Hypothermic Effect Of Ethanol Research Articles

Involvement of the Distal Fragment of Chromosome 13 in the Regulation of Sensitivity to Ethanol in Mice

The role of the fragment 57-65 cM of mouse chromosome 13 was studied in the regulation of ethanol action on locomotor activity, anxiety and sensitivity to hypnotic and hypothermic effects of ethanol. We used male mice of recombinant lines AKR/J and AKR.CBA-D13Mit76C, differing only in this fragment. After acute administration of ethanol only AKR mice showed the increase in the length of traveled distance in the open-field test (p < 0.05), only the AKR.CBA-D13Mit76C mice demonstrated the increase the time spent in the center of open-field arena (p < 0.05). Intact animals of both lines did not differ in sleep duration and intensity of hypothermia induced by injections of high doses of ethanol. At the same time, long-term alcohol treatment led to the weakening of the hypnotic effect of ethanol in the males of both lines compared to intact animals (p < 0.01 for the AKR, p < 0.001 for AKR.CBA-D13Mit76C). Chronic alcoholization led to increased ethanol-induced hypothermia in AKR males compared to intact animals (p < 0.01) and did not affect the intensity of ethanol hypothermic effect in AKR.CBA-D13Mit76C mice. The results suggest the involvement of the distal fragment 57-65 cM of chromosome 13 in the mechanisms of ethanol action in mice.

Chronic voluntary alcohol consumption results in tolerance to sedative/hypnotic and hypothermic effects of alcohol in hybrid mice

The continuous two-bottle choice test is the most common measure of alcohol consumption but there is remarkably little information about the development of tolerance or dependence with this procedure. We showed that C57BL/6J×FVB/NJ and FVB/NJ×C57BL/6JF1 hybrid mice demonstrate greater preference for and consumption of alcohol than either parental strain. In order to test the ability of this genetic model of high alcohol consumption to produce neuroadaptation, we examined development of alcohol tolerance and dependence after chronic self-administration using a continuous access two-bottle choice paradigm. Ethanol-experienced mice stably consumed about 16–18g/kg/day of ethanol. Ethanol-induced withdrawal severity was assessed (after 59days of drinking) by scoring handling-induced convulsions; withdrawal severity was minimal and did not differ between ethanol-experienced and -naïve mice. After 71days of drinking, the rate of ethanol clearance was similar for ethanol-experienced and -naïve mice. After 77days of drinking, ethanol-induced loss of righting reflex (LORR) was tested daily for 5days. Ethanol-experienced mice had a shorter duration of LORR. For both ethanol-experienced and -naïve mice, blood ethanol concentrations taken at gain of righting reflex were greater on day 5 than on day 1, indicative of tolerance. After 98days of drinking, ethanol-induced hypothermia was assessed daily for 3days. Both ethanol-experienced and -naïve mice developed rapid and chronic tolerance to ethanol-induced hypothermia, with significant group differences on the first day of testing. In summary, chronic, high levels of alcohol consumption in F1 hybrid mice produced rapid and chronic tolerance to both the sedative/hypnotic and hypothermic effects of ethanol; additionally, a small degree of metabolic tolerance developed. The development of tolerance supports the validity of using this model of high alcohol consumption in genetic studies of alcoholism.

Age and strain differences in the rat of development of functional tolerance to ethanol by mice.

