Up-regulation of gamma-aminobutyric acid transporter I mediates ethanol sensitivity in mice

Ethanol is among the most widely abused drugs in the world. Chronic ethanol consumption leads to ethanol tolerance and addiction, and impairs learning and memory. Na+/Cl- dependent GABA transporters play an important role in controlling the concentration of GABA in the synaptic cleft, and thus they control the intensity and duration of synaptic transmission of GABA. It has been suggested that GABAergic system is involved in ethanol consumption, tolerance and addiction, because chronic ethanol consumption alters the expression of GABAA receptors and drugs on GABA receptors affect ethanol actions. The results of the present study reveal that that activity of GABA transporters in mouse brain after 15-min acute ethanol injection or after chronic ethanol consumption is increased. Moreover, mice pre-injected with a competitive or a noncompetitive antagonist of gamma-aminobutyric acid transporter subtype 1 (GAT1) showed high sensitivity to the sedative/hypnotic effects of ethanol. In contrast, transgenic mice overexpressing GAT1 displayed low sensitivity to ethanol, as shown by the righting reflex test. Mice overexpressing GAT1 survived a lethal dose of ethanol (9 g/kg, i.p.) longer, maintained locomotor activity longer after a sub-lethal dose (1.75 g/kg, i.p.) and exhibited a higher median lethal dose than wild-type littermates. These results suggest that GAT1 plays an important role in sensitivity to ethanol, and might be a therapeutic target for alcoholism prevention and treatment. Acute and chronic ethanol administration resulted in the increase of GABA transporter function. Use of GAT1 selective inhibitors and GAT1 overexpressing mice thus demonstrate that GAT1 should be an important protein mediating sensitivity to ethanol in mice.     

A biometrical genetic analysis of ethanol response in selectively bred Long-Sleep and Short-Sleep mice

A classical Mendelian cross was derived from Long-Sleep (LS) and Short-Sleep (SS) mice, lines selectively bred for differences in response to hypnotic doses of ethanol (ETOH). Biometrical genetic procedures applied to the selection phenotype, namely, duration of the ETOH-induced loss of the righting reflex, suggest that a simple additive genetic system controls this depressant response. Sex differences were present in the Mendelian cross generations that had the longest duration responses. An estimate of the number of loci differentiated by the selection was nine. Blood ethanol levels at the time of regaining the righting reflex in the seven genotypes of the Mendelian cross showed that the selection operated solely by changing tissue sensitivity to ethanol.This work was supported by a grant from the SUNY Research Foundation.     

Modulation of extrasynaptic THIP conductances by GABAA-receptor modulators in mouse neocortex

THIP is a hypnotic drug, which displays a unique pharmacological profile, because it activates a subset of extrasynaptic gamma-aminobutyric acid type A (GABA(A)) receptors containing delta-subunits. It is important to study the physiology and pharmacology of these extrasynaptic receptors and to determine how THIP interacts with other hypnotics and anesthetics. Here, we study the modulation of the extrasynaptic response to THIP using three classes of GABA(A)-receptor ligands. In whole cell recordings from mouse neocortical layer 2/3 pyramidal cells, THIP induced an extrasynaptic tonic current of 44 +/- 5 pA. The benzodiazepine site agonist and hypnotic zolpidem (500 nM), which displays selectivity for alpha(1/2/3)- and gamma(2)-containing receptors, did not alter the tonic current induced by THIP. The anesthetic etomidate (1 microM), which shows selectivity for beta(2)- and beta(3)-containing GABA(A) receptors, potentiated the THIP current by 126%. Etomidate also induced a small tonic GABA(A) current per se. The anesthetic propofol (1 microM), which displays broad-spectrum modulatory effects on several GABA(A)-receptor subtypes, enhanced the tonic THIP current by 117%. Finally, all three compounds modulated the function of intrasynaptic receptors activated by synaptically released GABA. Our study shows that the extrasynaptic GABA(A) receptors responsible for the tonic THIP conductance likely do not contain alpha(1)-, alpha(2)-, alpha(3)-, and gamma(2)-subunits. Thus the tonic GABAergic conductance in the neocortex is presumably mediated by alpha(4)beta(2/3)delta receptors, which are likely to play a major role for neocortical excitability. Furthermore, our study has deepened the knowledge about the cellular actions of THIP as well as THIP's interactions with other hypnotics and anesthetics.     

