No effect of albinism on sedative-hypnotic sensitivity to ethanol and anesthetics

BACKGROUND: Studies using the long-sleep (LS) X short-sleep (SS) (LSXSS) recombinant inbred mice and inbred long-sleep (ILS) by inbred short-sleep (ISS) intercrosses have found genetic linkage between Tyr albinism (c/c) and differential sensitivity to sedative-hypnotic doses of ethanol and general anesthetics. This linkage could be due to a gene or genes near Tyr or Tyr itself. With regard to the latter possibility, the absence of tyrosinase activity (encoded by Tyr) in albinos could alter tyrosine availability and thus the rate-limiting step in catecholamine synthesis. In addition, albinism is associated with altered brain development that could have pleiotropic effects on behavior. Therefore, in this study, we asked whether albinism affects sedative-hypnotic sensitivity. METHODS: Loss of righting reflex (LORR) duration was measured using doses of ethanol (4.1 g/kg), pentobarbital (70 mg/kg), isoflurane (2 g/kg), and etomidate (20 mg/kg) that were previously associated with differential sensitivity of albino versus nonalbino mice. Tyr transgenics (c/c, Tg(Tyr+)) were backcrossed to ISS (c/c) to compare pigmented (c/c, Tg(Tyr+)) and albino (c/c) mice in the context of an ISS-like background. ISS was also crossed with C57BL/6 (B6) mice heterozygous for a spontaneous albino mutation (c2j) to compare pigmented (c/+) and albino (c/c2j) mice. Pigmented B6 (c2j/+ and +/+) and albino B6 (c2j/c2j) mice were also compared (pentobarbital). RESULTS: For each sedative hypnotic, albinism had no effect on LORR duration. Each expected difference was ruled out at the 95% or 99% confidence level. For each sedative hypnotic, males were more sensitive than females even though the effect size was usually smaller than the expected albino effect size, arguing empirically that the inability to detect an albino effect was not due to systematic error or an insufficient number of mice. CONCLUSION: We conclude that the differential sensitivity associated with albinism is most likely due to a gene or genes near Tyr rather than Tyr itself.     

Quantitative Trait Locus Analyses of Sleep-Times Induced by Sedative-Hypnotics in LSXSS Recombinant Inbred Strains of Mice

The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n -propanol, and n -butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.     

Withdrawal Severity After Chronic Intermittent Ethanol in Inbred Mouse Strains

Background: To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption. The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling‐induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens. Methods: Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced. Results: Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00–2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol‐exposed and air‐exposed groups were tested hourly for handling‐induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups. Conclusion: The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high‐dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.     

Strategies for Mapping and Identifying Quantitative Trait Loci Specifying Behavioral Responses to Alcohol

Most responses to alcohol in both humans and animals are heritable, and this genetic sensitivity to ethanol is determined by multiple genes. However, the number of genes, their identities, and just how they determine susceptibility to the actions of alcohol are unknown. Herein, we describe a multistage strategy for mapping quantitative trait loci (QTLs) using recombinant inbred strains and F2 mice. Precise mapping of the chromosome positions of these QTLs should increase our understanding of the genetic causes for individual differences in behavioral sensitivity to alcohol by (1) identifying genomic markers associated with sensitivity to alcohol, (2) allowing the genes specifying behavior to be cloned by position, and (3) elucidating "candidate" genes demonstrating linkage to markers associated with behavioral responses to alcohol. Syntenic conservation between the mouse and human genomes should facilitate the eventual mapping and cloning of human homologs of these QTLs. Ultimately, cloning of these genes may allow the development of gene therapies or other therapeutic interventions for management or prevention of alcoholism and alcohol abuse.     

