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Ethanol preference, a component of alcoholism, has been known for four decades to differ greatly between C57BL/6 and BALB/c inbred mouse strains. For mapping quantitative trait loci (QTLs) that affect ethanol preference, we used a set of B6.C Recombinant QTL Introgression (RQI) strains, which carry about 5% of the donor BALB/cJ (C) genome on a C57BL/6ByJ (B6) background. After characterizing males of the progenitor and RQI strains for variations in ethanol preference, we scanned their genome for polymorphisms at 244 dinucleotide-repeat marker loci known to differ between B6 and C. Because of the introgression of BALB/c-type QTLs onto the B6 background, some strains showed ethanol preference significantly lower or higher than that of the background strain, suggesting that genetic interaction between ethanol preference QTLs and the background can be operative. The genomic region showing the strongest influence on ethanol preference was on mouse chromosome 15, and corresponds to human chr.12q11-q13.

The effects of orally self-administered ethanol (ETOH) on responding for rewarding brain stimulation were studied. Bipolar electrodes were implanted in either the lateral hypothalamic region of the medial forebrain bundle (MFB-LH) or the ventral tegmental area (VTA) of 6 male F-344 rats. After surgery subjects were trained in a continuous reinforcement procedure (CRF) for constant current rewarding brain stimulation. On alternate days subjects were allowed to drink an ethanol and sucrose solution (12% and 5%, respectively) for 30 min and subsequently tested on the brain stimulation procedure. All subjects showed facilitation of responding (increase in rate) after ingesting low to moderate doses of ETOH (0.4-1.7 g/kg). Depression of responding (decrease in rate) or return to baseline levels (control solution rate) was observed only in those subjects which ingested 2 g/kg or greater during the drinking period. These results indicate that low to moderate doses of self-administered ethanol will increase responding for rewarding brain stimulation. Further, the results suggest that this facilitation of responding is, at least in part, a function of the method of administration and/or the contingent nature of the ethanol delivery (self-administration).

Previously, results of studies from our laboratory have shown that the offspring of ethanol-fed female rats have a significant decrease in serotonin (5-HT) neurons and glia that contain S100B, an essential trophic factor for the development of 5-HT neurons. The deficiency of S100B-immunopositive glia was detected during the vulnerable period in 5-HT neuron development and in brain areas proximal to these neurons. The reductions of both 5-HT neurons and S100B-positive glia were prevented by maternal treatment with a 5-HT(1A) agonist (i.e., ipsapirone or buspirone). In the current study, we investigated whether the offspring of ethanol-fed rats had a general decrease in the density of glial cells in the brain areas that contain 5-HT neurons, and we determined whether these changes were prevented by maternal treatment with ipsapirone between gestational days (GDs) 13 and 20. We estimated the density of vimentin-positive glia of the midline raphe glial structure (MRGS) at GD 20 and postnatal day (PND) 5 and of glial fibrillary acidic protein (GFAP)-positive astrocytes proximal to the dorsal and median raphe at PNDs 5 and 19. The results of this study provide evidence that in utero ethanol exposure is associated with a reduced density of GFAP-immunopositive astrocytes proximal to the dorsal and median raphe. Maternal ipsapirone treatment significantly increased astroglial density in the dorsal raphe at PNDs 5 and 19 and in the median raphe at PND 5, such that it either prevented (dorsal raphe, PNDs 5 and 19) or blunted (median raphe, PND 5) the effects of ethanol.

Chick embryos given a single dose of ethanol (1.0 g/kg) at the start of incubation (day 0) had widely differing levels of blood alcohol when sacrificed on day 7 and the blood alcohol levels were inversely correlated with whole body and brain weight. Clearance of the alcohol by the embryos was inhibited by simultaneous treatment with 4-methyl pyrazole and this treatment potentiated the brain growth inhibition due to ethanol. Treatment with indomethacin lowered blood alcohol levels on day 7 and protected against the growth inhibition. These data suggest that early chick embryos have varying amounts of alcohol dehydrogenase-like metabolic activity and that higher levels of this activity protect against alcohol-induced brain growth inhibition in this model. If similar variations in the ability to metabolize alcohol exist in human fetuses, it may represent a mechanism by which comparable maternal doses of alcohol produce widely varying fetal effects.