Sensitivity to ethanol in inbred mice: genotypic correlations among several behavioral responses

The sensitivity of several inbred strains of mice was assessed for ethanol's effects on activity, body temperature, ataxia, balance, and the righting reflex. Genotypic correlations among the mean responses for the strains were estimated as indexes of pleiotropic influences of genes on drug responses. Three major groups of genetic influence were detected: (a) hypothermic sensitivity to ethanol, (b) activity change (increase after ethanol), and (c) high basal activity. In the first group of variables, strains that had large reductions in body temperature after being given ethanol had high baseline temperatures, pronounced ataxic response to ethanol, and a long-lasting loss of righting reflex. Home cage baseline activity was negatively correlated with body temperature variables. The second group of variables was composed largely of ethanol-induced increases and decreases in activity, which were negatively intercorrelated. Strains with larger increases in activity showed more rapid loss of balance after ethanol. The third group of variables indicated that high levels of basal activity in an open field and in the home cage were determined by the action of common genes. Strains with higher basal activity levels had reduced sensitivity to ambulatory ataxia following ethanol. Thus, there were substantial pleiotropic effects of common genes on several behavioral responses to ethanol in inbred mice. Conversely, the three major groups were not systematically correlated with one another to a major extent. This suggests the influence of three reasonably distinct sets of genes on these responses to ethanol.     

Sensitivity to ethanol-induced motor incoordination in 5-HT(1B) receptor null mutant mice is task-dependent: implications for behavioral assessment of genetically altered mice

Neuromuscular impairment by ethanol likely involves complex effects on balance, gait, muscle strength, and other features of motor coordination. The present experiments showed that relative sensitivity to ethanol-induced motor impairment in serotonin 1B (5-HT(1B)) null mutant and control mice was task dependent. We found that ethanol-treated null mutant mice made fewer missteps on a balance beam than did ethanol-treated wild-type mice, and confirmed a previous finding of their lesser ethanol sensitivity in the grid test. The genotypes did not differ in ethanol sensitivity as measured by the screen test, static dowel, fixed-speed rotarod, accelerating rotarod, grip strength, or loss of righting reflex tests. These experiments suggest that within a behavioral domain, alternative tests of function are not equivalent, so multiple assessment tools should be used to avoid misinterpretation of gene function.     

Behavioral Differences Between C57BL/6J × FVB/NJ and C57BL/6J × NZB/B1NJ F1 Hybrid Mice: Relation to Control of Ethanol Intake

C57BL/6J × FVB/NJ F1 (B6 × FVB) mice consume more alcohol than C57BL/6J × NZB/B1NJ F1 (B6 × NZB) mice and this high alcohol consumption is stable after abstinence whereas B6 × NZB show reduced consumption, thus providing models of Sustained Alcohol Preference (SAP) and Reduced Alcohol Preference (RAP). In female hybrids, we assessed several behavioral responses to define behaviors which might predict SAP and RAP. B6 × FVB exhibited less severe ethanol-induced conditioned taste aversion and were less sensitive to ethanol-induced loss of righting reflex than B6 × NZB. Both hybrids demonstrated ethanol-induced place preference and a low ethanol withdrawal severity. We found that these hybrids differ in their sensitivity to the aversive and sedative, but not rewarding, effects of ethanol. Results of elevated plus maze, mirror chamber, and locomotor tests reveal B6 × FVB mice are less anxious and more active than B6 × NZB mice. Results obtained offer insights about factors that determine SAP and RAP in these new genetic models of alcohol consumption.     

Genetic correlational analyses of ethanol reward and aversion phenotypes in short-term selected mouse lines bred for ethanol drinking or ethanol-induced conditioned taste aversion

Short-term selective breeding created mouse lines divergent for ethanol drinking (high drinking short-term selected line [STDRHI], low drinking [STDRLO]) or ethanol-induced conditioned taste aversion (CTA; high [HTA], low [LTA]). Compared with STDRLO, STDRHI mice consumed more saccharin and less quinine, exhibited greater ethanol-induced conditioned place preference (CPP), and showed reduced ethanol stimulation and sensitization under some conditions; a line difference in ethanol-induced CTA was not consistently found. Compared with LTA, HTA mice consumed less ethanol but were similar in saccharin consumption, sensitivity to ethanol-induced CPP, and ethanol-induced locomotor stimulation and sensitization. These data suggest that ethanol drinking is genetically associated with several reward-and aversion-related traits. The interpretation of ethanol-induced CTA as more genetically distinct must be tempered by the inability to test the CTA lines beyond Selection Generation 2.     

