Effect of Lipid Solubility on the Development of Chronic Cross-Tolerance Between Ethanol and Different Alcohols and Barbiturates

doi:10.1016/S0091-3057(96)00163-3

Pharmacology Biochemistry and Behavior

Volume 57, Issues 1–2, May–June 1997, Pages 101-110

https://doi.org/10.1016/S0091-3057(96)00163-3 Get rights and content

Abstract

Tolerance to ethanol and cross-tolerance to other alcohols ( n-propanol, n-butanol, t-butanol, isobutanol, t-amyl alcohol, n-amyl alcohol, and benzyl alcohol) and barbiturates (pentobarbital, secobarbital, amobarbital, thiopental, barbital and phenobarbital) that differ in lipid:water partition coefficient was examined in rats after chronic pretreatment with ethanol. Tolerance and cross-tolerance were studied with three different measures (hypothermia, tilt-plane, and rotarod). Tolerance to ethanol resulted in significant cross-tolerance to alcohols with low lipid solubility ( n-propanol and t-butanol), whereas no cross-tolerance was seen with alcohols of high lipid solubility (isobutanol, n-amyl alcohol, t-amyl alcohol and benzyl alcohol). Cross-tolerance to n-butanol (which has intermediate lipid solubility) appeared to be metabolic rather than functional. Tolerance to ethanol also resulted in significant cross-tolerance to barbital and phenobarbital, but not to pentobarbital, secobarbital, amobarbital or thiopental. These studies suggest that lipid solubility is an important factor in relation to specificity of cross-tolerance to alcohols and barbiturates.

Section snippets

Animals

Male Sprague–Dawley rats weighing 150–200 g were obtained from Charles River Laboratories (Montreal, Quebec). They were housed singly and fed a standard laboratory rat chow in a daily ration which was individually adjusted to bring them all to a body weight of 250–280 g before any training or testing was carried out. Thereafter, each animal received five standard pellets daily for the balance of this study. Tap water was available at all times. The temperature of the colony room was maintained

Preliminary Dose-Response Studies

Groups of well-trained rats were used for preliminary log-dose response studies of various alcohols and barbiturates on the accelerod test. Each group was divided, on the basis of their initial scores, into four or five balanced subgroups. Each subgroup ( n = 5 or 6) received an assigned dose of the drug to be tested. The rats were then tested on the accelerod at 2.5, 7.5, 12.5 and 17.5 min after drug injection. Dose-response curves for the drugs examined in this way are shown in Fig. 1. The

Preliminary Dose-Response Studies

As shown in Fig. 1, the dose-response curves for the four alcohols (ethanol, n-propanol, n-butanol, t-butanol) and four barbiturates (barbital, phenobarbital, pentobarbital and thiopental) studies in detail were essentially parallel. It was therefore possible to estimate, by simple interpolation in the respective dose-response graphs, the dose of each drug that would produce a 60% impairment response (ED60). The ED60 was found to be inversely related to the octanol/water partition coefficient

Discussion

The results of this work indicate that chronic treatment with ethanol resulted in tolerance to ethanol on three different tests. The degree of tolerance to ethanol was roughly comparable in the three tests, but animals in the rotarod test took longer to develop tolerance than those in the other two tests. Since we used different batches of animals for different studies, we cannot tell whether the difference in time required to produce comparable levels of tolerance is due to differences between

References (29)