Abstract The time course of development of functional tolerance to ethanol was investigated in mice during the inhalation of ethanol vapour, using loss of righting reflex as the behavioural end-point. In male mice of the TO Swiss strain, weanling mice (18 days) showed no development of tolerance during continuous or repeated exposure to ethanol vapour for 6 h. Adolescent TO Swiss mice (35–40 days) showed rapid development of functional tolerance, reaching a state where 2x the original effective concentration of ethanol in blood was required to produce loss of righting reflex within 5 h. Older adult mice (150–200 days) showed some development of tolerance during continuous or repeated exposure to ethanol for 5 h but this was much less than that seen in adolescent mice. When adolescent males of the C57BL, TO Swiss and DBA2 strains were compared, marked differences were observed. C57BL mice showed very rapid development of functional tolerance to ethanol in which more than 2 × the original effective dose was required to produce loss of righting reflex after about 3 h of ethanol exposure. TO Swiss mice showed somewhat slower development of ethanol tolerance. DBA2 mice showed little evidence of development of functional tolerance over the time course of these experiments. Evidence was also obtained that similar age and strain differences may exist with respect to tolerance to the hypothermic effects of ethanol. These results are discussed in relation to current concepts of ethanol sensitivity, tolerance and physical dependence.

Autonomic responses to ethanol in adolescent and adult rats: a dose–response analysis

Athough the exact cause of the increase in ethanol consumption during adolescence is not known, age differences in sensitivity to some of ethanol's effects may play a contributory role. Prior research has shown little difference in the expression of ethanol-induced tachycardia between adolescents and adults following ethanol inhalation. In contrast, there is mounting evidence of ontogenetic differences in ethanol-induced hypothermia, although the nature of the ontogenetic effect observed has been found to vary across studies and even within labs. Relative ontogenetic differences in body temperature (BT) after ethanol administration appear to be driven in part by the amount of experimental perturbation associated with the test protocol, although differing ethanol exposure levels across studies may also have contributed to the variations in ontogenetic patterns that have been observed. To explore the latter possibility, the present study assessed ethanol-induced hypothermia and tachycardia in adolescent and adult male Sprague-Dawley rats examined in their home cages in the presence of their housing partner following intraperitoneal administration of 0.5, 1.5, or 3.0 g/kg ethanol. The results showed that, although adolescents did not show an adult-typical tachycardic effect at any dose, they proved more sensitive than adults to ethanol's hypothermic effects at the two highest doses. These findings suggest that not only the degree of experimental perturbation, but also the amount of ethanol exposure may differentially effect expression of age differences in ethanol-induced hypothermia, with adolescents showing greater hypothermia than adults at higher doses. Together with previous findings, these data contribute to the emerging picture that age differences in autonomic effects of ethanol appear to be particularly sensitive to dosing parameters and experimental protocols, unlike the generally more consistent ontogenetic findings observed across studies when using behavioral measures of ethanol sensitivity.

Influence of epipregnanolone on the modulation of rapid tolerance to ethanol by neurosteroids

The objective of the present study was to investigate the effect of epipregnanolone on the influence of neurosteroids on the development of rapid tolerance to the motor impairing and hypothermic effects of ethanol. Experiment 1: on Day 1 groups of mice were pretreated with saline or with epipregnanolone. After 30 min each group was further divided in subgroups that received ethanol or saline. Thirty, 60 and 90 min after the injections the animals were tested on the rota-rod or the body temperature was measured. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Experiment 2 and 3: On Day 1 groups of mice were treated with epipregnanolone and after 15 min each group was divided into three groups in order to receive pregnenolone sulfate, dehydroepiandrosterone sulfate or saline. Thirty minutes later, each group was further divided into two subgroups in order to receive ethanol or saline, respectively, and 30, 60 and 90 min later the animals were tested as in the experiment 1. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Pretreatment with epipregnanolone (0.10-0.30 mg/kg) significantly blocked the development of tolerance to the motor impairing and hypothermic effects induced by ethanol in mice. Considering tolerance to ethanol-induced motor impairment, epipregnanolone (0.15 mg/kg) reversed the stimulatory action of dehydroepiandrosterone sulfate (0.15 mg/kg), but did not affect the actions of pregnenolone sulfate (0.08 mg/kg). Moreover, epipregnanolone prevented the inhibitory action of allotetrahydrodeoxycorticosterone (0.10 mg/kg). In relation to ethanol-induced hypothermia, the results showed that pretreatment with epipregnanolone (0.30 mg/kg) significantly prevented the stimulatory action of dehydroepiandrosterone sulfate and pregnenolone sulfate, as well as the inhibitory action of allotetrahydrodeoxicorticosterone (0.20 mg/kg), on tolerance to this effect. The results suggest a differential interaction between neurosteroids that might modulate the development of rapid tolerance to ethanol.

