption. The QTL data point to the potential involvement of NO signaling and/or the unfolded protein response.

Characterization of the quantitative trait locus for haloperidol-induced catalepsy on distal mouse chromosome 1.

We report here the confirmation of the quantitative trait locus for haloperidol-induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2-Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes.

Internet resources for genomic, bioinformatics, and medical genetics information.

Many diseases are influenced by multiple genetic and environmental factors. Identifying the genes contributing to the probability of developing such diseases poses an extraordinary challenge because each gene may have a small influence. Further, in the presence of other influential genes and environmental factors, the impact of a single gene may be amplified. Many approaches are being taken to address the challenge presented by complex trait genetics, and data are being amassed at an alarming rate. Access to these data is crucial for coordination of efforts and avoidance of unnecessary duplication of research. This appendix describes some of the resources available on the World Wide Web that provide genetic and genomic data, tools for analyzing genome data, information on funding opportunities, and information about ethical, legal and social issues associated with the genetic analysis of disease traits.

Multiple cross mapping (MCM) markedly improves the localization of a QTL for ethanol-induced activation.

This study examines the use of multiple cross mapping (MCM) to reduce the interval for an ethanol response QTL on mouse chromosome 1. The phenotype is the acute locomotor response to a 1.5-g/kg i.p. dose of ethanol. The MCM panel consisted of the six unique intercrosses that can be obtained from the C57BL/6J (B6), DBA/2J (D2), BALB/cJ (C) and LP/J (LP) inbred mouse strains (N > or = 600/cross). Ethanol response QTL were detected only with the B6xD2 and B6xC intercrosses. For both crosses, the D2 and C alleles were dominant and decreased ethanol response. The QTL information was used to develop an algorithm for sorting and editing the chromosome 1 Mit microsatellite marker set (http://www.jax.org). This process yielded a cluster of markers between 82 and 85cM (MGI). Evidence that the QTL was localized in or near this interval was obtained by the analysis of a sample (n = 550) of advanced cross heterogenous stock animals. In addition, it was observed that one of the BXD recombinant inbred strains (BXD-32) had a recombination in the interval of interest which produced the expected change in behavior. Overall, the data obtained suggest that the information available within existing genetic maps coupled with MCM data can be used to reduce the QTL interval. In addition, the MCM data set can be used to interrogate gene expression data to estimate which polymorphisms within the interval of interest are relevant to the QTL.

Harnessing the mouse to unravel the genetics of human disease.

Complex traits, i.e. those with multiple genetic and environmental determinants, represent the greatest challenge for genetic analysis, largely due to the difficulty of isolating the effects of any one gene amid the noise of other genetic and environmental influences. Methods exist for detecting and mapping the Quantitative Trait Loci (QTLs) that influence complex traits. However, once mapped, gene identification commonly involves reduction of focus to single candidate genes or isolated chromosomal regions. To reach the next level in unraveling the genetics of human disease will require moving beyond the focus on one gene at a time, to explorations of pleiotropism, epistasis and environment-dependency of genetic effects. Genetic interactions and unique environmental features must be as carefully scrutinized as are single gene effects. No one genetic approach is likely to possess all the necessary features for comprehensive analysis of a complex disease. Rather, the entire arsenal of behavioral genomic and other approaches will be needed, such as random mutagenesis, QTL analyses, transgenic and knockout models, viral mediated gene transfer, pharmacological analyses, gene expression assays, antisense approaches and importantly, revitalization of classical genetic methods. In our view, classical breeding designs are currently underutilized, and will shorten the distance to the target of understanding the complex genetic and environmental interactions associated with disease. We assert that unique combinations of classical approaches with current behavioral and molecular genomic approaches will more rapidly advance the field.

Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex.

OBJECTIVE: The role of dopamine in the addictive process (loss of control and compulsive drug intake) is poorly understood. A consistent finding in drug-addicted subjects is a lower level of dopamine D2 receptors. In cocaine abusers, low levels of D2 receptors are associated with a lower level of metabolism in the orbitofrontal cortex. Because the orbitofrontal cortex is associated with compulsive behaviors, its disruption may contribute to compulsive drug intake in addicted subjects. This study explored whether a similar association occurs in methamphetamine abusers. METHOD: Fifteen methamphetamine abusers and 20 non-drug-abusing comparison subjects were studied with positron emission tomography (PET) and [11C]raclopride to assess the availability of dopamine D2 receptors and with [18F]fluorodeoxyglucose to assess regional brain glucose metabolism, a marker of brain function. RESULTS: Methamphetamine abusers had a significantly lower level of D2 receptor availability than comparison subjects (a difference of 16% in the caudate and 10% in the putamen). D2 receptor availability was associated with metabolic rate in the orbitofrontal cortex in abusers and in comparison subjects. CONCLUSIONS: Lower levels of dopamine D2 receptor availability have been previously reported in cocaine abusers, alcoholics, and heroine abusers. This study extends this finding to methamphetamine abusers. The association between level of dopamine D2 receptors and metabolism in the orbitofrontal cortex in methamphetamine abusers, which replicates previous findings in cocaine abusers, suggests that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a common mechanism for loss of control and compulsive drug intake in drug-addicted subjects.

Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence.

Methamphetamine is a popular drug of abuse that is neurotoxic to dopamine (DA) terminals when administered to laboratory animals. Studies in methamphetamine abusers have also documented significant loss of DA transporters (used as markers of the DA terminal) that are associated with slower motor function and decreased memory. The extent to which the loss of DA transporters predisposes methamphetamine abusers to neurodegenerative disorders such as Parkinsonism is unclear and may depend in part on the degree of recovery. Here we assessed the effects of protracted abstinence on the loss of DA transporters in striatum, in methamphetamine abusers using positron emission tomography and [(11)C]d-threo-methylphenidate (DA transporter radioligand). Brain DA transporters in five methamphetamine abusers evaluated during short abstinence (<6 months) and then retested during protracted abstinence (12-17 months) showed significant increases with protracted abstinence (caudate, +19%; putamen, +16%). Although performance in some of the tests for which we observed an association with DA transporters showed some improvement, this effect was not significant. The DA transporter increases with abstinence could indicate that methamphetamine-induced DA transporter loss reflects temporary adaptive changes (i.e., downregulation), that the loss reflects DA terminal damage but that terminals can recover, or that remaining viable terminals increase synaptic arborization. Because neuropsychological tests did not improve to the same extent, this suggests that the increase of the DA transporters was not sufficient for complete function recovery. These findings have treatment implications because they suggest that protracted abstinence may reverse some of methamphetamine-induced alterations in brain DA terminals.

Overexpression of dopamine D2 receptors reduces alcohol self-administration.

The mechanism(s) underlying predisposition to alcohol abuse are poorly understood but may involve brain dopamine system(s). Here we used an adenoviral vector to deliver the dopamine D2 receptor (DRD2) gene into the nucleus accumbens of rats, previously trained to self-administer alcohol, and to assess if DRD2 levels regulated alcohol preference and intake. We show that increases in DRD2 (52%) were associated with marked reductions in alcohol preference (43%), and alcohol intake (64%) of ethanol preferring rats, which recovered as the DRD2, returned to baseline levels. In addition, this DRD2 overexpression similarly produced significant reductions in ethanol non-preferring rats, in both alcohol preference (16%) and alcohol intake (75%). This is the first evidence that overexpression of DRD2 reduces alcohol intake and suggests that high levels of DRD2 may be protective against alcohol abuse.

QTL analysis and genomewide mutagenesis in mice: complementary genetic approaches to the dissection of complex traits.

Quantitative genetics and quantitative trait locus (QTL) mapping have undergone a revolution in the last decade. Progress in the next decade promises to be at least as rapid, and strategies for fine-mapping QTLs and identifying underlying genes will be radically revised. In this Commentary we address several key issues: first, we revisit a perennial challenge--how to identify individual genes and allelic variants underlying QTLs. We compare current practice and procedures in QTL analysis with novel methods and resources that are just now being introduced. We argue that there is no one standard of proof for showing QTL = gene; rather, evidence from several sources must be carefully assembled until there is only one reasonable conclusion. Second, we compare QTL analysis with whole-genome mutagenesis in mice and point out some of the strengths and weakness of both of these phenotype-driven methods. Finally, we explore the advantages and disadvantages of naturally occurring vs mutagen-induced polymorphisms. We argue that these two complementary genetic methods have much to offer in efforts to highlight genes and pathways most likely to influence the susceptibility and progression of common diseases in human populations.

Further characterization and high-resolution mapping of quantitative trait loci for ethanol-induced locomotor activity.