Ethanol-Induced Conditioned Taste Aversion in BXD Recombinant Inbred Mice

Genetic differences in sensitivity to ethanol's aversive effects may play an important role in the development of alcohol-seeking behavior and alcoholism. The present study examined the development of ethanol-induced conditioned taste aversion in 20 BXD/Ty recombinant inbred strains of mice and their progenitor inbred strains, C57BL/6J (B6) and DBA/2J (D2). Adult male mice were given 1-hr access to a saccharin-flavored solution every 48 hr for 12 days. After all but the first and last saccharin access periods, they received ethanol injections (0, 2, or 4 g/kg, ip). Separate groups of unpaired control mice received 4 g/kg of ethanol 1 hr after water access. Saline control mice were also used for examining preference across a wide range of saccharin concentrations (0.019 to 4.864% w/v). As expected, saccharin consumption during taste conditioning declined over conditioning trials in a dose-dependent manner, indicating development of ethanol-induced conditioned taste aversion. Correlational analyses using strain means from recently published papers indicated no significant genetic correlation between taste conditioning and two phenotypes thought to reflect ethanol reinforcement or reward (ethanol drinking, conditioned place preference). However, there were significant genetic correlations between taste conditioning at the high dose and sensitivity to ethanol-induced hypothermia, rotarod ataxia, and acute withdrawal. Quantitative trait locus (QTL) analyses of strain means indicated that taste aversion was associated (p 0.01) with genetic markers on nine chromosomes (1, 2, 3, 4, 6, 7, 9,11, and 17). These QTLs were located near several candidate genes, including genes encoding several different acetylcholine receptor subunits, the 6 opioid receptor, and two serotonin receptors (lB and 1D). QTLs for saccharin preference were located on several of the same chromosomes (2,3,4,6, and 11). Two of these saccharin QTLs overlap candidate genes influencing sensitivity to sweet or bitter taste stimuli. In general, these findings support the conclusion that multiple genes influence ethanol-induced conditioned taste aversion. Some of these genes appear to influence taste sensitivity, whereas others appear to mediate sensitivity to aversive pharmacological effects of ethanol.     

Newborn Organ Weight and Spontaneous Hypertension: Recombinant Inbred Strain Study

Heart and kidney weight of newborn rats was studied in two progenitor strains (Brown Norway - BN, and spontaneously hypertensive rats - SHR) and in 31 recombinant inbred (RI) strains developed by inbreeding of F2 cross derived from these two progenitors. The relative weight of both organs was significantly higher in SHR newborns than in BN ones. No differences in relative DNA, protein and water contents were detected in hearts from SHR and BN newborns. On the other hand, in SHR kidneys there was lower DNA and protein content accompanied by a higher water content. This suggested that kidneys of SHR babies had less cells with higher water content.

The average body weight of newborns in individual RI strains was continuously distributed between both progenitor strains but more RI strains resembled values of SHR newborns. The opposite was true for relative heart and kidney weights where the predominant influence of BN genes was visible. Moreover, there was an important difference between two reciprocal crosses of RI strains because the relative heart weight was clustered around SHR values only in BxH but not in HxB cross. This was, however, not observed for body weight and relative kidney weight.     

Effects of Acute and Repeated Ethanol Exposures on the Locomotor Activity of BXD Recombinant Inbred Mice

Investigations of ethanol's (EtOH's) complex response profile, including locomotor and other effects, are likely to lead to a more in-depth understanding of the constituents of alcohol addiction. Locomotor activity responses to acute and repeated EtOH (2 g/kg, ip) exposures were measured in BXD recombinant inbred (RI) mice and their C57BL/6J (B6) and DBA/2J (D2) progenitors. Both the acute response and the change in initial EtOH response with repeated treatments were strain-dependent. The coefficient of genetic determination was 0.38–0.49 for initial locomotor response to EtOH, and 0.29 for change in response. Changes in response were largely attributable to sensitization of locomotor stimulation. Quantitative trait loci (QTL) analyses identified significant marker associations with basal activity, acute locomotor response, and change in response. Markers were for QTL on several chromosomes, and there was only one case of overlap in marker associations among phenotypes. Acute locomotor response and locomotor sensitization were negatively correlated with 3% EtOH preference drinking data collected in BXD Rl strains. Overall, these results demonstrate locomotor sensitization induced by EtOH, suggest independence of genetic determination of locomotor responses to acute and repeated EtOH exposure, and partially support a relationship between reduced sensitivity to the locomotor stimulant/sensitizing effects of EtOH and EtOH consumption.     

A Comparison of Sensitivity to Oxotremorine and Muscarinic Receptors in LS and SS Mice

Several studies have suggested that ethanol interacts with muscarinic cholinergic systems in the brain. In order to assess whether muscarinic systems regulate sensitivity to ethanol, the effects of oxotremorine pretreatment on sensitivity to ethanol were determined in the long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differential sensitivity to ethanol. In addition, the relative sensitivity of these two lines to intraperitoneally (ip) injected oxotremorine and total muscarinic receptors, as measured by quinuclidinyl benzilate (QNB) binding, M1 receptor subtypes, as measured by pirenzepine (PZ) binding, and ratios of high and low agonist affinity were measured in seven brain regions. SS mice were more sensitive to oxotremorine-induced increases in sensitivity to ethanol but the LS mice were more sensitive to the effects elicited by ip oxotremorine injection. Because the effects of oxotremorine were blocked by scopolamine but not by methylscopolamine, it is likely that the effects of oxotremorine that were measured are centrally mediated. QNB binding did not differ between the LS and SS mice except for cortex where the SS mice exhibited slightly larger numbers. The mouse lines did not differ in the number of M1 receptors or in ratio of high to low affinity agonist sites. Therefore, it does not seem likely that differences in receptor numbers are important in regulating the differential sensitivities of the LS and SS mice to oxotremorine or ethanol. Differences in receptor coupling processes may be critically involved.     