Sensitivity and Tolerance to Autonomic Effects of Ethanol in Adolescent and Adult Rats During Repeated Vapor Inhalation Sessions

It is during adolescence that most drinkers initiate ethanol intake, with some of this use being excessive. One possible contributor to the increased ethanol consumption often seen during adolescence in humans and in various animal models is age differences in ethanol sensitivity and tolerance. The present study examined the impact of age on ethanol-related alterations in the autonomic nervous system. Sensitivity to the initial ethanol challenge and chronic tolerance as well as acute and protracted withdrawal-like phenomena were assessed in male adolescent and adult Sprague-Dawley rats, using implanted telemetry probes with ethanol delivered via vapor inhalation. Both ages showed similar ethanol-induced tachycardia and activity suppression; however, adolescents were found to be more sensitive than adults to the hypothermic effect of ethanol, data opposite other results from our laboratory and elsewhere using intragastric intubations or intraperitoneal administrations of ethanol. Although little tolerance to ethanol's tachycardic or activity suppressant effects was seen after repeated ethanol inhalation sessions, chronic tolerance to ethanol's hypothermic effect developed faster in adults than in adolescents. A withdrawal-like syndrome, characterized by bradycardia and hypoactivity, typically emerged during the dark phase of the diurnal cycle after ethanol vapor exposure sessions. These effects were observed in animals of both ages, with the bradycardic effect more pronounced in adolescents. In contrast to results indicating that adolescents may be less sensitive than adults to ethanol's hypothermic effect when ethanol is administered via bolus injection/intubation, adolescents appear more sensitive and develop tolerance to ethanol's hypothermic effects more slowly than adults when ethanol is administered at a more moderate rate via vapor inhalation.

Background genotype modulates the effects of γ‐PKC on the development of rapid tolerance to ethanol‐induced hypothermia

The role of γ-PKC in initial sensitivity and in the development of rapid tolerance to the hypothermic effects of ethanol were investigated in γ-PKC null mutant mice. Effects of the single gene mutation were evaluated on three different genetic backgrounds. Null mutants from a C57BL/6J X 129/SvJ mixed genetic background failed to develop rapid tolerance after 4 days of i.p. ethanol injections. However, when the null mutation was introgressed onto a C57BL/6J background for six generations to create a congenic line, the expression of rapid tolerance unexpectedly reoccurred in the null mutant mice. Subsequent outcrossing of the γ-PKC null mutation to a C57BL/6J X 129/SvEvTac mixed background did not restore the no tolerance phenotype. These observations, taken together with similar results reported previously concerning the development of chronic tolerance to ethanol in these same genotypes, ¹ indicate that the gene coding for gamma-PKC has pleiotropic effects in the expression of both rapid and chronic tolerance to ethanol-induced hypothermia. However, the impact of γ-PKC is modulated by the background genotype. These results stress the necessity of understanding interactions with genetic background when interpreting the effects of single gene mutations on complex behavioral traits.

