Ethanol Hypothermia Research Articles

Abstract 2981: Neuroprotective Effect Of Acute Ethanol Administration In Rat With Transient Cerebral Ischemia

Background and Purpose _ Despite a focus on the pathological effects of alcohol abuse, numerous studies published over the past several decades also demonstrate beneficial effects of light-to-moderate consumption of alcoholic beverages. Recent studies have demonstrated that elevated serum ethanol levels are associated with increased survival in patients with traumatic brain injury (TBI), suggesting that an acute exposure to alcohol exerts a neuroprotective effect. In a rat model of transient cerebral ischemia, we identified administration of ethanol as a possible treatment for acute ischemic stroke. Methods _Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for two hours. Five sets of experiments were conducted: 1) to determine the dose-response effect of ethanol (0.5, 1.0 and 1.5g/kg) on brain infarction and functional outcome; 2) to determine whether combining ethanol (1.5g/kg) and hypothermia produces synergistic neuroprotection; 3) to determine the therapeutic windows of opportunity for ethanol in stroke; to test whether ethanol promotes intracerebral hemorrhage (ICH) in hemorrhagic or ischemic stroke, or after administration of thrombolytics in ischemic stroke; and 5) to test the affect of ethanol on HIF-1α protein expression. Results —Ethanol at 1.5 g/kg, which produce blood levels (89mg/dL) within the legally intoxicated range for driving (80-100 g/dL), most effectively reduced infarct volume and behavioral dysfunction when administered at 2, 3 or 4 hours after MCAO. We find that ethanol and moderate hypothermia (32-34 °C) exert neuroprotective effects of similar magnitude at both the lesion volume and functional levels, but do not exert a synergistic effect in this model. Ethanol did not promote cerebral hemorrhage in hemorrhagic or ischemic stroke in combination with recombinant tissue plasminogen activator (rt-PA) or urokinase (UK). Up-regulation of HIF-1α protein levels was enhanced by ethanol, in association with reduced brain infarct volume and improved functional recovery in rats subjected to stroke using the same dose (1.5 g/kg). Conclusions —Ethanol exerts a strong neuroprotective effect when administered up to 4 hours after ischemia, and does not promote ICH when used with thrombolytics. Ethanol is a potential neuroprotectant for acute ischemic stroke.

Differential Expression of Ethanol‐Induced Hypothermia in Adolescent and Adult Rats Induced by Pretest Familiarization to the Handling/Injection Procedure

Previous work examining ethanol's autonomic effects has found contrasting patterns of age-related differences in ethanol-induced hypothermia between adolescent and adult rats. Most studies have found adolescents to be less sensitive than adults to this effect, although other work has indicated that adolescents may be more sensitive than adults under certain testing conditions. To test the hypothesis that adolescents show more ethanol hypothermia than adults when the amount of disruption induced by the test procedures is low, but less hypothermia when the experimental perturbation is greater, the present study examined the consequences of manipulating the amount of perturbation at the time of testing on ethanol-induced hypothermia in adolescent and adult rats. The amount of test disruption was manipulated by administering ethanol through a chronically indwelling gastric cannula (low perturbation) versus via intragastric intubation (higher perturbation) in Experiment 1 or by either familiarizing animals to the handling and injection procedure for several days pretest or leaving them unmanipulated before testing in Experiment 2. The results showed that the handling manipulation, but not the use of gastric cannulae, altered the expression of ethanol-induced hypothermia differentially across age. When using a familiarization protocol sufficient to reduce the corticosterone response to the handling and injection procedure associated with testing, adolescents showed greater hypothermia than adults. In contrast, the opposite pattern of age differences in hypothermia was evident in animals that were not manipulated before the test day. Surprisingly, however, this difference across testing circumstances was driven by a marked reduction in hypothermia among adults who had been handled before testing, with handling having relatively little impact on ethanol hypothermia among adolescents. Observed differences between adolescents and adults in the autonomic consequences of ethanol were dramatically influenced by whether animals were familiarized with the handling/injection process before testing. Under these circumstances, adolescents were less susceptible than adults to the impact of experimental perturbation on ethanol-induced hypothermia. These findings suggest that seemingly innocuous aspects of experimental design can influence conclusions reached on ontogenetic differences in sensitivity to ethanol, at least when indexed by ethanol-induced hypothermia.

Physiological and behavioral effects of acute ethanol hangover in juvenile, adolescent, and adult rats.

