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PubMed1981

Reactions to ischemic pain: interactions between individual, situational and naloxone effects.

Fifty-two paid volunteers participated in two separate factorial investigations of the effects of naloxone on time tolerance of and affective reactions to ischemia, as a function of the interaction between expectations of involvement in the experimental situation and experimental variables involving stress or suggestions of analgesia. Naloxone-induced reduction in tolerance to ischemia interacted significantly with the level of involvement expectancies. The suggestion of analgesia provided no significant naloxone-saline discrimination, but there was a significant interaction between variable memory task conditions and drug effects on the time ischemia was tolerated. These findings suggest that naloxone-opiate receptor interactions may depend on individual differences in attitudes to the situation, but may be potentiated by select environmental stimuli. Analyses of the effects of treatment on affective reactions to ischemia failed to show consistent results.

Adult↗
PubMed1986

Dose-response analysis of nicotine tolerance and receptor changes in two inbred mouse strains.

Mice of two inbred strains, DBA and C3H, were infused i.v. with saline, or 2, 4 or 6 mg/kg/hr of nicotine for 10 days. Two hours after termination of infusion the mice were challenged with one of several nicotine doses and the effects on respiration rate, Y-maze activity and rears, acoustic startle response, heart rate and body temperature were measured. Saline-infused C3H mice were less responsive than were DBA mice for all these tests with the exception of the acoustic startle response test. Nicotine-treated DBA mice developed a dose-related tolerance for most measures, whereas C3H mice did not appear to develop tolerance to any measure until the infusion dose reached 4 mg/kg/hr. The two mouse strains did not differ in the number of [3H] nicotine binding sites in six brain regions, and chronic nicotine treatment elicited similar changes in the binding of this ligand in the two strains. C3H mice had greater concentrations of alpha-[125I] BTX binding in hippocampus, midbrain and hypothalamus than did DBA mice. Chronic nicotine treatment resulted in an identical increase in bungarotoxin binding in the two mouse strains such that the initial strain differences were maintained. These results indicate that a threshold in drug response must be surpassed before a mouse develops tolerance to nicotine. In addition, mechanisms other than differences in receptor numbers must be invoked to explain differences in response to nicotine.

Animals↗
PubMed2005

Effects of digitonin on hyperglycaemia and dyslipidemia induced by high-sucrose intake.

This study examined whether high-sucrose intake effects on lipid profile and oral glucose tolerance may be inhibited by a single administration of digitonin, a saponin from the seeds of Digitalis purpurea Male Wistar 24 rats were initially divided into two groups (n=12): (C) was given standard chow and water; (S) received standard chow and 30% sucrose in its drinking water. After 30 days of treatments, C rats were divided into two groups (n=6): (CC) given an intra-gastric dose 0.5 mL saline; (CD) given a single intra-gastric dose of 15 mg/kg digitonin. S rats were also divided into two groups (n=6): (SC) given intra-gastric saline and (SD) given digitonin. Rats were sacrificed after the oral glucose tolerance test (OGTT) at 2 h after the digitonin administration. S rats had higher total energy intake and final body weight than C. SC rats had fasting hyperglycaemia and impaired OGTT. Digitonin in SD group improved the glucose tolerance. Triacylglycerol (TG), very-low-density lipoprotein (VLDL-C) and free fatty acid (FFA) serum concentrations were increased in SD rats from CC. Digitonin in SD rats decreased FFA and led TG and VLDL-C concentrations at the levels observed in the CC group. Despite the enhanced cholesterol in CD group from CC, the high-density lipoprotein (HDL-C) was increased in these animals. HDL-C/TG ratio was higher in CD and SD than in CC and SC, respectively. No significant differences were observed in lipid hydroperoxide(LH) between the groups. VLDL-C/LH ratio and gamma-glutamyl transferase (GGT) activity were increased in SC group and were decreased in SD rats from the SC. In conclusion digitonin enhanced glucose tolerance and had beneficial effects on serum lipids by improve antioxidant activity.

Animals↗
PubMed1983

Demonstration of central nervous system tolerance to ethanol in mice: consequent effects on smooth muscle in vitro.