Decreased Ethanol Sensitivity and Tolerance Development in γ‐Protein Kinase C Null Mutant Mice Is Dependent on Genetic Background

Initial sensitivity and tolerance development to the sedative-hypnotic and hypothermic effects of ethanol were investigated in gamma-protein kinase C (PKC) null mutant mice. Null mutants from a C57BL/6J x 129/SvJ mixed genetic background demonstrated decreased ethanol sensitivity and failed to develop chronic tolerance after 10 days of ethanol liquid diet. However, when the null mutation was introgressed onto a C57BL/6J background for six generations, the "no tolerance" phenotype for sedative-hypnotic and hypothermic effects of ethanol was no longer apparent Outcrossing the gamma-PKC null mutation to a C57BL/6J x 129/SvEvTac mixed background restored the "no tolerance" phenotype to ethanol-induced sedation after chronic ethanol diet; however, as measured by hypothermia, tolerance was still evident in the null mutant mice. These observations and the results of tests of chronic tolerance in the C57BL/6J, 129/SvJ, and 129/SvEvTac background inbred strains indicate that gamma-PKC plays an important role in initial sensitivity and tolerance to ethanol. However, the impact of gamma-PKC is modulated by the background genotype. These results stress the importance of including the effect of genetic background when evaluating the effects of single gene mutations on quantitative behavioral traits.

Modification by taurine of the metabolism and hypothermic effect of ethanol in the rat.

Taurine is a β-aminosulfonic acid which occurs ubiquitously both among animal species and in animal tissues12. Although the role of taurine in the conjugation of bile acids is well established, this compound has also demonstrated a myriad of nonmetabolic actions which are exerted throughout the animal body, notably in the heart, brain, reproductive system, muscle and eye8.KeywordsTaste AversionALDH ActivityEthanol MetabolismBlood Ethanol ConcentrationHypothermic EffectThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Effect of neonatal thyroid hormone alterations on CNS ethanol sensitivity in adult LS and SS mice

LS and SS mice develop their differential sensitivity to the motor-incoordinating and hypothermic effects of ethanol at 10–16 days after birth, when thyroid hormones (T 4) show a transient peak. This rise in thyroid hormones is an important element in the normal development of monoaminergic systems and thyroid hormones reach a significantly higher level in the less ethanol-sensitive SS mice than in the more ethanol-sensitive LS mice. Previous investigations have suggested the differential ethanol response of brain monoaminergic neuronal systems in adult LS and SS mice may be related to this development difference in thyroid status. To test the hypothesis that neonatal thyroid status can influence adult. CNS ethanol sensitivity, LS and SS mice were treated neonatally with thyrotropin-releasing hormone (TRH) and propylthiouracil (PTU) to enhance of diminish, respectively, thyroid status at this critical developmental period. The subsequent effect on adult CNS ethanol sensitivity was then determined. Contrary to expectations, both PTU and TRH administration attenuated the transient rise in plasma T 4 levels at postnatal days 10–16 in LS mice and in both instances this was associated with decreased CNS ethanol sensitivity (sleep time and hypothermia) in adults. In SS mice, PTU treatment attenuated the postnatal rise in T 4 levels as expected, whereas TRH treatment had no significant effect. However, neither neonatal treatment altered CNS ethanol sensitivity in adult SS mice. The decrease in ethanol-induced sleep times and hypothermia of neonatally treated LS mice was associated with an attenuation of ethanol-induced decreases in in vivo tyrosine and tryptophan hydroxylase activity that was not seen in the SS mice. These findings are consistent with the notion that the response of monoaminergic neuronal systems to ethanol is an important determinant of behavioral intoxication. However, the observation that neonatal administration of both TRH and PTU blunted the postnatal rise in thyroid levels in LS mice, yet both treatments resulted in a decrease in adult ethanol sensitivity in LS mice, that the relationship between postnatal thyroid development and CNS ethanol sensitivity is more complex than originally hypothesized.