A Gougos et al.
Tolerance to ethanol and cross-tolerance to pentobarbital and barbital
Pharmacol. Biochem. Behav.
(1986)
J.M Khanna et al.
Effect of NMDA antagonists on rapid and chronic tolerance to ethanolImportance of intoxicated practice
Pharmacol. Biochem. Behav.
(1994)
A.D Lê et al.
Tolerance to and cross-tolerance among ethanol, pentobarbital and chlordiazepoxide
Pharmacol. Biochem. Behav.
(1986)
A Arvola et al.
A test for level of alcohol intoxication in the rat
Q.J. Stud. Alcohol
(1958)
V Bogo et al.
Comparisons of accelerod and rotarod sensitivity in detecting ethanol- and acrylamide-induced performance decrement in ratsReview of experimental considerations of rotating rod systems
Neurotoxicology
(1981)
J.H Chin et al.
Drug tolerance in biomembranesa spin label study of the effects of ethanol
Science
(1977)
M.A Curran et al.
Barbiturate anesthesia and alcohol tolerance in a rat model
Anesth. Analg.
(1988)
M El-Ghundi et al.
The contribution of environmental cues to cross-tolerance between ethanol and pentobarbital
Psychopharmacology
(1989)
J Ferguson
The use of chemical potentials as indices of toxicity
Proc. Roy. Soc. Ser. B.
(1939)
N.P Franks et al.
Mechanism of general anesthesia
Environmental Health Perspectives
(1990)

R.D Hawkins et al.

Effect of chronic intake of ethanol on rate of ethanol metabolism

Can. J. Physiol. Pharmacol.

(1966)

T.C Howerton et al.

Lipid solubility is correlated with hypnotic and hypothermic responses of long-sleep (LS) and short-sleep (SS) mice to various depressant drugs

J. Pharmacol. Exp. Ther.

(1983)

T.C Howerton et al.

Differential effect of long-chain alcohols in LS and SS mice

Psychopharmacology

(1983)

H Kalant et al.

Environmental-neurochemical interactions in ethanol tolerance

Cited by (16)