Mice were given ethanol (9 g/kg) or saline (57 ml/kg) daily in three divided doses for periods of 1 and 4 days to study the effects of such ethanol (ETOH) exposure on central nervous system (CNS) and peripheral smooth muscle (vasa deferentia) function. After 1 day, ETOH-treated mice were functionally tolerant to the hypothermic (3 g/kg, intraperitoneal), but not to the hypnotic (3.25 g/kg, intraperitoneal) effect of ETOH. Functional tolerance to both CNS effects of ETOH was demonstrated in mice after the 4-day ETOH exposure. Norepinephrine (NE) and high K+-depolarizing solutions each elicited dose-dependent contractions in the mouse vasa deferens preparation in vitro that consisted of a phasic and tonic component. The tonic components of the NE and K+ responses were more dependent upon extracellular Ca2+ (Ca2+ext) than the phasic components. Addition of ETOH (120 to 480 mM) or the Ca2+ channel-antagonist nifedipine (1 X 10(-9) to 3 X 10(-7) M) to the preparation selectively inhibited the tonic component of the NE and K+ responses, suggesting that both agents acted to inhibit the responses by interfering with the translocation of Ca2+ext. Vasa deferentia isolated from ETOH-treated mice did not exhibit altered reactivity to NE in the phasic or tonic component of the response. The isolated smooth muscle from mice centrally tolerant to ETOH did not appear to be tolerant to inhibitory effect of ETOH or cross-tolerant to the inhibitory effect of nifedipine on stimulant-induced contractions.

Animals↗
PubMed2005

Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.

Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease.

Administration, Inhalation↗
PubMed1988

Effect of naloxone infusion on analgesia and respiratory depression after epidural fentanyl.

The efficacy of two dosage regimens of intravenous naloxone were compared to avoid nonrespiratory side effects and respiratory depression and yet to preserve analgesia (maximum tolerance to periostial pressure over the tibia) after administration of 200 micrograms epidural fentanyl. Three groups of eight patients were studied: group 1 patients received a loading dose of 0.4 mg IV naloxone followed by naloxone infusion at a rate of 10 micrograms.kg-1.hr-1. Group II patients received a loading dose of 0.2 micrograms naloxone followed by a naloxone infusion at a rate of 5 micrograms.kg-1.hr-1. Group III patients received a saline infusion at a rate of 20 ml/hr. Epidural fentanyl significantly increased tolerance to periostial pain in all three groups (respectively, +38 +/- 20%, +36 +/- 16%, and +35 +/- 14%) (mean +/- SD; P less than 0.05). The naloxone infusion significantly reduced this effect in groups I and II, respectively, -40 +/- 20% and -37 +/- 28% below prenaloxone levels) (P less than 0.05). Nonrespiratory side effects were also reversed in groups I and II. In group III, neither periostial analgesia nor nonrespiratory side effects were affected. The baseline slopes of VE/PETCO2 were 2.34 +/- 1.01, 2.14 +/- 0.66, and 2.68 +/- 1.14 L.min-1.mm Hg-1, respectively, in groups I, II, and III. Epidural fentanyl significantly decreased the slope below baseline levels in each group: -21 +/- 16%, -22 +/- 17%, and -19 +/- 32%, respectively, in groups I, II and III.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Reduction of adverse citrate reactions during autologous large-volume PBPC apheresis by continuous infusion of calcium-gluconate.