SYNAPTIC MEMBRANE RESPONSES TO ACUTE AND CHRONIC ALCOHOL INTOXICATION IN HIGH ALCOHOL SENSITIVE (HAS) AND LOW ALCOHOL SENSITIVE (LAS) SELECTIVELY BRED RATS

HAS (high alcohol sensitive) and LAS (low alcohol sensitive) lines of rats have been selectively bred based on their differences in ethanol-induced sleep time. In the present study, the two lines were compared to examine another central effect of acute alcohol intoxication: namely, hypothermia. As the disturbances in membrane microorganization have been associated with the nervous system's sensitivity and tolerance to ethanol, the synaptic plasma membrane fluidity and acute sensitivity to ethanol were also evaluated by fluorescence polarization of DPH probes in the HAS and LAS rats. The two lines did not differ in the magnitude of their hypothermic response after acute injection of ethanol (3 g/kg body wt, i.p.). Although membranes in the HAS line were slightly more rigid than in the LAS line, the level of membrane disordering after acute ethanol addition was identical for the two lines in the region examined with the DPH probe. Following the chronic intoxication of the rats, the two lines developed tolerance to the hypnotic and hypothermic effects of ethanol. In the same way, a membrane resistance (i.e. tolerance) to the disordering effect of acute ethanol addition developed in the region probed with DPH. In general, the LAS line showed a more pronounced level of tolerance than the HAS line at both the functional and membrane level. These results suggest that different measures used to assess the depressant action of ethanol, such as sleep time, hypothermia or membrane disordering, may not be related and could indicate different genetic origins.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of NMDA antagonists on rapid and chronic tolerance to ethanol: Importance of intoxicated practice

Recent studies from our laboratory have shown that NMDA antagonists ((+)MK-801 and ketamine) inhibit the development of both rapid and chronic tolerance to the motor-impairing (moving belt test) and hypothermic effects of ethanol. The present experiments were designed to determine a) the generality of this inhibition, by using a different test of motor function, the tilt-plane test, and b) the possible importance of the experimental paradigm (i.e., with and without intoxicated practice), for the effect of the NMDA antagonist on ethanol tolerance. Daily administration of ethanol 3.3 g/kg for 5 days produced the same degree of tolerance on this test, whether it was given as a single dose of 3.3 g/kg before the daily training session or as divided doses of 2.3 g/kg before and 1 g/kg immediately after the session. The inhibitory effect of a single dose of (+)MK-801 (0.25 mg/kg IP) on rapid tolerance did not lost longer than 1 day. Therefore, daily administration of the NMDA antagonists was necessary to block development of chronic tolerance. Daily injection of (+)MK-801 (0.25 mg/kg IP) failed to block chronic tolerance, but inclusion of a second dose of (+)MK-801 daily, and progressive increase of this second dose during the chronic treatment period did block chronic tolerance. Unlike (+)MK-801, ketamine does not have motor-impairing effects of its own, and does not potentiate those of ethanol; it was, therefore, used in the remaining experiments. Groups of rats received ethanol (3.3 g/kg) or saline, either before a daily practice session on the tilt-plane or after it. Tolerance to the ethanol effect developed on both regimens, but more rapidly in the animals receiving ethanol before the practice sessions. Ketamine inhibited the development of tolerance in the before group, but had no effect on the tolerance development in the after group. These results suggest that ketamine will block only practice-learned tolerance and not tolerance acquired purely by pharmacological exposure, and posttrial administration of ketamine was ineffective in blocking tolerance. These experiments provide further evidence consistent with the hypothesis that NMDA antagonists block tolerance development through inhibition of learning.

Tolerance to Ethanol Hypothermia in HOT and COLD Mice

COLD and HOT mice have been selected to be sensitive or resistant, respectively, to the acute hypothermic effect of ethanol. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. By administering several doses of ethanol and recording multiple postdrug temperatures, in the current study we equated the selected lines for area under the curve describing initial hypothermic response over time, a measure reflecting both maximal hypothermia achieved and the duration of total hypothermic response. The dose-response function for COLD mice was much steeper than that for HOT mice, and HOT mice recovered to baseline body temperatures more slowly. Doses were administered daily for 5 days. Both lines developed tolerance to ethanol hypothermia. The magnitude of tolerance developed was greater in COLD than in HOT mice. At higher doses, HOT mice showed a progressively enhanced hypothermic response over days (i.e., sensitization).