Benzyl alcohol increases voluntary ethanol drinking in rats
2014, Pharmacology Biochemistry and Behavior
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The present finding of longer lasting high frequencies of ethanol-mediated testosterone elevations in the high-drinking AA compared with low-drinking Wistar rats support our previous hypotheses about the role of testosterone in promoting ethanol drinking. BA is known to cause cross-tolerance to other alcohols, as e.g. ethanol (Khanna et al., 1997). On the other hand, tolerance has in several studies with experimental animals (McBride and Li, 1998) and with humans (Schuckit, 1994) been linked to the propensity to consume more ethanol.
The anabolic steroid nandrolone decanoate has been reported to increase voluntary ethanol intake in Wistar rats. In recent experiments we received opposite results, with decreased voluntary ethanol intake in both high drinking AA and low drinking Wistar rats after nandrolone treatment. The difference between the two studies was that we used pure nandrolone decanoate in oil, whereas in the previous study the nandrolone product Deca-Durabolin containing benzyl alcohol (BA) was used. The aims of the present study were to clarify whether the BA treatment could promote ethanol drinking and to assess the role of the hypothalamic–pituitary–adrenal–gonadal axes (HPAGA) in the potential BA effect. Male AA and Wistar rats received subcutaneously BA or vehicle oil for 14 days. Hereafter followed a 1-week washout and consecutively a 3-week voluntary alcohol consumption period. The median (± median absolute deviation) voluntary ethanol consumption during the drinking period was higher in BA-treated than in control rats (4.94 ± 1.31 g/kg/day vs. 4.17 ± 0.31 g/kg/day, p = 0.07 and 1.01 ± 0.26 g/kg/day vs. 0.38 ± 0.27 g/kg/day, p = 0.05, for AA and Wistar rats, respectively; combined effect p < 0.01). The present results can explain the previous discrepancy between the two nandrolone studies. No significant BA effects on basal and ethanol-mediated serum testosterone and corticosterone levels were observed in blood samples taken at days 1, 8 and 22. However, 2 h after ethanol administration significantly (p = 0.02) higher frequency of testosterone elevations was detected in high drinking AA rats compared to low drinking Wistars, which supports our previous hypotheses of a role of testosterone elevation in promoting ethanol drinking. Skin irritation and dermatitis were shown exclusively in the BA-treated animals. Altogether, the present results indicate that earlier findings obtained with Deca-Durabolin containing BA need to be re-evaluated.
Improved transformation of morphometric measurements for a priori parameter estimation in a physiologically-based pharmacokinetic model of ethanol
2007, Biomedical Signal Processing and Control
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As suggested, an unconstrained optimization does not mandate that VP (the “peripheral” volume) be larger than VB (the “blood” volume) or even positive, an obvious physiological constraint. Further, as the estimated volume of distribution for alcohol is approximately equal to the entire total body water [36–38,57], the sum of VP and VB was constrained to be less than 120% of TBW, allowing for error in that estimation and the influence of weak perfusion of alcohol into body fat [40,57]. Additionally, the diffusion constant kAT was held to be within the bounds of [0 1], mandating that this process must occur (non-zero), and is neither instantaneous and not facilitated (less than unity).
Prescription of the brain's time course of exposure to experimentally administered ethanol can be achieved with intravenous infusion profiles computed from a physiologically-based pharmacokinetic (PBPK) model of alcohol distribution and elimination. Previous parameter estimation employed transformations of an individual's age, height, weight and gender inferred from the literature, with modeling errors overcome with real-time, intermittent feedback. Current research applications, such as ethanol exposures administered during fMRI scanning, require open-loop infusions, thus improved transformation of morphometric measurements.
Records of human breath alcohol concentration (BrAC) clamp experiments were analyzed. Optimal, unique PBPK parameters of a model of the distribution and elimination of ethanol were determined for each record and found to be in concordance with parameter values published by other investigators. A linear transformation between the readily measurable physical characteristics or morphometrics, including gender, age, height, weight, and TBW estimates, and the model parameters were then determined in a least squares sense according to the formula θ = F(x) = F_mx where x = (age height weight TBW)^T ∈ R⁴ and θ = (R_C V_P V_B m_max k_AT)^T ∈ R⁵.
The transformation was then evaluated with several parameter prediction performance measures. A substantial improvement in all error statistics, in relation to an earlier affine transformation that used only body weight as the relevant morphometric was obtained. Deviation from the measured response was reduced from 27 to 20%. Error in parameter estimation was reduced from 109 to 38%. Percent alcohol provided in error was reduced from 46 to 28%. Error in infusion profile estimation was reduced from 55 to 33%.
The algorithm described, which optimizes individual pharmacokinetic parameter values and then subsequent extension to a priori prediction, while not unique, can be readily be adapted to other molecules and pharmacokinetic models. This includes those used for distinct purposes, such as automated control of anesthetic agents.
Behavioral sensitization to ethanol is modulated by environmental conditions, but is not associated with cross-sensitization to allopregnanolone or pentobarbital in DBA/2J mice
2005, Neuroscience
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 3α-hydroxy-5α-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.
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.
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.
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.
Selection for pentobarbital withdrawal severity: Correlated differences in withdrawal from other sedative drugs
2004, Brain Research
Citation Excerpt :
Preclinically, the development of tolerance to a given sedative agent can confer cross-tolerance to other sedatives (see Ref. [16]). However, cross-tolerance does not necessarily extend among all classes of sedative drugs or members of a given class of sedatives [16–18,20]. These findings suggest that even though physical dependence displays certain similarities across sedatives, some differences in the mechanisms of tolerance and/or dependence specific to each drug or type of drug may exist.