This study examined differential responding of juvenile, adolescent, and adult rats after intoxication from an acute alcohol challenge. Experiment I generated blood ethanol curves for subjects 25, 35, or 110 days postnatal, after doses of 2.0 or 4.0 g/kg, assessing elimination rates and time of drug clearance. Experiment 2 compared ethanol's initial hypothermic and delayed hyperthermic effect across age by 48-hr temperature measurement with telemetry. At clearance or 24 hr after alcohol exposure, Experiment 3 tested subjects for changes in acoustic startle reactivity and ultrasonic vocalization (USV). Younger rats showed an absent or reduced tendency for residual hyperthermia, and adults showed alterations in USV observed as aftereffects of intoxication, despite greater initial blood alcohol levels and ethanol hypothermia in the former. The lesser ethanol hangover effects in weanlings and adolescents may be due in part to faster ethanol elimination at these ages compared with adults.

Altered behavior and alcohol tolerance in transgenic mice lacking MAO A: a comparison with effects of MAO A inhibitor clorgyline

The influence of deficiency of monoamine oxidase A (MAO A) gene and the lack of enzyme MAO A on the behavior of transgenic mouse strain (Tg8) was studied. It was shown that MAO-A-lacking mice differed from mice of the wild-type strain C3H/HeJ (C3H) by an attenuated acoustic startle response, prepulse inhibition (PPI) was unchanged. In Tg 8 mice, the exploratory nose-poking in the holeboard test as well as exploratory line crossing in the “light–dark” test were decreased. No effect of MAO A deficiency on locomotor activity was found. No alcohol preference or difference between Tg8 and C3H in ethanol consumption in the free-choice test has been found, although an increase in alcohol tolerance has been demonstrated. Ethanol-induced (0.3 g/100 g ip) sleep latency was longer, duration of sleep was shorter and ethanol hypothermia was reduced in MAO-A-lacking mice. Comparison of effects of MAO A knockout with those of irreversible MAO A inhibitor clorgyline (5 and 10 mg/kg ip) on C3H mice showed a similar reducing effect on ethanol-induced sleep, but potentiated ethanol-induced hypothermia. Clorgyline administration provoked a tendency to decrease of exploratory activity in the nose-poking test and decreased the frequency of exploratory rearings in the light–dark test. Clorgyline (5 and 10 mg/kg) did not affect the acoustic startle response, but a dose of 5 mg/kg diminished PPI. Therefore, Tg8 mice exhibited a decreased startle response and exploratory activity and an increased tolerance to ethanol. A similar increase in tolerance to ethanol-induced sleep and a tendency to decrease exploratory behavior were displayed by clorgyline. Other effects on behavior were different, suggesting the influence of long-lasting action of MAO A knockout and the involvement of a compensatory mechanism in Tg8 mice.

Ontogeny of ethanol elimination and ethanol-induced hypothermia

Ontogeny of ethanol elimination rates and ethanol-induced hypothermia were examined as possible mechanisms contributing to the marked reduction in ethanol sensitivity early in life (Little et al., 1996; Silveri & Spear, 1998) and the notable gender difference in ethanol sleep-time seen in adult animals (Silveri & Spear, 1998). Elimination rates and brain/blood ethanol levels were determined following doses of 1.5 or 4.5 g/kg ethanol in male and female Sprague–Dawley rats at postnatal days (P)16, 26, 36, or 56. Animals were sacrificed at 40, 80, or 160 min post-injection, with ethanol elimination rates estimated from the slope of the regression of blood and brain alcohol levels across the three sampling periods. P16 animals exhibited the slowest rate of ethanol metabolism, while no gender effects were evident at any age. Observed ontogenetic increases in ethanol hypothermia were not systematically related to the ontogeny of ethanol metabolism. Factors other than ontogenetic changes in ethanol metabolism, hypothermia, or the distribution of ethanol between brain and blood must underlie the relative insensitivity to ethanol often reported in young and adolescent organisms, a fruitful area for future studies given the frequent use and misuse of alcohol by human adolescents.