Dehydroepiandrosterone enhances the hypnotic and hypothermic effects of ethanol and pentobarbital

Recent reports have indicated that the neurosteroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) interact with the GABA A receptor complex. Because many of the behavioral effects of ethanol and pentobarbital are due to activity at this complex, DHEA and DHEAS were tested for their ability to interact with the hypnotic and hypothermic effects of ethanol and pentobarbital. DHEA, but DHEA and DHEAS themselves cause a fall in body temperature. DHEA enhances the hypothermic effect of both ethanol and pentobarbital. DHEAS enhances the hypothermic effect of ethanol, but with pentobarbital it only delays the return of body temperature to baseline levels. Neither DHEA nor DHEAS affects the metabolism of ethanol.

Interactions of intracerebroventricular pertussis toxin treatment with the ataxic and hypothermic effects of ethanol

Pretreatment with pertussis toxin (0.5 and 1.0 microgram/animal, i.c.v., seven days prior to testing) reversed the reduction in locomotor activity in the holeboard test caused by administration of the alpha 2-adrenoceptor agonist, medetomidine (0.1 mg/kg, i.p.). Intrinsic behavioral effects of pertussis toxin treatment were also observed, these included a reduction in exploratory head-dipping and an increase in locomotor activity. These doses of pertussis toxin also reduced the ataxia induced by a 2.4 g/kg dose of ethanol. Pertussis toxin treated animals also exhibited a diminished hypothermic response to ethanol (2 g/kg), although the pertussis toxin treated animals had lower body temperatures prior to ethanol administration compared to sham treated animals. Neither the behavioral effect of pertussis holotoxin in the holeboard nor its effects on reversing medetomidine hypolocomotion or ethanol-induced ataxia were seen following administration of the binding oligomer of pertussis toxin which binds to the cell membrane but does not possess the enzymatically active subunit. These findings implicate mechanisms involving pertussis toxin sensitive G-proteins in modulating some behavioral and physiological effects of ethanol.

Effect of 3-amino-1,2,4-triazole on the hypothermic effect of ethanol and on ethanol tolerance development

The effect of aminotriazole (AT), inhibitor of catalase activity, on hypothermia and narcosis induced by ethanol and on the acquisition of tolerance to the ethanol hypothermic and narcotic effect was studied. Rats were pretreated with AT (1 g/kg IP) 1 hour before the test dose of ethanol (2.76 g/kg IP) and narcosis time, hypothermia and ethanol blood levels evaluated (first test). For studies on tolerance to ethanol, rats of the first test received daily (for 7 days) a dose of AT (1 g/kg IP) 1 hour before ethanol (2.76 g/kg) given by gavage, and the same parameters evaluated (8th day test). Results were compared to similar groups of rats without AT pretreatment (controls, 1st and 8th day test). Rats pretreated with AT exhibited a shorter narcosis time induced by ethanol but this treatment did not alter the hypothermic effect of ethanol nor ethanol disposal rate. Chronic ethanol treatment induced tolerance to the narcotic and hypothermic effect of ethanol as well as a metabolic tolerance. AT administered daily before the dose of ethanol produced a partial blockade of the development of tolerance to the narcotic effect of ethanol, but did not alter the development of hypothermic or metabolic tolerance. The brain catalase system seems to play a role in narcosis and on the development of tolerance to this effect of ethanol, but not in the hypothermic effect or in the development of tolerance to this ethanol effect. Since the inhibition of liver catalase activity by AT treatment was not correlated with changes in ethanol disposal rate, the liver catalase system appears not to play a role in the metabolic tolerance.