Differential sensitivity to the stimulant effects of ethanol on locomotor activity is determined in part by genetic differences. Among inbred strains of mice, moderate doses of ethanol (1-2 g/kg) stimulate locomotor activity in some strains, e.g., the DBA/2J (D2), but only mildly affect activity in other strains, e.g., C57BL/6J (B6) (Crabbe et al., 1982, 1983; Crabbe, 1986; Dudek and Phillips, 1990; Dudek et al., 1991; Dudek and Tritto, 1994). Quantitative trait loci (QTL) for the acute ethanol (1.5 g/kg) locomotor response has been identified in the BXD recombinant inbred (RI) series (N = 25 strains), a C57BL/6J x DBA/2J (B6D2) F2 intercross (N = 1800), and heterogeneous stock (HS) mice (N = 550). QTLs detected (p < .01) in the RI series were found on chromosomes 1, 2, and 6 and these QTLs were expressed in a time-dependent fashion. The QTLs on chromosomes 1 and 2 were confirmed in the F2 intercross at p < 10(-7) or better. HS mice from G32 to G35 were used to fine-map the chromosome 2 QTL. Compared to the consensus map, the genetic map in the HS animals was expanded 10- to 15-fold. Over the region flanked by D2Mit94 to D2Mit304, three separate QTLs were detected in the HS animals. The data obtained confirm the usefulness of HS mice for the fine-mapping of QTLs to a resolution of 2 cM or less.

Evidence that L-deprenyl treatment for one week does not inhibit MAO A or the dopamine transporter in the human brain.

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects.

Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers.

OBJECTIVE: Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to dopamine terminals. The authors evaluated if similar changes occur in humans and assessed if they were functionally significant. METHOD: Positron emission tomography scans following administration of [(11)C]d-threo-methylphenidate (a dopamine transporter ligand) measured dopamine transporter levels (a marker of dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function. RESULTS: Methamphetamine abusers showed significant dopamine transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine transporter reduction was associated with motor slowing and memory impairment. CONCLUSIONS: These results provide evidence that methamphetamine at dose levels taken by human abusers of the drug leads to dopamine transporter reduction that is associated with motor and cognitive impairment. These results emphasize the urgency of alerting clinicians and the public of the long-term changes that methamphetamine can induce in the human brain.

Higher cortical and lower subcortical metabolism in detoxified methamphetamine abusers.

OBJECTIVE: Methamphetamine has raised concerns because it may be neurotoxic to the human brain. Although prior work has focused primarily on the effects of methamphetamine on dopamine cells, there is evidence that other neuronal types are affected. The authors measured regional brain glucose metabolism, which serves as a marker of brain function, to assess if there is evidence of functional changes in methamphetamine abusers in regions other than those innervated by dopamine cells. METHOD: Fifteen detoxified methamphetamine abusers and 21 comparison subjects underwent positron emission tomography following administration of [(18)F]fluorodeoxyglucose. RESULTS: Whole brain metabolism in the methamphetamine abusers was 14% higher than that of comparison subjects; the differences were most accentuated in the parietal cortex (20%). After normalization for whole brain metabolism, methamphetamine abusers exhibited significantly lower metabolism in the thalamus (17% difference) and striatum (where the differences were larger for the caudate [12%] than for the putamen [6%]). Statistical parametric mapping analyses corroborated these findings, revealing higher metabolism in the parietal cortex and lower metabolism in the thalamus and striatum of methamphetamine abusers. CONCLUSIONS: The fact that the parietal cortex is a region devoid of any significant dopaminergic innervation suggests that the higher metabolism seen in this region in the methamphetamine abusers is the result of methamphetamine effects in circuits other than those modulated by dopamine. In addition, the lower metabolism in the striatum and thalamus (major outputs of dopamine signals into the cortex) is likely to reflect the functional consequence of methamphetamine in dopaminergic circuits. These results provide evidence that, in humans, methamphetamine abuse results in changes in function of dopamine- and nondopamine-innervated brain regions.

Identification and time dependence of quantitative trait loci for basal locomotor activity in the BXD recombinant inbred series and a B6D2 F2 intercross.