Acute and Chronic Alcohol–Cocaine Interactions in Rats

The widespread combined use of alcohol and cocaine across the United States underscores the importance of understanding how the actions of those two agents interact upon important physiological regulatory processes. In an experiment exploring acute ethanol–cocaine interactions, 16 rats were given 2.0 g/kg (IP) doses of ethanol at time zero. Two hours later, half of the rats were given cocaine (20 mg/kg, IP), while the other half were given injections of saline. The group given cocaine displayed a prolongation of the hypothermia condition induced by ethanol injection. In a chronic experiment, three groups of rats ( n = 6–8) were exposed for an 11-day period to daily IP injections of 10 mg/kg cocaine, 20 mg/kg of cocaine, or saline. On day 12 these groups did not differ in their response to loss of the righting reflex induced by a 3.0 g/kg dose of ethanol. However, recovery from ethanol hypothermia was more rapid in the rats exposed to chronic cocaine. In summary, these initial studies provide evidence for exacerbation of the acute hypothermic effects of ethanol when a cocaine challenge is given 2 h after ethanol. In contrast, ethanol hypothermia was observed to be reduced when tested on day 12 after an 11-day chronic regimen of cocaine. Other dosage regimens and response measures need to be tested to understand the full scope of acute and chronic cocaine–ethanol interactions and the possible health consequences.

Effect Of NMDA Antagonists On Rapid Tolerance To Ethanol Under Two Different Testing Paradigms

KHANNA J. M., G. SHAH AND A. CHAU. Effect of NMDA antagonists on rapid tolerance to ethanol under two different testing paradigms. PHARMACOL BIOCHEM BEHAV 57 [4]693–697, 1997.—We have recently reported that pretreatment with NMDA receptor antagonists [(+)MK-801 and ketamine] inhibited the development of rapid tolerance to ethanol hypothermia and motor-impairment on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. In these studies rats were tested at 30, 60, 90 and 120 min after ethanol on both day 1 and 2. In the present report we compared the development of rapid tolerance under 2 different conditions: [1]in groups of rats that were tested on the tilt-plane at all test times (Testing or Intoxicated Practice group), [2]in groups of rats that were not tested on the tilt-plane but were handled at all test times on day 1 (dummy testing). Rats were pretreated with ethanol or saline on day 1 and tested with ethanol on day 2 in all the above studies. Both testing (intoxicated practice) and dummy testing of animals on day 1 after pretreatment with ethanol produced rapid tolerance to ethanol on day 2. However, (+)MK-801 or ketamine pretreatment, which blocked rapid tolerance in the intoxicated practice testing paradigm, failed to block rapid tolerance in the dummy testing paradigm. Similar results were obtained for rapid tolerance and for the effect of ketamine in the hypothermia experiment. These findings suggest that NMDA antagonists block rapid tolerance in the intoxicated testing paradigm but not in the dummy testing paradigm. However, whether the two types of rapid tolerance tested in the present experiments are indeed different or interrelated remains to be further investigated.

Sensitivity to ethanol-induced ataxia in HOT and COLD selected lines of mice.

Studies with inbred strains of mice have suggested that there may be a genetic correlation between strain sensitivities to the ataxic and hypothermic responses to ethanol (EtOH), which would suggest that some genes influence both responses. To test this hypothesis, EtOH sensitivity was determined in replicate lines of mice selectively bred for sensitivity (COLD) or resistance (HOT) to acute ethanol hypothermia. Several tests were used to index ataxia, related traits such as muscle strength, and locomotor activity. The screen test yielded a dose-dependent EtOH-induced decrease in performance that did not differ between the selected lines. Based on the dose-response characteristics of this task, 2.5 g/kg of EtOH was used as the test dose for the remaining experiments. Results from the fixed-speed rotarod and the grid test of motor incoordination also indicated no significant differences between HOT and COLD mice in sensitivity to EtOH impairment. When the selected lines were tested on an accelerating rotarod, COLD mice were impaired by the acute EtOH injection, but HOT mice were unaffected. COLD mice were more sensitive to EtOH-induced decrements in grip strength and locomotor activity. Overall, the results indicated that HOT and COLD mice were only differentially sensitive to EtOH in some tasks related to ataxia, suggesting that some genes must be associated uniquely with EtOH-induced hypothermia or ataxia. The mixed results from the various tests indicate that ataxia can best be conceived as a group of related complex behaviors that cannot be assessed adequately by the use of a single task and that ataxia-related behaviors are influenced by different groups of genes.