Quantitative trait loci for ethanol sensitivity in the LS X SS recombinant inbred strains: Interval mapping

We are mapping the genes (quantitative trait loci or QTLs) that are responsible for individual differences in ethanol sensitivity, measured as the duration of loss of righting reflex (LORR) and blood ethanol concentrations upon recovery of the righting reflex (BEC). The Long-Sleep (LS) and Short-Sleep (SS) selected lines of mice manifest an 18-fold difference in LORR and serve as a rodent model for ethanol sensitivity. The LS x SS recombinant inbred (RI) series, developed from LS and SS lines, are an important resource for QTL mapping of ethanol-related responses. The current report summarizes the initial QTL analysis of LORR and BEC in the LS x SS strains and compares the results of correlational analysis with an interval-mapping approach. The data provide strong evidence for QTLs that influence ethanol sensitivity on mouse chromosomes 1 and 2 and possible QTLs on chromosomes 1, 3, 4, 5, 6, 7, 12, 13, 16, and 18. These results are compared to those from an F₂ cross which confirms QTLs on chromsomes 1, 2, 4, and 18.     

Ventral tegmental area region governs GABA(B) receptor modulation of ethanol-stimulated activity in mice

Locomotor stimulation in response to ethanol in mice may model human ethanol-induced euphoria. The associated neural substrates, possibly relevant to alcoholism, have not been fully elucidated. Systemic injection of baclofen, a GABA(B) receptor agonist, attenuates ethanol's stimulant effects. GABA(B) receptors on dopamine cell bodies in the ventral tegmental area (VTA) may modulate ethanol-induced dopamine release, a postulated mechanism for ethanol's stimulant effects. However, baclofen's attenuating effects could be associated with peripheral receptor actions. Baclofen was injected i.c.v. or into the VTA of FAST mice, bred for extreme sensitivity to ethanol-induced locomotor stimulation, to test the hypotheses that (1) central GABA(B) receptors influence baclofen's effects on ethanol-stimulated activity, and (2) VTA GABA(B) receptors specifically modulate ethanol's stimulant effects. I.c.v. baclofen dose-dependently attenuated ethanol stimulation, supporting a central locus for baclofen's effects. Anterior VTA baclofen also attenuated ethanol stimulation. However, more posterior VTA infusions unexpectedly potentiated ethanol stimulation. In SLOW mice, bred for resistance to ethanol stimulation, posterior intra-VTA baclofen did not alter EtOH response. However, anterior VTA baclofen alone produced a locomotor depressant effect in SLOW mice, not seen in FAST mice. GABA(B) receptor autoradiography using [(3)H]CGP 54626, a potent GABA(B) receptor antagonist, did not reveal line differences in binding density in the VTA, or in the substantia nigra pars compacta, a nearby brain structure associated with motor control. These results suggest that anterior VTA GABA(B) receptors play a role in baclofen's attenuation of ethanol's stimulant effects, and that posterior VTA GABA(B) receptors serve an opposite role that is normally masked. Selection for differential ethanol stimulant sensitivity has altered VTA GABA(B) systems that influence locomotor behavior. However, differences in GABA(B) receptor densities in the VTA or substantia nigra pars compacta cannot explain the selected line difference.     

Behavioral sensitization to ethanol is modulated by environmental conditions, but is not associated with cross-sensitization to allopregnanolone or pentobarbital in DBA/2J mice