Preclinical and clinical evidence suggest an association between alcoholism and the primary regulator of extracellular dopamine concentrations, the dopamine transporter (DAT). However, the nature of this association is unclear. We determined if 10 days of voluntary alcohol self-administration followed by withdrawal could directly alter DAT function, or if genetically mediated changes in DAT function and/or availability could influence vulnerability to alcohol abuse. Heterozygous (DAT+/-) and homozygous mutant (DAT-/-) and wild-type (DAT+/+) mice were allowed to consume 5% alcohol in a schedule-induced polydipsia (SIP) task. In vivo fixed potential amperometry in anesthetized mice was used to (1) identify functional characteristics of mesoaccumbens dopamine neurons related to genotype, including dopamine autoreceptor (DAR) sensitivity, DAT efficiency, and DAT capacity, (2) determine if any of these characteristics correlated with alcohol drinking observed in DAT+/+ and DAT+/- animals, and (3) determine if SIP-alcohol self-administration altered DAR sensitivity, DAT efficiency, and DAT capacity by comparing these characteristics in wild-type (DAT+/+) mice that were SIP-alcohol naïve, with those that had undergone SIP-alcohol testing. DAT-/- mice consumed significantly less alcohol during testing and this behavioral difference was related to significant differences in DAR sensitivity, DAT efficiency, and DAT capacity. These functional characteristics were correlated to varying degrees with g/kg alcohol consumption in DAT+/+ and DAT+/- mice. DAR sensitivity was consistently reduced and DAT efficiency was enhanced in SIP-alcohol-experienced DAT+/+ mice when compared with naïve animals. These results indicate that DAR sensitivity is reduced by SIP-alcohol consumption and that DAT efficiency is modified by genotype and SIP-alcohol exposure. DAT capacity appeared to be strictly associated with SIP-alcohol consumption.

Recent studies have systematically indicated that newborn rats are highly sensitive to ethanol's positive reinforcing effects. Central administrations of ethanol (25-200mg %) associated with an olfactory conditioned stimulus (CS) promote subsequent conditioned approach to the CS as evaluated through the newborn's response to a surrogate nipple scented with the CS. It has been shown that ethanol's first metabolite, acetaldehyde, exerts significant reinforcing effects in the central nervous system. A significant amount of acetaldehyde is derived from ethanol metabolism via the catalase system. In newborn rats, catalase levels are particularly high in several brain structures. The present study tested the effect of catalase inhibition on central ethanol reinforcement. In the first experiment, pups experienced lemon odor either paired or unpaired with intracisternal (IC) administrations of 100mg% ethanol. Half of the animals corresponding to each learning condition were pretreated with IC administrations of either physiological saline or a catalase inhibitor (sodium-azide). Catalase inhibition completely suppressed ethanol reinforcement in paired groups without affecting responsiveness to the CS during conditioning or responding by unpaired control groups. A second experiment tested whether these effects were specific to ethanol reinforcement or due instead to general impairment in learning and expression capabilities. Central administration of an endogenous kappa opioid receptor agonist (dynorphin A-13) was used as an alternative source of reinforcement. Inhibition of the catalase system had no effect on the reinforcing properties of dynorphin. The present results support the hypothesis that ethanol metabolism regulated by the catalase system plays a critical role in determination of ethanol reinforcement in newborn rats.

Alcohol exposure during pregnancy has been associated with altered brain development and facial dysmorphology. While autism spectrum disorder (ASD) is not specifically related to distinct facial phenotypes, recent studies have suggested certain facial characteristics—increased facial masculinity and asymmetry—may be associated with ASD and its clinical presentations. In the present study, we conducted a preliminary investigation to examine the effects of prenatal alcohol exposure on facial morphology in autistic children with (n = 37; mean age = 8.21 years, SD = 2.72) and without (n = 100; mean age = 8.37 years, SD = 2.47) prenatal alcohol exposure. Using three-dimensional facial scans and principal component analysis, we identified a facial shape associated with prenatal alcohol exposure in autistic children. However, variations in the alcohol-related facial shape were generally not associated with behavioural and cognitive measures. These findings suggest that while early exposure to alcohol may influence the development of facial structures, it is does not appear to be associated with ASD phenotypic variability. Importantly, although these findings do not implicate a role for prenatal alcohol exposure in the etiology of ASD, further research is warranted to investigate the link between prenatal alcohol exposure and facial morphology differences among neurodevelopmental conditions.

The effect of the lesion of central serotonergic neurons by 5,7-dihydroxytryptamine (5,7-DHT), on ethanol-induced taste and place aversion conditioning was studied in male Wistar rats. Control biochemical analysis revealed that 5,7-DHT (250 micrograms per rat, free base, i.c.v.) produced marked and selective depletion of serotonin (5-HT) in the hippocampal formation and the limbic forebrain complex. Ethanol-induced (1.5 g/kg, i.p.) conditioned taste aversion (CTA) to saccharin solution was unaffected by the lesion of central serotonergic neurons. The 5,7-DHT-lesioned and sham-lesioned rats showed comparable ethanol-induced CTA even 30 days after the last ethanol injection. Similarly, ethanol-induced (1.5 g/kg, i.p.) conditioned place aversion (CPA) was unaffected by 5,7-DHT administration. These results suggest that central serotonergic pathways are not primarily involved in the aversive effects of high ethanol doses in rats.