Ethanol anapyrexia in rats

In the present series of experiments we tested whether ethanol decreases body temperature by impairing thermal regulation (poikilothermia) or by shifting the set point downwards. The central temperature of rats kept in a thermocline and the selected ambient temperature were recorded by telemetry. After an IP injection of 2 g/kg of ethanol the rats selected an ambient temperature 7 °C lower than the one they selected before the ethanol injection and 8 °C lower than the one selected by the same rats after saline injection. At the same time the central temperature decreased by 2.5 °C. After about 40 min the rats preferred warmer ambient temperatures and 10 min later the central temperature began to rise. When, after ethanol, the rats were kept at 30 °C the central temperature remained at the normal level. At 35–36 °C the central temperature of normal rats without ethanol rose, in 1 h, from 37 °C to 39.75 °C. The results suggest that ethanol hypothermia is due to a downward shift of the set point and, in fact, is an anapyrexia, a condition inverse to fever.

Attenuation of alcohol-induced hypothermia by cyclo (His-Pro) and its analogs

Acute administration of cyclo (His-Pro) to rats cause a dose-dependent decrease in ethanol-induced hypothermia. Bromination of the imidazole moiety of histidine in cyclo (His-Pro) resulted in a significant increase in its potency to attenuate ethanol hypothermia. In contrast, benzylation of the imidazole moiety of histidine or the substitution of one or both of the amino acids in cyclo (His-Pro) led to a total loss of its thermomodulatory activity. In conclusion, it appears from these preliminary data that it may be possible to design analogs of CHP that may be effective antagonists for ethanol hypothermia.

Age effects on chronic tolerance to ethanol hypnosis and hypothermia

Male Fischer 344 rats of three different ages (young, 4 months; middle, 13 months; and old, 25 months) were tested for their hypnotic and hypothermic response to a 3.5 g/kg dose of ethanol on day 1 and after an 8-day exposure to 4.0 g/kg of ethanol administered via intragastric intubation. All three age groups displayed, to a similar extent, an increased rate of blood ethanol disapperance (metabolic tolerance) on day 10 and day 16, as compared to day 1. Both young and middle-age rats demonstrated tolerance to ethanol hypothermia, but older rats did not. The same test dose of ethanol (3.5 g/kg, IP) administered on day 16, after a 5-day interval with no ethanol, produced a hypnosis response similar to that observed on day 1 (no tolerance), but the response to ethanol hypothermia was still significantly reduced over the day 1 and day 10 value in young and middle-age rats, suggesting a persistence and intensification of tolerance to hypothermia over the 5-day rest interval. However, tolerance to ethanol hypothermia was not observed in old rats. Thus, the effects of age on the development of chronic functional tolerance were complex and depended upon the test measure used.

Influence of age on the development of rapid tolerance to ethanol

Fischer-344 rats of three different ages (4, 13, and 25 months) were tested to determine the extent and duration of raoid tolerance to ethanol-induced hypothermia and hypnosis. There were no significant differences among groups with regard to maximal ethanol hypothermia (3.0–3.5 g/kg ethanol), nor did any of the groups display a significant change (rapid tolerance) in the maximal hypothermic response when tested with a second identical challenge 48 h later. Rapid tolerance to ethanol hypnosis was observed across groups at 48 h, utilizing two different dosing schemes. No tolerance was observed if 14 days were allowed to elapse between the initial and the test challenge. Young rats were observed to develop a greater degree of rapid tolerance than did middle-aged or old rats, using hypnosis as a measure.

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).

Taste cues control ethanol-induced conditioned taste avoidance but not conditioned tolerance

This experiment tested the ability of taste cues to serve as the conditioned stimulus (CS) for conditioned tolerance to ethanol hypothermia. Rats were exposed to a differential Pavlovian conditioning procedure in which the manual oral infusion of one flavor solution was consistently followed by injection of ethanol (2.25 g/kg), whereas exposure to another flavor was followed by injection of saline (16 trials each). Control rats received saline after both flavors. Body temperature was recorded continuously using radio telemetry. Ethanol-treated rats developed tolerance to ethanol’s hypothermic effect and aversion for the ethanol-paired flavor. However, flavor had no effect on the expression of tolerance, indicating that taste was not an effective CS for conditioned tolerance. This outcome may represent an instance of selective association in which taste cues more readily gain control over ethanol’s effect on ingestive behavior, whereas environmental cues more readily gain control over ethanol’s thermal effect. These results may also bear on the hypothesized role that ethanol’s thermal effect plays in ethanol self-administration and ethanol-induced conditioned taste aversion.