A complimentary two-phase strategy was used to detect and map quantitative trait loci (QTLs) associated with the basal locomotor response to a saline challenge (10 ml/kg). In phase 1, putative QTLs, significant at p < 0.01 or better, were identified by analysis of the strain means for 25 strains of the B x D recombinant inbred series. QTLs were identified on chromosomes 1, 3, 5, 9, 10, 16, and 18. Some of these QTLs were detected across the entire experimental period (0-20 min), while others were associated with specific 5-min blocks. Eighteen hundred C57BL/6J (B6) x DBA/2J (D2) F2 intercross animals were phenotyped for the basal locomotor response, and of this group, 500 to 700 individuals, pseudo-randomly selected, were used for a genomewide scan to confirm the RI-generated QTLs and to detect new QTLs. No new QTLs were detected but the QTLs on chromosome 1 were confirmed at p < 10(-5) to p < 10(-9), depending on the time interval. In addition, the QTLs on chromosomes 5 and 9 were confirmed at p < 0.001, providing a combined probability (RI + F2) which exceeds the threshold for a significant association. Two additional phenotypes which showed significant RI strain differences were examined--adaptation and thigmotaxis. Adaptation mapped to the same region of chromosome 9 and thigmotaxis to the same region of chromosome 1 as the distance-traveled QTL. Overall, the data presented here and elsewhere (Flint et al., 1995; Gershenfeld et al., 1997) illustrate that QTLs for basal activity are both robust and reliable.

Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain.

The route of administration influences the reinforcing effects of cocaine. Here we assessed whether there were differences in the efficacy of cocaine to block the dopamine transporters (major target for cocaine's reinforcing effects), as a function of route of administration. Positron emission tomography and [11C]cocaine, a dopamine transporter radioligand, were used to compare the levels of dopamine transporter blockade induced by intravenous, smoked and intranasal cocaine in 32 current cocaine abusers. In parallel, the temporal course for the self-reports of "high" were obtained. Cocaine significantly blocked dopamine transporters. The levels of blockade were comparable across all routes of administration and a dose effect was observed for intravenous and intranasal cocaine but not for smoked cocaine. For equivalent levels of cocaine in plasma and DAT blockade, smoked cocaine induced significantly greater self reports of "high" than intranasal cocaine and showed a trend for a greater effect than intravenous cocaine. The time to reach peak subjective was significantly faster for smoked (1.4+/-0.5 min) than for intravenous cocaine (3.1+/-0.9 min), which was faster than intranasal cocaine (14.6+/-8 min). Differences in the reinforcing effects of cocaine as a function of the route of administration are not due to differences in the efficacy of cocaine to block the dopamine transporters. The faster time course for the subjective effects for smoked than intravenous and for intravenous than for intranasal cocaine highlights the importance of the speed of cocaine's delivery into the brain on its reinforcing effects.

Regional brain metabolism during alcohol intoxication.

BACKGROUND: Ethanol has a broad range of actions on many neurotransmitter systems. The depressant actions of ethanol in the brain are related in part to facilitation of gamma-aminobutyric acid (GABA) neurotransmission via its interaction with the benzodiazepine/GABA receptor complex. The purpose of this study was to evaluate the effects of ethanol on regional brain metabolism in 10 healthy right-handed men. The results were compared with those we previously published in a different group of 16 normal male subjects who received intravenous lorazepam, a benzodiazepine drug that also enhances GABA neurotransmission. METHODS: The subjects were scanned with positron emission tomography and [F-18] fluorodeoxyglucose twice: 40 min after the end of placebo (diet soda) or ethanol (0.75 g/kg) oral administration. Image data sets were analyzed by using both the region of interest and the statistical parametric mapping (SPM) approach. SPM was used to generate a difference image between baseline and ethanol, which we compared to the difference image between baseline and lorazepam (30 microg/kg). RESULTS: Ethanol significantly increased self-reports of "high" (p < or = 0.0001), dizziness (p < or = 0.004), and intoxication (p < or = 0.0001). Ethanol significantly decreased whole brain (-25 +/- 6%, p < or = 0.0001) and regional metabolism. Normalization of the regional measures by whole brain metabolism (relative measures) showed that ethanol decreased relative metabolic activity in occipital cortex (-4.9 +/- 4.1%, p < or = 0.006), whereas it increased relative metabolic act in left temporal cortex (+3.5 +/- 2.9%, p < or = 0.006) and left basal ganglia (+9 +/- 6.3%, p < or = 0.0009). SPM analyses revealed the same pattern of responses as the relative measures, showing decreases in occipital cortex and increases in left temporal cortex. Comparison of the relative measures and the SPM analyses obtained with lorazepam data revealed a similar pattern of effects, with relative decreases in occipital cortex (-7.8 +/- 4.8%) and relative increases in left temporal cortex (+3.8 +/- 5.7%). Lorazepam, but not ethanol, also decreased thalamic metabolism (-11.2 +/- 7.2%). CONCLUSIONS: These results support similar though not identical mechanisms for the effects of alcohol and benzodiazepines on brain glucose metabolism. The fact that lorazepam, but not alcohol, reduced thalamic metabolism, an effect associated with sleepiness, could explain the higher sedative effects of lorazepam than of alcohol.