BACKGROUND: Citrate-related side effects are common adverse reactions during PBPC apheresis. To reduce the incidence of citrate-related reactions, the effect of a continuous calcium-gluconate infusion on the appearance of hypocalcemic symptoms and on the subjective tolerance toward large-volume leukapheresis (LVL) was tested. STUDY DESIGN AND METHODS: A double-blinded, placebo-controlled trial was carried out in 50 patients undergoing standardized LVL at a median ACD-A ratio of 1.99 mg per kg and minute. Patients were randomly assigned to receive a continuous IV infusion of either saline or calcium-gluconate at a dose of 1.8 mmol calcium per hour. Subjective tolerance toward LVL was determined by standardized rating systems. Further, hormonal and electrolyte changes were monitored to assess the effect of continuous calcium infusion on calcium homeostasis. RESULTS: Continuous IV administration of calcium-gluconate throughout LVL reduced the incidence of citrate-related effects by 65 percent. In patients who developed signs of hypocalcemia, the symptoms were weaker, and less medical intervention was needed to resolve clinical symptoms. The subjective tolerance toward LVL was superior in patients receiving calcium support compared to control patients. Continuous calcium infusion attenuated changes in serum phosphorus compared to patients receiving saline. No differences were observed in the variation of serum potassium and serum magnesium between the control group and the treatment group. The administration of calcium was not associated with technical problems related to the apheresis procedure, neither was any effect of calcium support on the total number of CD34+ cells collected observed. CONCLUSION: These results indicate that continuous support of calcium-gluconate during LVL is an effective means of reducing the incidence of citrate-related symptoms and improving subjective tolerance toward LVL, without affecting the technical performance or the number of CD34+ cells collected.

Adolescent↗
PubMed1979

Cross-tolerance to centrally injected barbiturates.

Hypnotic responses to intracerebroventricular (i.c.v) injections of either barbital, pentobarbital, R(-) and S(+) mephorbarbital, or racemic metharbital were compared to those produced by phenobarbital. Dose--response relationships were obtained for all except S(+) mephorbarbital and metharbital. Chronic i.c.v. phenobarbital administration resulted in tolerance to the drug's hypnotic effects. However, chronic barbital administration using an identical regimen did not produce tolerance, nor were phenobarbital tolerant rats cross-tolerant to barbital. Chronic i.c.v pentobarbital resulted in an irreversible decrease in responsiveness to its own effects and to those of other barbiturates. This was attributed to the high alkalinity of the solution (pH 9.6) since i.c.v. injection of saline adjusted to the same pH also reduced responsiveness to i.c.v. barbiturates. However, rats tolerant to i.c.v. phenobarbital were tolerant to acute i.c.v. injection of pentobarbital. Similar cross-tolerance was observed on systemic administration of the barbiturates. The efflux rates of i.c.v. phenobarbital or barbital and their distribution to different brain areas were identical in tolerant and nontolerant rats. Awakening phenobarbital brain levels of the tolerant rats were approximately three times higher than those in nontolerant controls. The conclusion is reached that central administration of phenobarbital provides a valid model for studying functional tolerance.

Animals↗
PubMed1995

[Postoperative infusion therapy: electrolyte solution in comparison with hypocaloric glucose and carbohydrate exchange-amino acid solutions].

OBJECTIVES: Comparison of early postoperative hypocaloric nutrition with glucose or xylitol/sorbitol- amino acid solutions versus saline alone. Influence on substrate, especially protein metabolism. DESIGN: Prospective randomized study. SETTING: Intensive care unit of an university hospital. PATIENTS: 44 patients in three groups after major surgery with necessity of intensive care. RESULTS: Hypocaloric infusions were well tolerated immediately after operation and positively influenced functional proteins and N-balance. During saline infusion protein parameters deteriorated significantly already after 24 to 36 hours. Glucose was not inferior to the xylitol/sorbitol solution and both resulted in a stable metabolic state during four days. CONCLUSIONS: After major trauma or surgery hypocaloric nutrition should be started within 24 hours and can be given already directly after the operation period without metabolic deterioration.

Abdomen↗
PubMed2025

Comparison of stress tolerance mechanisms between Saccharomyces cerevisiae and the multistress-tolerant Pichia kudriavzevii.

Yeasts play a vital role in both research and industrial biomanufacturing. Saccharomyces cerevisiae has been extensively utilized as a model system. However, its application is often constrained by limited tolerance to the diverse stress conditions encountered in bioprocesses. These challenges have driven increasing interest in nonconventional, multistress-tolerant yeasts as alternative biomanufacturing hosts. This review highlights Pichia kudriavzevii as a promising nonconventional yeast for industrial applications. Unlike S. cerevisiae, P. kudriavzevii exhibits exceptional tolerance to high temperatures, elevated concentrations of furanic and phenolic inhibitors, osmotic stress, salinity, and extreme pH. These traits make it an attractive candidate for industrial processes without requiring extensive genetic modifications to enhance stress resistance. As a result, P. kudriavzevii has emerged as a flagship species for advancing bioeconomy. Despite its industrial potential, the molecular mechanisms underlying P. kudriavzevii's superior stress tolerance remain poorly understood. This review compiles current knowledge on P. kudriavzevii and compares its stress tolerance mechanisms with those of S. cerevisiae, providing insights into its innate resilience. By expanding our understanding of nonconventional yeasts, this review aims to facilitate their broader adoption as robust microbial platforms for industrial biomanufacturing.

