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A E LeBlanc

Publications and source records attributed to A E LeBlanc.

At least 19 recordsLinked to original sources
PubMed1985

Initial sensitivity versus acquired tolerance to ethanol in rats selectively bred for ethanol sensitivity.

Chronic tolerance to ethanol-induced sleep, motor impairment (moving belt test), and hypothermia were examined in two lines of rats that had been selectively bred for their different initial sensitivities to ethanol. In agreement with previous work (Mayer et al. 1982, 1983), the least-affected (LA) rats were found to be less sensitive than their most-affected (MA) counterparts in all three tests. Chronic treatment with ethanol resulted in a more rapid and more marked tolerance development in MA animals than in LA ones. The two lines did not differ in final level of tolerance achieved for either sleep time or hypothermia. However, significant differences were observed with respect to the moving belt test, in that at the end of chronic ethanol treatment the MA animals were more resistant to ethanol than the LA ones. These studies support the existence of a relationship, but not necessarily a direct genetic linkage, between initial sensitivity and acquired tolerance.

Analysis of Variance↗
PubMed1981

Effect of modification of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA) on ethanol tolerance.

Rats were permanently depleted of brain dopamine (DA), serotonin (5-HT), 5-HT + norepinephrine (NE), or NE + DA by intraventricular injection of either 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) with or without pretreatment with desmethylimipramine (DMI). Following 1 week of recovery from surgery, daily treatment with ethanol (5 g/kg, PO) or isocaloric sucrose was carried out for a period of 20-25 days. Testing at 5-day intervals showed that chronic ethanol treatment produced tolerance to the hypothermic and motor impairing effects of ethanol. Depletion of 5-HT alone retarded tolerance, while depletion of NE or DA alone produced no effect. Combined depletion of both NE and 5-HT, however, completely inhibited tolerance development. The inhibition of tolerance development by combined depletion of both NE and 5-HT is discussed in terms of a reciprocal relationship between these two systems.

5,7-Dihydroxytryptamine↗
PubMed1981

The effect of lesions in the dorsal, median and magnus raphe nuclei on the development of tolerance to ethanol.

Electrolytic lesions were made in the median, the dorsal, the dorsal + median or magnus raphe nuclei of rats. Sham-control animals were also prepared through the same procedure with the exception that no current was delivered. After 1 week of recovery from surgery, a dose-response curve to the hypothermic and motor-impairment effects (moving belt test) was carried out to assess the initial response to ethanol. The maximal fall in temperature and maximum motor impairment were used to quantify the ethanol effects. Two days after the dose-response study, hypothermia and motor impairment were again determined in all animals after a test dose of ethanol. The animals in each main treatment group were than divided into two subgroups matched on the basis of their maximum hypothermic or motor impairment response. The subgroups received daily treatment with either ethanol (5 g/kg p.o.) or calorically equivalent amounts of sucrose. Tolerance to the ethanol-induced hypothermia or motor impairment was assessed at intervals of 5 days for 25 days. Lesions of the dorsal and magnus raphe nuclei produced a negligible effect on the development of ethanol tolerance. Lesions of the median raphe nucleus delayed the development of tolerance. Combined lesions of the median + dorsal raphe nuclei did not significantly increase the effect produced by the lesions of the median raphe nuclei alone. Biochemical analysis confirmed the differential depletion of 5-hydroxytryptamine by the various lesions. These results indicate that the 5-hydroxytryptamine pathway from the median raphe nucleus to the dorsal hippocampus is important in the development of tolerance to ethanol.

Animals↗
PubMed1980

Role of serotonin (5-HT) in tolerance to ethanol and barbiturates.

Previously it has been shown that chronic administration of p-chlorophenylalanine (p-CPA), slowed the development of tolerance to ethanol, pentobarbital and cross-tolerance development to ethanol in rats chronically treated with pentobarbital. These findings have been extended by the following observations: (1) p-CPA slowed the development of tolerance to barbital as measured by motor impairment on the moving belt test, without altering the acute response. (2) p-CPA also reduced the tolerance to barbital as measured by sleeping time, in animals chronically treated with pentobarbital. (3) Administration of L-tryptophan increased the rate of tolerance development to ethanol as measured by motor impairment and hypothermia. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives.

Animals↗
PubMed1980

Cross-tolerance between ethanol and morphine.

Adult male Wistar rats were fed chronically a liquid diet providing 35% of the calories as ethanol (10-12 g/kg ethanol daily), while pair-fed controls received the corresponding diet with alcohol replaced by an equicaloric concentration of sucrose. Rectal temperatures, after test doses of ethanol or morphine, were measured in several groups of rats at various times during chronic ethanol treatment. The fall in rectal temperature after a challenge dose of ethanol (3.0 g/kg) was significantly lower in the chronic alcohol group than in controls, indicating tolerance to ethanol-induced hypothermia. The same animals also developed cross-tolerance to the hypothermic effect of morphine (15 and 30 mg/kg), but not to the hyperthermic effect of morphine (5 mg/kg). Administration of morphine (30 mg/kg i.p.) for 3 days resulted in tolerance to morphine hypothermia, and cross-tolerance to ethanol-induced hypothermia. These studies fit with out hypothesis that tolerance and cross-tolerance among drugs develop to drug effects rather than to drug per se. Therefore drugs sharing a common effect, even by different mechanisms, might show cross-tolerance for that effect.