Cellular and learned tolerances for ethanol hypothermia

Four groups of rats received ethanol: 1) intermittently while experiencing hypothermia, 2) chronically while experiencing hypothermia, 3) intermittently while protected from hypothermia, and 4) chronically while being protected from hypothermia. On postchronic testing, Group 1 showed tolerance to 2.0 and 2.3 but not 2.7 g/kg ethanol, Group 2 was tolerant to all 3 doses, Group 3 was tolerant to none, and Group 4 was tolerant only to 2.7 g/kg. On withdrawal of chronic ethanol or vehicle, Groups 1 and 2 showed trends to lose tolerance which became significant after subsequent extinction training. The treatments were repeated in other rats up to postchronic test for test for tolerance, after which they were killed at 15–120 min after ethanol to assay serum and brain concentrations. Serum and brain levels of ethanol were higher in Groups 2 and 4 despite less intense hypothermia (i.e., no metabolic tolerance). Analysis of covariance indicated less tolerance in Group 1 vs. Group 2 and Group 3 vs. Group 4 for the same brain levels of ethanol (i.e., cellular tolerance in Groups 2 and 4). Therefore, both learned and cellular tolerances were observed in these subjects and appeared to be separable phenomena according to the various treatments imposed.

Differential actions of RO 15-1788 and diazepam on poikilothermia, motor impairment and sleep produced by ethanol

In adult male Sprague-Dawley rats kept at an ambient temperature of 23–25°C, ethanol was injected intraperitoneally in a dose of 4.0 g/kg to produce a clear-cut impairment of autonomic and motorial functions. Following the injection of ethanol, motor coordination, measured on a rotorod, behavioral sleep, righting reflex and colonic temperature were monitored at predetermined intervals for 5.0–7.0 hr. In the first experiment, either 1.0 mg/kg RO 15-1788 (flumazenil), a benzodiazepine (BZ) receptor antagonist, or 1.0–5.0 mg/kg diazepam, a classical benzodiazepine receptor agonist, were injected intraperitoneally either alone or concurrently with ethanol's administration. In the second study, either RO 15-1788 (1.0 or 2.0 mg/kg) or diazepam (1.0 or 5.0 mg/kg) was injected at the nadir of the fall of body temperature induced by ethanol. Although RO 15-1788 alone failed to affect the rats' temperature, it did not prevent the characteristic ethanol-induced hypothermia but rather potentiated it in a dose-dependent manner. Further, this BZ receptor antagonist exacerbated motor incoordination and other behavioral effects when given either simultaneously with ethanol or at the nadir in the animals' core temperature. Although diazepam evoked a dose-dependant hypothermia, it did not enhance ethanol-induced hypothermia when both drugs were administered simultaneously. However, diazepam augmented motor incoordination and other effects and served to delay their recovery. When given to the rats at the nadir of ethanol hypothermia, diazepam did not potentiate ethanol's thermolysis but retarded the recovery from hypothermia; it caused also a dose-dependent delay in the recovery of motor coordination and other responses. These results show that diazepam and RO 15-1788 in this dose range do not act in an opposite manner as receptor agonist and antagonist, respectively, in terms of their actions on ethanol induced autonomic and motor impairment. Nevertheless, since the BZ agonist and antagonist exhibit differential functional effects, it thus is envisaged that diazepam and ethanol could share a similar substrate and site of action in the brain to produce hypothermia. On the other hand, RO 15-1788 could act at the level of signal transduction in brainstem neurons to potentiate the effects of ethanol. However, since both drugs augment incoordination, a common central mechanism of action is implied for motor incoordination which is distinguishable from the autonomic incapacitation induced by ethanol.

Response to selection for sensitivity to ethanol hypothermia: Genetic analyses

Selective breeding has been used to produce lines of mice differing in sensitivity to the hypothermic effects of ethanol (EtOH). Two genetically independent HOT (insensitive) and two COLD (sensitive) lines are maintained along with two nonselected control (CON) lines. The breeding program is currently in selected generation 14, and HOT and COLD mice differ by about 4 degrees C in selected hypothermic response. Estimates of heritability indicate that approximately 20% of the variance in EtOH-induced hypothermic response in mice is of additive genetic origin. Inbreeding has increased at a rate of about 1.7% per generation and no fertility problems have been detected as a result of selection. Projects designed to evaluate apparent correlated responses to selection are discussed.

Roles of intoxicated practice in the development of ethanol tolerance.