Biometrical Genetic Analysis of Ethanol's Psychomotor Stimulant Effect

Hereditary influences on psychomotor stimulant effects of ethanol (ETOH) were studied in a classical Mendelian cross of DBA/2Abg (D2) and C57BL/6Abg (B6) inbred mouse strains. A dose-response study with nine doses (0–3.5 g/kg ip) indicated that B6 mice lack the activational limb of the biphasic curve ( 1.5 g/kg), as assessed in a 15-min test. D2 mice ran greater distances and ran faster, at doses up to 2.5 g/kg. B6 mice showed no increments in speed or distance at these doses that activated D2 mice. Several other indices reinforced the conclusion of ETOH-induced behavioral activation in D2 mice and lack there of in B6 mice (traditional photobeam interruptions—horizontal counts; center distance; vertical movements; inactive time; as well as derived indices of running speed and average length of each movement). The F₁, F₂, and backcross generations produced dose-response curves that showed additive inheritance of the activational response to doses below 1.5 g/kg. A second study ( n = 1446) examined response to 1.5 g/kg with a within-subjects design in the full Mendelian cross. This study verified the completely additive mode of inheritance for the total distance measure suggested in the dose-response study, and showed that sex linkage and sex differences were not present. Narrow sense heritability of the ETOH activation response (indexed by total distance) was calculated at 0.35 and ∼3 loci were estimated to be responsible for the B6/D2 difference. The other phenotypes (described above) also showed strongly additive genetic control. These studies indicate that the psychomotor stimulant effect of ETOH in mice is under genetic influence and that the control mechanism is a simple, small-sized polygenic system, with an uncomplicated mode of inheritance that should make it amenable to further characterization at a functional level.     

Mutations Affecting Sensitivity to Ethanol in the Nematode, Caenorhabditis elegans

Mutations in nine genes have been identified in the nematode, Caenorhabditis elegans , which control sensitivity to ethanol. The interaction of these genes has been examined and used to determine a genetic pathway controlling sensitivity to ethanol. The nature of this pathway indicates that ethanol exerts its anesthetic actions at more than one site of action. These results also indicate that ethanol is similar in its effects to the volatile anesthetics, enflurane and isoflurane.     

A Genetic Analysis of Ethanol, Pentobarbital, and Methyprylon Sleep-Time Response

The sleep-time responses to ethanol, pentobarbital, and methyprylon were assessed in various generations derived from crossing the long-sleep (LS) and short-sleep (SS) mouse lines in order to assess whether common or different genes regulate response to these agents. The LS and SS mice were selectively bred for differences in duration of ethanol-induced sleep time. Ethanol and pentobarbital responses segregate in a different fashion into F1 and F2 generations derived from the LS and SS lines, indicating different genie control and probably different mechanisms of action for these two agents. Ethanol and methyprylon response segregated similarly but fewer genes seem to influence methyprylon response. These results support the notion that water-soluble depressants have common mechanisms of action.     

Neuroadaptive Responses to Chronic Ethanol

Cellular responses of neuronal tissue to chronic ethanol exposure are reviewed. Evidence for adaptive responses to the acute actions of ethanol is available for five systems: GABA-activated chloride channels, voltage-sensitive calcium channels, NMDA-activated cation channels, receptors coupled through stimulatory guanine nucleotide binding proteins, and membrane lipid order. We suggest that at least some of these adaptive responses occur because of ethanol actions at the level of gene expression.     

Ethanol Teratogenesis in Five Inbred Strains of Mice

Background:  Previous studies have demonstrated individual differences in susceptibility to the detrimental effects of prenatal ethanol exposure. Many factors, including genetic differences, have been shown to play a role in susceptibility and resistance, but few studies have investigated the range of genetic variation in rodent models.
Methods:  We examined ethanol teratogenesis in 5 inbred strains of mice: C57BL/6J (B6), Inbred Short-Sleep, C3H/Ibg, A/Ibg, and 129S6/SvEvTac (129). Pregnant dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of maltose–dextrin (MD) on day 9 of pregnancy. Dams were sacrificed on day 18 and fetuses were weighed, sexed, and examined for gross morphological malformations. Every other fetus within a litter was then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in ethanol for subsequent skeletal analyses.
Results:  B6 mice exposed to ethanol in utero had fetal weight deficits and digit, kidney, brain ventricle, and vertebral malformations. In contrast, 129 mice showed no teratogenesis. The remaining strains showed varying degrees of teratogenesis.
Conclusions:  Differences among inbred strains demonstrate genetic variation in the teratogenic effects of ethanol. Identifying susceptible and resistant strains allows future studies to elucidate the genetic architecture underlying prenatal alcohol phenotypes.     