Animals↗
PubMed1980

Reversal of ethanol tolerance and cross-tolerance to pentobarbital in the rat.

Adult male Wistar rats were fed nutritionally adequate liquid diets providing 35% of the total calories as ethanol, while pair-fed controls received the corresponding diet with ethanol replaced by an equicaloric concentration of sucrose. After 2, 4, 6, 8, 10 and 14 weeks of chronic ethanol treatment, separate groups of rats were injected with a test dose of either ethanol (3 g/kg) or pentobarbital (40 mg/kg). Rectal temperatures were determined prior to and at 30, 60, 90 and 120 min after injection. The fall in rectal temperature after a test dose of ethanol or pentobarbital was significantly lower at 2 and 4 weeks in ethanol-treated rats than in pair-fed controls. After 6 and 8 weeks of chronic ethanol treatment, the fall in temperature after the same test doses was still less in ethanol-treated rats than in controls. However, at 10 and 14 weeks the fall in temperature was virtually identical in the two groups. A similar pattern of results was obtained when ethanol-induced sleep was compared in ethanol-treated rats and control rats. These intriguing results challenge the generally believed concept that tolerance and cross-tolerance, once produced, are sustained with chronic treatment, and may raise the possibility that such processes are reversible even during chronic treatment, at least under certain regimens.

Animals↗
PubMed1980

Effect of 5,7-dihydroxytryptamine on the development of tolerance to ethanol.

5,7-Dihydroxytryptamine (5,7-DHT) or the vehicle was administered once into both lateral ventricles of the rat. Desmethylimipramine (DMI) was administered IP prior to the intraventricular injection of 5,7-DHT to prevent the destruction of norepinephrine (NE) terminals. Following recovery from surgery, ethanol (5 g/kg, PO) or isocaloric sucrose was given daily for 25 days. Tests at 5-day intervals showed that chronic ethanol treatment produced tolerance to the motor impairment on the moving belt test and to hypothermic effects of ethanol. The 5,7-DHT treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. However, 5,7-DHT treatment produced a 75% depletion of brain serotonin (5-HT) without altering NE concentration and retarded the development of tolerance to ethanol in both measurements. This study with a specific central depletor of 5-HT, without alteration in NE concentration, extends and supports our hypothesis that brain 5-HT modulates the development of tolerance to ethanol.

5,7-Dihydroxytryptamine↗
PubMed1980

Effect of p-chlorophenylalanine on the acquisition of tolerance to barbital.

The effect of p-chlorophenylalanine (p-CPA) pretreatment on barbital tolerance in the rat as measured by motor impairment on the moving belt test was examined in two separate studies. The first used a 2 X 2 design with doses of p-CPA (125 mg/kg) or water, and sodium barbital (300 mg/kg) or water. The treatments continued for 28 days with tests every 7 days. The p-CPA dose used was previously shown to produce and maintain greater than 95% depletion of brain serotonin (5-HT). Tolerance developed to the test doses, and even greater tolerance to the chronic treatment doses. In both cases the p-CPA slowed the development of tolerance without altering the acute response to the challenge dose of barbital. The second study involved only a p-CPA-barbital group and a water-barbital group. In this case treatment lasted for up to 8 days, with separate subgroups being tested only once each at 2-day intervals, in order to prevent the tests from affecting the rate of tolerance development. This experiment confirmed that p-CPA slowed the development of barbital tolerance. The present findings provide additional support for the possibility that 5-HT may be involved in the development of tolerance to sedatives (e.g., alcohol, pentobarbital).

Animals↗
PubMed1980

Effect of p-chlorophenylalanine on the acquisition of tolerance to the hypnotic effects of pentobarbital, barbital, and ethanol.

Rats were given pentobarbital by daily intubation. Sleeping times and blood levels of drug at awakening, after intraperitoneal test doses of ethanol, pentobarbital, or barbital, were measured at various times during chronic treatment in order to assess the degree of tolerance developed. No central nervous system (CNS) tolerance to pentobarbital or cross-tolerance to barbital or ethanol occurred on treatment with sodium pentobarbital, 50 mg/kg, daily. However, when the size and frequency of pentobarbital treatment doses were increased (50-80 mg/kg, three times daily) a clear CNS tolerance to barbital occurred. Chronic administration of p-chlorophenylalanine (p-CPA), in a dose previously shown to maintain more than 95% depletion of brain serotonin (5-HT), enhanced the acute hypnotic effect of barbiturates and ethanol. Independently of this effect, p-CPA treatment also resulted in a reduction in the development of CNS tolerance. These results are consistent with earlier findings that brain 5-HT depletion retards tolerance development to central depressant drugs as measured by a variety of unrelated tests.

Animals↗
PubMed1979

Effect of L-tryptophan on the acquisition of tolerance to ethanol-induced motor impairment and hypothermia.