The development of tolerance to the motor impairment effect of ethanol was examined in separate groups of rats receiving and not receiving intoxicated practice. Tolerance to the motor impairment effect of ethanol developed whether or not rats received intoxicated practice during chronic ethanol treatment. Depending on the treatment dosage and test dose, intoxicated practice might enhance the level of tolerance attained. Tolerance to other effects of ethanol (hypothermia and narcosis) developed as a function of the treatment dosage. Intoxicated practice on the moving belt did not modify the development of tolerance to these effects of ethanol. Tolerance to the motor impairment effect of ethanol, however, was retained much longer in the intoxicated practice group following the termination of ethanol treatment.

Alcohol-induced poikilothermia, sleep and motor impairment: Actions on brain of EGTA and verapamil

In the early 1970's, calcium ions were implicated in the mechanism underlying the perturbation of the “set point” for body temperature produced by a thermolytic drug. Since Ca ++ is thought to be involved in the incapacitating effects of ethanol on body temperature and motor coordination, this investigation sought to compare the differential central actions of a Ca ++ chelating agent with those of a Ca ++ channel antagonist on ethanol-induced poikilothermia and motor functions. A chronically indwelling cannula for intracerebroventricular (ICV) injection was implanted stereotaxically in each of 25 adult male Sprague-Dawley rats. Following postoperative recovery, each rat was given ethanol in a 20% v/v solution by the intraperitoneal route in a dose of 4.0 g/kg, which was selected to insure a clear-cut impairment of autonomic and motorial functions. Colonic temperature, behavioral sleep, righting reflex and degree of motor coordination on a rotorod were monitored at selected intervals for 5.0–7.0 hr after the injection of ethanol. Two experimental designs were used: First, either 12.5, 25 or 50 μg ethyleneglycol-bis-(β-amino ethyl ether) N,N′-tetra-acetic acid (EGTA), or 25 or 50 μg verapamil, both dissolved in an artificial CSF vehicle, were infused ICV at the same time as ethanol's administration. In the second design, the compounds were infused at the nadir of the ethanol-induced temperature decline. EGTA infused ICV in the rat together with ethanol produced a dose-dependent inhibition of ethanol hypothermia and a more rapid recovery of the animal's righting reflex, arousal and motor coordination than that following ethanol alone. Although verapamil infused ICV in the 50 μg but not 25 μg dose minimized the poikilothermic response to ethanol, it was not as efficacious as that of EGTA. When infused ICV at the point of maximum fall in the rats' temperature, EGTA entirely reversed the hypothermia induced by ethanol and evoked a thermogenic response in the rat. In contrast, verapamil infused ICV in the same doses tended only to retard the further decline in the animal's body temperature. Similarly EGTA was far more effective than verapamil in ameliorating the other physiological actions of ethanol in terms of the reversal of areflexia, behavioral sleep and motor incoordination. These results suggest that the characteristic attributes of membrane Ca ++ in terms of its binding and other neuronal properties play a significant functional role in the incapacitating action of ethanol on the diverse physiological processes mediated by the brain. The differential potency of EGTA in comparison to verapamil indicates also that Ca ++ channel mechanisms do not participate to as great a degree in ethanol's impairment of these vegetative control systems as the membrane Ca ++ component.

Relationship between initial sensitivity, acute tolerance and chronic tolerance to ethanol in a heterogeneous population of Swiss mice.

Acute and chronic tolerance to ethanol hypothermia as a function of the initial sensitivity were examined in a heterogeneous population of Swiss mice. Based on their day 1 hypothermic response to a challenge dose of ethanol (4 g/kg, IP), 60 mice were divided into three groups: high responders (HR: delta Tmax 6.5-9 degrees C, n = 14); medium responders MR: delta Tmax 4.75-6.25 degrees C, n = 31); and low responders (LR: delta Tmax 3-4.5 degrees C, n = 15). Animals were injected once daily (between 9 and 11 A.M.) with 4 g/kg ethanol (20% w/v) for a period of 7 days. Testing was repeated on days 3 and 7 after the administration of the same dose of ethanol. The HR group showed the highest degree of chronic tolerance to ethanol hypothermia, followed by the MR group, while the LR group developed no chronic tolerance. Acute tolerance was considered to be present when delta T was lower at the same blood alcohol concentration (BAC), or BAC was higher at the same delta T, at later times in the same mouse. On days 3 and 7, the HR and MR showed acute tolerance, while the LR did not. Although metabolic tolerance to ethanol was detected in all three groups, ethanol metabolism played a minor role in initial sensitivity and acute and chronic ethanol tolerance.