Locomotor Activity Responses to Ethanol in Selectively Bred Long- and Short-Sleep Mice, Two Inbred Mouse Strains, and Their F1 Hybrids

Locomotor activity responses to sub-hypnotic doses of ethanol (ETOH) were assessed in selected lines of mice (LS and SS), inbred strains, and their F1 hybrids. Data were obtained as photocell beam interruptions in a 15-min test for a dose range of 0 to 2.75 or 3.5 g/kg for LS and SS mice, respectively. Biphasic dose-response curves were obtained for LS and SS mice with the SS mice showing a sedative limb of the dose-response curve shifted to the right. The effects of 2.0 g/kg ETOH were also assessed in a diallel cross of the selected LS/SS lines and C57BL/6Abg and MOLD/RkAbg inbred strains. The 2.0 g/kg dose produced a wide range of responses, from sedation in C57BL/6Abg mice to extreme activation in SS and MOLD/RkAbg mice, and no effect in LS mice. The responses of F₁ hybrids reflected a typical pattern of partial dominance, with heterosis in some crosses. When present, dominance was in the direction of greater locomotor activation. These patterns were confirmed by biometrical genetic analysis of the 4 × 4 diallel cross of the two lines and the two inbred strains. The data indicate that loci in addition to those responsible for selection for sedative sensitivity in LS and SS mice can influence locomotor activation produced by sub-hypnotic ETOH doses, and that SS and MOLD mice show locomotor activation for different genetic reasons.     

Effects of Ethanol on Structural Parameters of Rat Brain Membranes: Relationship to Genetic Differences in Ethanol Sensitivity

Fluorescent probes located in different membrane regions were used to evaluate effects of ethanol (50 and 100 mM) on structural parameters (protein distribution, fluidity of total and annular lipid, and thickness of the bilayer) of synaptic plasma membranes (SPMs) from brain cortex of High-Alcohol Sensitivity (HAS) and Low-Alcohol Sensitivity (LAS) rats. An experimental procedure based on radiationless energy transfer from tryptophan of membrane proteins to pyrene, 1,3-bis-(1-pyrene)propane(pyr-C₃-pyr), or 1,6-diphenyl-1,3,5-hexatriene (DPH), as well as pyr-C₃-pyr monomer-eximer formation and DPH polarization, and energy transfer from pyrene monomers to 1-anilinonaphthalene-8-sulfonic acid (ANSA) was utilized. The efficiency of energy transfer from tryptophan to pyrene was sensitive to protein clustering induced in SPMs by concanavalin A. Efficiency of energy transfer from pyrene monomers to ANSA was different for vesicles of dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline, and distearoyl phosphatidyl choline, consistent with differences in the thickness of these lipid bilayers. Without ethanol, there were no significant differences between the structural parameters of SPMs from HAS and from LAS rats. Addition of ethanol (50 mM) changed protein distribution (increased clustering) only in membranes from HAS rats and had no effect on the structure of membranes from LAS rats. A larger concentration of ethanol (100 mM) changed the fluidity of annular and total lipid in both lines of rats, but changed protein distribution and decreased thickness of the membranes from HAS rats with no effect on these parameters in SPMs from LAS animals. Ethanol (50 and 100 mM) decreased the binding affinity of ANSA for membranes from HAS, but not LAS rats. Genetic differences in ethanol sensitivity of HAS and LAS rats may be related to effects of ethanol on protein mobility, protein-protein interactions, or membrane thickness, but do not appear to be due to effects of ethanol on the fluidity of membrane lipids.     