In mice, withdrawal from agents that depress central nervous system function, such as barbiturates and benzodiazepines, results in the production of a withdrawal syndrome, one feature of which is increased severity of handling induced convulsions (HICs). High and Low Pentobarbital Withdrawal mice (HPW and LPW) were selectively bred to display severe and mild pentobarbital withdrawal HICs, respectively. These mice provide a valuable means to assess genetic correlations between withdrawal from pentobarbital and other sedative agents. We tested HPW and LPW mice for severity of HICs elicited during withdrawal from ethanol, diazepam, and zolpidem, and measured consumption of and preference for pentobarbital solutions in HPW and LPW mice. HPW mice displayed greater HICs than LPW mice during ethanol and zolpidem withdrawal, but differed less robustly during diazepam withdrawal. LPW mice consumed more pentobarbital in a solution of a moderate concentration than did HPW mice, but did not consume more pentobarbital at a higher or lower concentration. These results indicate that some of the same genes that affect the severity of withdrawal from pentobarbital also influence ethanol and zolpidem withdrawal, but that diazepam withdrawal may be less influenced by these genes.
Behavioral action of ethanol in Porsolt's forced swim test: Modulation by 3alpha-hydroxy-5alpha-pregnan-20-one
2002, Neuropharmacology
Ethanol is known to increase cortical and plasma content of GABAergic neurosteroid 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP) which is responsible for some of its behavioral and electrophysiological effects. We have previously demonstrated the antidepressant like effect of 3α,5α-THP in mice. This study investigated the role of 3α,5α-THP in acute, chronic and withdrawal effects of ethanol using mouse forced swim test (FST) paradigm. While acute systemic ethanol (2 or 2.5 g/kg) administration exhibited an antidepressant like effect, its prolonged consumption produced tolerance to this effect and its withdrawal, on the other hand, elicited enhanced behavioral despair (depression). The antidepressant like effect of ethanol was potentiated by GABA_A receptor agonist, muscimol (0.5 mg/kg, i.p.), 3α,5α-THP (0.5, 1 or 2 μg/mouse, i.c.v.) and by neurosteroidogenic drugs viz. selective serotonin reuptake inhibitor (SSRI), fluoxetine (5 or 20 mg/kg, i.p.), agonist at mitochondrial diazepam binding inhibitor receptor, FGIN 1-27 (0.5 or 1 μg/mouse, i.c.v.), or 11β-hydroxylase inhibitor, metyrapone (0.5 or 1 μg/mouse, i.c.v.) which are known to increase endogenous 3α,5α-THP content. Furthermore, inhibition of the endogenous neurosteroid biosynthesis by drugs like 5α-reductase inhibitor, finasteride (50 mg/kg, s.c.), 3β-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg i.p.) or 3α-hydroxysteroid dehydrogenase inhibitor, indomethacin (5 mg/kg, i.p.) and GABA_A receptor antagonist, bicuculline (1 mg/kg, i.p.) blocked the antidepressant like effect of ethanol. Withdrawal of ethanol from mice consuming it chronically displayed enhanced behavioral despair and elicited tolerance to antidepressant like action of acute ethanol (2.5, 3 or 3.5 g/kg). Moreover, sub-antidepressant doses (0.25 or 0.5 μg/mouse, i.c.v.) of 3α,5α-THP and fluoxetine (5 mg/kg, i.p.) but not imipramine (1 mg/kg, i.p.) reversed the depression associated with ethanol withdrawal indicating sensitization to their antidepressant action. Thus, 3α,5α-THP plays a pivotal role in the actions of ethanol and in the depression associated with ethanol withdrawal. These findings may be of potential ramification to contribute to the depression associated with alcoholism and its treatment using neurosteroids.
Importance of magnesium ions in development of tolerance to ethanol: Studies on cultured cerebral vascular smooth muscle cells, type-2 astrocytes and intact rat brain
2001, Brain Research Bulletin
Citation Excerpt :
There is a decrease in the intoxicating effects of ethanol and a requirement for greater amounts of ethanol intake to achieve the near-identical intoxicating effects seen with acute initial ethanol administration. Such adaptation effects of ethanol are thought to be brought about via effects on cell membranes, lipid ordering, ligand-gated ion channels, voltage-gated calcium channels, diverse cell signaling pathways, and subcellular elements (see reviews [13,14,17,19,20,23,25,29,53]). Among signal transduction pathways, PKC, Ca2+ influx/release, and NMDA and GABAA receptors are the most sensitive to ethanol, and are clearly involved in the mechanisms that underlie tolerance to ethanol in the brain (see reviews [14,17,19,20,23,25,53]).
This study was designed to examine the roles of intracellular free magnesium ion concentration ([Mg²⁺]_i) in ethanol-induced intoxication and development of tolerance in cultured canine cerebral vascular smooth muscle cells and astrocytes as well as intact rat brain. The basal, resting level of [Mg²⁺]_i in cerebrovascular cells was 732.5 ± 82.4 μM. Exposure of cultured canine cerebral vascular smooth muscle cells to ethanol (10 and 25 mM) for 24 h reduced the concentrations of [Mg²⁺]_i to 521.1 ± 59.6 μM, and 308.2 ± 37.8μM, respectively. However, exposure of these cultured vascular cells to the same concentrations of ethanol, after initial pretreatment with ethanol for 24 h, failed to interfere with the levels of [Mg²⁺]_i. Measurement of [Mg²⁺]_i at 48 h and 72 h indicated that the decreased levels of [Mg²⁺]_i induced by ethanol at 24 h treatment returned toward baseline. Similar experiments were performed in cultured type-2 astrocytes isolated from neonatal rat brain. The basal level of [Mg²⁺]_i in type-2 astrocytes was about 125 μM. Incubation of these cells with 10 mM ethanol for 10 min resulted in a 27% reduction in the level of [Mg²⁺]_i, whereas incubation with 25 mM ethanol resulted in almost a 50% reduction in [Mg²⁺]_i. The decreased levels of [Mg²⁺]_i lasted around 30 min, until the measurement finished. Continuous incubation of these cultured astrocytes, with ethanol (either 10 mM or 25 mM), for more than 24 h, indicated that the concentrations of [Mg²⁺]_i in type-2 astrocytes were equivalent to those at basal, resting levels. In vivo ³¹P-NMR spectroscopy, performed on intact rat brains, indicated that an initial administration of 4 mg/kg ethanol (∼20–25 mM blood alcohol level) resulted (after 20–40 min of exposure) in severe deficits in whole brain [Mg²⁺]_i (550 ± 33 μM to 358 ± 24 μM). Repeated injections of ethanol (4 mg/kg) over the next 24–72 h resulted in progressively diminishing effects on brain [Mg²⁺]_i. These experimental data indicate that chronic ethanol treatment can induce a tolerance to depletion of [Mg²⁺]_i in cerebrovascular smooth muscle cells, type-2 astrocytes as well as intact rat brain. The results suggest that [Mg²⁺]_i might play a major role in alcohol-induced tolerance in the brain.