Flumazenil (Ro15-1788) does not affect ethanol tolerance and dependence

There are conflicting reports concerning whether flumazenil (Ro15-1788) can antagonize the central effects of ethanol and ethanol withdrawals reactions. C57BL/6J mice were treated chronically with an ethanol liquid diet. Control mice were pair fed an isocaloric diet containing no ethanol. These mice were injected with either Ro15-1788 (25 mg/kg) or vehicle immediately before, 14 h or 24 h before ethanol withdrawal. Under these conditions, no attenuation of the severity of handling-induced withdrawal seizures or of withdrawal hypothermia was observed in the ethanol-dependent mice injected with Ro15-1788. Likewise, there was no abolition or attenuation of tolerance to the ataxic effects (sleep time and horizontal dowel tests) and hypothermic effects of ethanol by Ro15-1788 when the mice were tested on day 3 of ethanol withdrawal. It is concluded that Ro15-1788 (25 mg/kg) has no effect on ethanol tolerance and dependence.

NMDA antagonist inhibits rapid tolerance to ethanol

To test whether N-methyl-D-aspartate (NMDA) receptors have a role in the development of ethanol tolerance, (+)MK-801, an NMDA antagonist, and (−)MK-801, an inactive isomer, were tested in a rapid tolerance paradigm. Results showed that (+)MK-801 blocked the development of rapid tolerance to ethanol in the tilt-plane and hypothermia tests, while (−)MK-801 was ineffective. Neither drug changed the blood ethanol levels in the treated and untreated animals. These data suggest that the known role of NMDA receptors in long-term synaptic facilitation may underlie the effect of learning in the development of tolerance to the motor-impairing and hypothermic effects of ethanol.

Evidence that genetic differences in habituation and GABAergic mechanisms may be related to sensitivity to ethanol and development of ethanol tolerance in mice

Habituation to a test environment following daily exposure for 5 days was examined in three genetically different strains of mice. C57 animals showed significant habituation to the new environment already on the second day. The habituation of NMRI mice was significant on the third day, whereas CBA mice showed no habituation at all during the experimental period. There was no difference between the animal strains in learning capacity in a passive avoidance test, but CBA mice displayed a significant increase in latency in their performance. When tested for sensitivity to the convulsant actions of GABAergic antagonists, picrotoxin produced seizures at lower doses in CBA as compared to NMRI and C57 mice, whereas there was no difference between the strains in the seizure activity produced by the specific GABA receptor antagonist bicuculline. When the animals were tested for sensitivity to ethanol in a horizontal wire test, ethanol (2 g/kg, IP) produced muscle relaxation in CBA mice whereas the performance of NMRI and C57 was not affected. A large dose of ethanol (4 g/kg, IP) produced a significantly longer sleeping time in CBA mice as compared to NMRI and C57 animals. Ethanol-produced hypothermia was, however, similar in all animals. Environment-dependent development of tolerance to ethanol following daily injections of ethanol for 4 days was examined. C57 mice showed the most rapid development of tolerance towards ethanol's hypnotic actions, whereas CBA mice showed no tolerance to this effect of ethanol. No difference between the strains to the development of tolerance to ethanol's hypothermic effects was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphine-ethanol interaction on body temperature

1. 1. The interaction between ethanol and morphine on core temperature was investigated in Swiss Webster mice. 2. 2. Morphine (2.5–30 mg/kg) and ethanol (0.5–3.0 mg/g) administered individually resulted in a dose dependent decrease in body temperature. 3. 3. When both drugs were injected simultaneously, body temperature decreased less than it would be expected to if the effects were additive. 4. 4. Naloxone antagonized the hypothermic effect of morphine, but the hypothermic effect of ethanol and that of the combination of morphine plus ethanol was only reversed with high doses of naloxone (10 mg/kg). 5. 5. Individual morphine and ethanol plasma levels were not significantly altered by their concomitant administration. 6. 6. Binding of tritiated naloxone to opiate receptors in mouse brain membrane preparations was unchanged by pretreatment with ethanol (0.5 and 2 mg/g). 7. 7. The interaction between morphine and ethanol was found to be less than additive and not related to pharmacokinetic changes of either drug.