A mutation in mitochondrial complex I increases ethanol sensitivity in Caenorhabditis elegans

BACKGROUND: The gene gas-1 encodes the 49-kDa subunit of complex I of the mitochondrial electron transport chain in Caenorhabditis elegans. A mutation in gas-1 profoundly increases sensitivity to ethanol and decreases complex I-dependent metabolism in mitochondria. METHODS: Mitochondria were isolated from wild-type and gas-1 strains of C. elegans. The effects of ethanol on complex I-, II-, and III-dependent oxidative phosphorylation were measured for mitochondria from each strain. Reversibility of the effects of ethanol was determined by measuring oxidative phosphorylation after removal of mitochondria from 1.5 M ethanol. The effects of ethanol on mitochondrial structure were visualized with electron microscopy. RESULTS: We found that ethanol inhibited complex I-, II-, and III-dependent oxidative phosphorylation in isolated wild-type mitochondria at concentrations that immobilize intact worms. It is important to note that the inhibitory effects of ethanol on mitochondria from either C. elegans or rat skeletal muscle were reversible even at molar concentrations. Complex I activity was lower in mitochondria from gas-1 animals than in mitochondria from wild-type animals at equal ethanol concentrations. Complex II activity was higher in gas-1 than in wild-type mitochondria at all concentrations of ethanol. No difference was seen between the strains in the sensitivity of complex III to ethanol. CONCLUSIONS: The difference in ethanol sensitivities between gas-1 and wild-type nematodes results solely from altered complex I function. At the respective concentrations of ethanol that immobilize whole animals, mitochondria from each strain of worms displayed identical rates of complex I-dependent state 3 respiration. We conclude that a threshold value of complex I activity controls the transition from mobility to immobility of C. elegans.     

The Rate of Ethanol Absorption is Influenced by Corticosterone in Long-Sleep and Short-Sleep Mice

Ethanol was administered by intragastric (IG) injection and absorption was measured in long-sleep (LS) and short-sleep (SS) mice under various conditions that alter levels of adrenal steroids. In naive mice, LS mice absorbed ethanol more quickly than SS mice. Ethanol absorption was slower in both lines of mice after adrenalectomy (ADX). Short-term inhibition of corticosterone synthesis had no effect on ethanol absorption in either line of mice. The effect of ADX was most pronounced in SS mice at 24 hr after surgery and at 168 hr after surgery in LS mice. Therefore, the effects of various steroid replacements were examined at these times. At 24 hr after ADX, ethanol absorption was replaced to SHAM-operated values in SS mice receiving corticosterone treatments. Likewise, in LS mice at 168 hr after ADX, corticosterone implants reversed the effects of ADX while dexamethasome was ineffective. These results support a role for corticosterone in regulation of gastric ethanol absorption and suggest that the lack of repeatability for pharmacokinetic measures of ethanol absorption and metabolism in previous human and animal studies may relate to environmental impact on stress responses.     

Confirmation of Correlations and Common Quantitative Trait Loci Between Neurotensin Receptor Density and Hypnotic Sensitivity to Ethanol

BACKGROUND: In previous studies, genetic correlations were observed between hypnotic sensitivity to ethanol and high-affinity neurotensin receptor (NTS1) binding. Provisional quantitative trait loci (QTLs) were identified for these traits, and some of these QTLs were found on common chromosomal regions. In continued efforts to examine the relationship between NTS1 binding capacity and hypnotic sensitivity to ethanol, studies were designed to confirm correlations between NTS1 densities in the brain, duration of ethanol-induced loss of righting reflex (LORR), and blood ethanol concentrations at regain of righting reflex (BECRR). Another purpose of the study was to confirm QTLs for these traits. METHODS: ILS X ISS F2 mice and HAS X LAS F2 rats as well as the progenitors were tested for LORR, BECRR, and NTS1 densities. Phenotypic correlations were calculated between LORR and BECRR and between these measures and NTS1 densities in striatum from both mice and rats. The F2 mice were genotyped by using polymorphic markers for five previously reported QTLs for LORR to confirm QTLs for BECRR and NTS1 densities in striatum, ventral midbrain, and frontal cortex. RESULTS: Phenotypic correlations were found between LORR and BECRR (r = -0.66 to -0.74, p < 10(-9)) and between these measures and NTS1 densities in striatum (r = 0.28-0.38, p < 10(-2)) from both mice and rats. QTLs for LORR and BECRR (lod score = 2-6) were found in common regions of chromosomes 1, 2, and 15. By using the combined results from a previous LSXSS RI study and the current results, a suggestive QTL (lod score = 3.1) for striatal NTS1 receptor densities was found on chromosome 15 at approximately 60 cM, in the same region as the chromosome 15 LORR/BECRR QTL. CONCLUSIONS: The results are in agreement with previously reported correlations and QTLs for NTS1 receptor densities and measures of hypnotic sensitivity to ethanol in mice and extend those correlations to another species, the rat. These findings support a role for NTS1 in genetically mediated differences in hypnotic sensitivity to ethanol.