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ArticlesEffect of Lipid Solubility on the Development of Chronic Cross-Tolerance Between Ethanol and Different Alcohols and Barbiturates

Abstract

Section snippets

Animals

Preliminary Dose-Response Studies

Preliminary Dose-Response Studies

Discussion

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

A test for level of alcohol intoxication in the rat

Q.J. Stud. Alcohol

Comparisons of accelerod and rotarod sensitivity in detecting ethanol- and acrylamide-induced performance decrement in ratsReview of experimental considerations of rotating rod systems

Neurotoxicology

Drug tolerance in biomembranesa spin label study of the effects of ethanol

Science

Barbiturate anesthesia and alcohol tolerance in a rat model

Anesth. Analg.

The contribution of environmental cues to cross-tolerance between ethanol and pentobarbital

Psychopharmacology

The use of chemical potentials as indices of toxicity

Proc. Roy. Soc. Ser. B.

Mechanism of general anesthesia

Environmental Health Perspectives

Effect of chronic intake of ethanol on rate of ethanol metabolism

Can. J. Physiol. Pharmacol.

Lipid solubility is correlated with hypnotic and hypothermic responses of long-sleep (LS) and short-sleep (SS) mice to various depressant drugs

J. Pharmacol. Exp. Ther.

Differential effect of long-chain alcohols in LS and SS mice

Psychopharmacology

Environmental-neurochemical interactions in ethanol tolerance

Articles
Effect of Lipid Solubility on the Development of Chronic Cross-Tolerance Between Ethanol and Different Alcohols and Barbiturates