Rats were rendered tolerant to ethanol by daily gavage of 4--5 g/kg. The degree of motor impairment on the moving belt test and of hypothermia after i.p. test doses of ethanol was measured prior to and at various times during the chronic treatment, to assess the rates of tolerance development. L-Tryptophan (75 mg/kg twice daily) was administered chronically to elevate brain serotonin level. This treatment did not alter the motor impairment or hypothermia produced by the initial test doses of ethanol (2.0 and 2.5 g/kg respectively). However, the development of tolerance to both the motor impairment and hypothermia effects of ethanol was accelerated in the tryptophan-treated rats. This finding complements our earlier observations that depletion of 5-HT with p-CPA slows down tolerance. Blood ethanol measurements at 20 min (motor impairment) or 90 min (hypothermia) after the administration of the test dose reveal no significant difference between the control and tryptophan-treated rats, suggesting that tryptophan did not influence the metabolism of ethanol. This finding supports the hypothesis that brain serotonin modulates the development of tolerance to ethanol.

Animals↗
PubMed1979

Effect of modification of brain serotonin (5-HT) on ethanol tolerance.

The effects of 5,7-dihydroxytryptamine and L-tryptophan treatment on ethanol tolerance in the rat, as measured by the moving-belt test of motor impairment and by hypothermia, were examined in separate studies. A 2 x 2 design was used for all experiments. 5,7-Dihydroxytryptamine (200 microgram in 20 microliter CSF) or vehicle alone was administered once into both lateral ventricles of the rat. Desmethylimipramine was administered intraperitoneally prior to an intraventricular injection of 5,7-dihydroxytryptamine to prevent the destruction of norepinephrine. L-Tryptophan (75 mg/kg p.o. twice daily) or water was administered chronically. Ethanol (4--5 g/kg p.o.) or sucrose was given daily, and the development of tolerance was monitored at 5--7-day intervals. Chronic ethanol treatment produced tolerance to both the motor impairment and hypothermia effects of ethanol. 5,7-Dihydroxytryptamine and L-tryptophan treatment did not alter either the motor impairment or hypothermia produced by the initial dose of ethanol. 5,7-Dihydroxytryptamine produced a 75% depletion of brain 5-HT and slowed the development of tolerance to ethanol in both measurements. In contrast, elevation of 5-HT by L-tryptophan (39% increase by a single dose) facilitated the development of tolerance to ethanol, as seen in both measures. These findings support our hypothesis that brain 5-HT has a modulating role in the development of tolerance to ethanol.

5,7-Dihydroxytryptamine↗
PubMed1978

Accelerated development of tolerance during repeated cycles of ethanol exposure.

Adult male rats were subjected to 1--4 cycles of daily gastric intubation with ethanol (6 g/kg) for 16 days, separated by 17-day alcohol-free periods. Tolerance produced by this treatment (designated 'physiological tolerance') was measured by change in effect of a 2.2 g/kg i.p. dose of ethanol on the moving-belt test. It occurred in each cycle, disappeared completely in the drug-free periods, and developed more rapidly in the second and later cycles than in the first. Tolerance produced by the 'behavioral augmentation' technique (daily test practice under the influence of ethanol) also developed more rapidly on a second than on a first cycle. The progression from within-session to between-session tolerance was still evident, but accelerated. With 25-day alcohol cycles, separated by a one-month drug-free period, the 'carry-over' effect (i.e., more rapid acquisition of tolerance in the second cycle) applied equally, regardless of whether or not tolerance was produced by the same technique in both cycles, or by a crossover in either direction between the two techniques.

Animals↗
PubMed1977

Parametric investigations of the effects of prior exposure to amphetamine and morphine on conditioned gustatory aversion.

Pretreatment by a psychoactive drug can greatly attenuate the conditioning of gustatory avoidance by that drug. Although such findings have been interpreted in terms of tolerance, alternative explanations are possible. In a series of experiments, it was found that pretreatments with morphine or amphetamine massed at 24-h intervals were no more effective in attenuating conditioning than pretreatments spaced at 120-h intervals, but pretreatment with morphine provided more persistent protection against subsequent conditioning by itself than did amphetamine in a comparable previous experiment. The similarity of massed and spaced pretreatment effects can be interpreted without appealing to tolerance as a factor, but the greater persistence of morphine pretreatment implicates tolerance as a mechanism.

Animals↗
PubMed1977

Effect of p-chlorophenylalanine on development of cross-tolerance between pentobarbital and ethanol.

Rats developed cross-tolerance to the motor-impairing effects of ethanol after daily oral administration of pentobarbital. Chronic administration of p-chlorophenylalanine (p-CPA), in a dosage regimen previously demonstrated to maintain extensive brain serotonin (5-HT) depletion, slowed down cross-tolerance development. p-CPA did not appear to exert this effect by altering the disposition of ethanol, since blood ethanol levels measured 20 min after ethanol administration were not affected by p-CPA treatment. This study extends our previous findings with respect to the inhibitory effects of p-CPA on tolerance development to ethanol and pentobarbital, and suggests that 5-HT may play a role in cross-tolerance development between ethanol and pentobarbital.

Animals↗