RATIONALE: The ability of ethanol to facilitate GABA(A) receptor-mediated transmission may result in GABA(A) receptor alterations during repeated ethanol administration, and lead to dynamic behavioral changes, including sensitization to the locomotor stimulant effect of ethanol. Since alterations in GABA(A) receptors are likely to alter sensitivity to GABAergic drugs such as 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and pentobarbital, we determined whether enhanced sensitivity to ethanol was associated with enhanced sensitivity (cross-sensitization) to these drugs. Two procedures that produced differences in the magnitude of expression of ethanol-induced locomotor sensitization were used. METHODS: After habituation to testing procedures for 2 days, female DBA/2J mice were injected with ethanol or saline for 12 days. On the following day, locomotion was recorded after a challenge injection of ethanol (2 g/kg), allopregnanolone (10 or 17 mg/kg), or pentobarbital (10 or 20 mg/kg). Due to evidence that exposure to the test chambers influenced sensitization, in some experiments, mice were exposed to the test apparatus on the day prior to challenge. RESULTS: Exposure to the test apparatus prior to drug challenge attenuated the expression of ethanol sensitization, compared with mice without this pre-exposure. Cross-sensitization was not observed to either allopregnanolone or pentobarbital under any condition; however, some groups of repeated ethanol-treated mice displayed tolerance to the initial stimulant effects of allopregnanolone and pentobarbital. CONCLUSIONS: These studies indicate that behavioral sensitization to ethanol is not associated with cross-sensitization to pentobarbital or allopregnanolone, and that the expression of ethanol sensitization is influenced by the relative novelty of the test chamber. In addition, these results do not support a mechanism in which alterations in the neurosteroid or barbiturate modulatory sites of the GABA(A) receptor are responsible for the expression of sensitization to the locomotor stimulant effects of ethanol.     

Age differences in ethanol-induced hypothermia and impairment in mice

This experiment examined the effects of ethanol on body temperature and ethanol-induced impairment among three different age groups (8 months, 18 months, and 28 months) of C57BL/6NNIA male mice. Mice were injected intraperitoneally with 3 g/kg ethanol or an equivalent volume of saline. Body temperature, blood ethanol levels, and time when the righting response (RR) was lost and regained were measured. Body temperature also was measured prior to injection and at 30 and 120 min post-injection The aged mice showed less ethanol-induced hypothermia but were impaired longer as compared to the younger mice. Blood ethanol levels at loss and regaining of the RR were lower for old mice than the younger mice. Body temperature for the youngest group was lower at each time of measurement as compared to the older groups. Age differences in body temperature prior to ethanol or saline injection were small and nonsignificant.     

Distinctive roles of Fyn and Lyn in IgD- and IgM-mediated signaling.

Src family kinases Fyn and Lyn associate with the B cell antigen receptor (BCR). Accumulating data show that Lyn plays important roles in BCR-mediated signaling, while the role of Fyn remains obscure. Here we dissected the role of Fyn and Lyn in BCR signaling using B cells from fyn(-/-), lyn(-/-) and fyn/lyn double-deficient (fyn(-/-)lyn(-/-)) mice. In contrast to previous reports, fyn(-/-) B cells were slightly hyporeactive to both anti-IgM and anti-IgD-dextran. Although lyn(-/-) B cells were hyper-reactive to anti-IgM, anti-IgD-induced proliferation was impaired in lyn(-/-) B cells. Most of the other phenotypes of fyn(-/-)lyn(-/-) mice were similar to that of lyn(-/-) mice, except that proliferative responses of B cells to various stimuli, such as BCR cross-linking and lipopolysaccharide, were significantly lower in fyn(-/-)lyn(-/-) mice than in lyn(-/-) mice. Finally, immune responses to thymus-independent type 2 antigen were affected in these mutant mice. These observations suggest that Fyn and Lyn are involved in B cell functions, and play similar, but partly distinct, roles in BCR signaling.     

Ethanol potentiates GABAergic synaptic transmission in a postsynaptic neuron/synaptic bouton preparation from basolateral amygdala

Interactions between ethanol and synaptic transmission mediated by gamma -amino-N-butyric acid (GABA) have been suggested to contribute to alcohol intoxication. Ethanol effects on postsynaptic GABAA receptors have been the major focus of this line of research. There is increasing evidence that ethanol potentiation of GABAergic transmission involves increased GABA release from presynaptic terminals. In the present study, a mechanically isolated neuron/bouton preparation from the basolateral amygdala was used to examine the effects of ethanol on spontaneous GABAergic synaptic currents elicited by GABA release from the presynaptic terminals. We found that ethanol application produced a rapid increase in the frequency of spontaneous GABAergic synaptic currents. An acute tolerance to ethanol was also observed, and this tolerance involved GABAB receptor activation. The ethanol-induced potentiation did not involve alterations in the function of postsynaptic GABAA receptors and was independent of presynaptic action potential firing. These findings indicate that ethanol potentiates GABA release, most likely via a direct action on presynaptic boutons.     

Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA(A) receptors

Extrasynaptic GABA(A) receptors (eGABARs) allow ambient GABA to tonically regulate neuronal excitability and are implicated as targets for ethanol and anesthetics. These receptors are thought to be heteropentameric proteins made up of two α subunits-either α4 or α6-two β2 or β3 subunits, and one δ subunit. The GABA analog 4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3(-ol) (THIP) has been proposed as a selective ligand for eGABARs. Behavioral and in vitro studies suggest that eGABARs have nanomolar affinity for THIP; however, all published studies on recombinant versions of eGABARs report micromolar affinities. Here, we examine THIP sensitivity of native eGABARs on cerebellar neurons and on reconstituted GABARs in heterologous systems. Concentration-response data for THIP, obtained from cerebellar granule cells and molecular layer interneurons in wild-type and δ subunit knockout slices, confirm that submicromolar THIP sensitivity requires δ subunits. In recombinant experiments, we find that δ subunit coexpression leads to receptors activated by nanomolar THIP concentrations (EC(50) of 30-50 nM for α4β3δ and α6β3δ), a sensitivity almost 1,000-fold higher than receptors formed by α4/6 and β3 subunits. In contrast, γ2 subunit expression significantly reduces THIP sensitivity. Even when δ subunit cDNA or cRNA was supplied in excess, high- and low-sensitivity THIP responses were often apparent, indicative of variable mixtures of low-affinity αβ and high-affinity αβδ receptors. We conclude that δ subunit incorporation into GABARs leads to a dramatic increase in THIP sensitivity, a defining feature that accounts for the unique behavioral and neurophysiological properties of THIP.     

Etomidate and propofol-hyposensitive GABAA receptor beta3(N265M) mice show little changes in acute alcohol sensitivity but enhanced tolerance and withdrawal

Gamma-aminobutyric acid-A (GABAA) receptors are ligand-gated ion channels comprised of subunits from several classes (alpha, beta, gamma, delta). Recent studies have clearly demonstrated that the functional properties of GABAA receptors are altered following chronic ethanol administration that could provide the molecular basis for the previously proposed role of these receptors in ethanol tolerance and dependence. Because the subunit composition of GABAA receptors determines receptor pharmacology, the present study was devoted to assess if the behavioral sensitivity after acute and chronic ethanol exposure depends on beta3-containing GABAA receptors. In the present study, we used knock-in mice harboring a point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABAA receptor in order to study acute and chronic behavioral effects of ethanol. More specifically, we tested tolerance to loss of righting reflex (LORR) and the development of withdrawal signs after chronic ethanol exposure using ethanol vapor chambers. Our results show that the beta3(N265M) mutation does not play a major modulatory role of acute ethanol-induced LORR. However, following repeated LORR testing, enhanced tolerance to the intoxicating effects of ethanol was observed--a finding which was unrelated to the pharmacokinetics of ethanol as both genotypes had the same blood alcohol concentrations following repeated LORR testing. In addition, following chronic alcohol vapor exposure, mouse mutants displayed increased handling-induced convulsions during withdrawal. The results of the present study suggest that the alcohol effects abolished by the beta3(N265M) mutation do not play a dominant role in acute alcohol intoxication but influence ethanol tolerance and withdrawal.     

Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor

Phosphorylation of C-termini of receptor subunits is thought to play a significant role in modulation of N-methyl-D-aspartic acid (NMDA) receptor function. To investigate whether the C-terminus of the NR2A subunit is involved in determining the sensitivity of NMDA receptors to ethanol we compared the effects of ethanol in vitro on NMDA-mediated field excitatory postsynaptic potentials (fEPSPs) in the CA1 and dentate gyrus (DG) of adult male NR2A(DeltaC/DeltaC) mice lacking the C-terminus of NR2A subunit and in their parental strain C57Bl/6. We also tested the in vivo effects of a hypnotic dose of ethanol in C57Bl/6 and NR2A(DeltaC/DeltaC) mice and their F2 offspring. Ifenprodil (10 microM) was used to distinguish between the NR2A and NR2B components of NMDA fEPSPs. Ethanol (100 mM) in the presence of ifenprodil inhibited the CA1 NR2A-mediated component of NMDA fEPSPs two times more in NR2A(DeltaC/DeltaC) than in C57Bl/6. Ethanol inhibition of the CA1 NR2B-mediated component was five to seven times lower in NR2A(DeltaC/DeltaC) than in C57Bl/6. In the DG ethanol had similar effects in the two strains. In vivo administration of ethanol (4 g/kg) induced sedation of similar duration in both strains of mice. A second administration of ethanol 7 days after the initial injection revealed an increased ethanol sensitivity of NR2A(DeltaC/DeltaC) and F2(DeltaC/DeltaC) mice including a shortened time to loss of righting reflex and an increased sleep time. The sensitization of NR2A(DeltaC/DeltaC) mice to alcohol was not accompanied by an altered ethanol sensitivity of NMDA fEPSPs recorded in vitro.Our data are consistent with the inhibitory action of ethanol on NMDA receptors being mediated by a site other than the intracellular C-terminus of the NR2A subunit. The altered sensitivities to ethanol of both NR2A- and NR2B-mediated responses in the CA1 of NR2A(DeltaC/DeltaC) imply that NR2A- and NR2B subunit-containing NMDA receptors may be linked by a common target of ethanol.     

Glutamate transporter type 3 knockout mice have a decreased isoflurane requirement to induce loss of righting reflex

Excitatory amino acid transporters (EAAT) uptake extracellular glutamate, the major excitatory neurotransmitter in the brain. EAAT type 3 (EAAT3), the main neuronal EAAT, is expressed widely in the CNS. We have shown that the volatile anesthetic isoflurane increases EAAT3 activity and trafficking to the plasma membrane. Thus, we hypothesize that EAAT3 mediates isoflurane-induced anesthesia. To test this hypothesis, the potency of isoflurane to induce immobility and hypnosis, two major components of general anesthesia, was compared in the CD-1 wild-type mice and EAAT knockout mice that had a CD-1 strain gene background. Hypnosis was assessed by loss of righting reflex in this study. The expression of EAAT1 and EAAT2, two widely expressed EAATs in the CNS, in the cerebral cortex and spinal cord was not different between the EAAT3 knockout mice and wild-type mice. The concentration required for isoflurane to cause immobility to painful stimuli, a response involving primarily reflex loops in the spinal cord, was not changed by EAAT3 knockout. However, the EAAT3 knockout mice were more sensitive to isoflurane-induced hypnotic effects, which may be mediated by hypothalamic sleep neural circuits. Interestingly, the EAAT3 knockout mice did not have an altered sensitivity to the hypnotic effects caused by ketamine, an i.v. anesthetic that is a glutamate receptor antagonist and does not affect EAAT3 activity. These results suggest that EAAT3 modulates the sensitivity of neural circuits to isoflurane. These results, along with our previous findings which suggests that isoflurane increases EAAT3 activity, indicate that EAAT3 may regulate isoflurane-induced behavioral changes, including anesthesia.     

Locomotor activity responses to ethanol,other alcohols,and GABA-A acting compounds in forward- and reverse-selected FAST and SLOW mouse lines

Mice selectively bred for high (FAST) or low (SLOW) locomotor stimulant response to ethanol have been found to differ in response to drugs with gamma-aminobutyric acid (GABA)-ergic actions. Reverse selection produced lines that are similar in sensitivity to ethanol stimulation (r-FAST and r-SLOW) and provided a unique model for testing hypotheses about shared genetic influence on sensitivity to ethanol and GABAergic drugs. FAST mice were more stimulated than SLOW mice by all drugs tested: ethanol, methanol, n-propanol, t-butanol, pentobarbital, diazepam, and allopregnanolone. In contrast, r-FAST and r-SLOW mice differed in sensitivity to only a few isolated drug doses. Locomotor responses of each reverse-selected line were significantly different from the responses of their respective forward-selected line for all drugs. Results support an effect of selection for ethanol sensitivity on allosteric modulation of the GABA-A receptor.     

Effect of monoamine oxidase A knockout on resistance to long-term exposure to ethanol

It was shown that transgenic Tg8 mice with monoamine oxidase A (MAO A) gene knockout demonstrate higher resistance to acute ethanol exposure compared to wild type C3H mice. This difference was observed at the early age (28-30 days). Long-term ethanol treatment changed the resistance to hypnotic, but not hypothermic action of this agent. Seven-day exposure increased the resistance to ethanol-induced narcotic sleep in Tg8 and C3H mice. After 30-day ethanol treatment the duration of narcotic sleep sharply decreased in C3H mice and increased in Tg8 mice, which attested to their decreased tolerance to ethanol.