Saccharomyces cerevisiae↗
PubMed2002

Tolerance and sensitization to the locomotor-activating effects of cocaine are mediated via independent mechanisms.

Tolerance or sensitization to the locomotor-activating effects of cocaine occurs depending upon the treatment regimen that is used. When cocaine is injected on a daily basis, sensitization occurs, whereas continuously infused cocaine leads to tolerance. Male Sprague-Dawley rats were treated for 7 days with continuous cocaine (50 mg/kg/day) via subcutaneously implanted osmotic minipumps, after which the pumps were removed. Locomotor activity was measured for 1 h each day. Some rats were challenged with an injection of cocaine (7.5, 15 or 30 mg/kg) either 2 or 9 days after pump removal. Two days after the pumps were removed (Day 10), there were no significant differences between cocaine- or saline-treated rats in the amount of locomotor activity produced by the challenge injections. However, cocaine-treated rats challenged with cocaine 9 days after pumps were removed (Day 17) exhibited significant tolerance, as evidenced by a shift downward of the cocaine curve, as compared to saline controls. When the rats were injected again on the next day (Day 18), the activity levels of both groups increased, as compared to the effects observed on Day 17. Thus, although the cocaine-treated rats were still tolerant compared to the saline-treated rats, they were sensitized compared to their previous response to a challenge injection. These findings indicate that tolerance and sensitization to the locomotor-activating effects of cocaine can exist simultaneously, which suggests that they are mediated by separate mechanisms.

Animals↗
PubMed1992

Effect of chromium administration on glucose tolerance in stroke-prone spontaneously hypertensive rats with streptozotocin-induced diabetes.

The present study was conducted to assess the effect of chromium (Cr) administration on glucose tolerance in insulin-dependent diabetes that accompanies hypertension. Four rat groups were used: stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) with and without streptozotocin (SZ, 40 mg/kg)-induced diabetes. Each group of rats was subdivided to the Cr-dose group and the control group. The Cr-dose group, which was intraperitoneally administered Cr solution (20 micrograms trivalent chromium/kg body weight/d for 4 weeks), and the control group (saline) were studied for plasma glucose and plasma insulin during intraperitoneal glucose tolerance test (IPGTT) and insulin action by isolated adipocytes. For diabetic SHRSP showing the highest plasma glucose and lowest plasma insulin among the four groups, Cr administration led to the greatest reduction in plasma glucose without a significant effect on plasma insulin during IPGTT. For each diabetic WKY and normal SHRSP and WKY, those given Cr showed lower levels of plasma glucose with lower levels of plasma insulin than the controls. For diabetic SHRSP, glucose uptake by isolated adipocytes in the Cr-dose group was higher than that in the control group. This effect of Cr administration involved enhancement of insulin responsiveness and sensitivity, attributed to enhanced affinity of the insulin receptor. A similar tendency was observed for diabetic WKY. However, for normal SHRSP and WKY, the increase in glucose uptake due to Cr administration coincided only with enhanced insulin responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Associative control of tolerance to the sedative and hypothermic effects of chlordiazepoxide.

Pavlovian control of tolerance to the sedative and hypothermic effects of chlordiazepoxide (CDP) was demonstrated in two experiments. In Experiment I, drug-experienced rats were repeatedly treated with CDP (30 mg/kg) in one environment (CS+); on alternate days, they were given saline injections in a different environment (CS-). Duration of sleeping and inactivity were used as measures of sedation. A comparable conditioning procedure was used in Experiment II, but tolerance to the hypothermic effect of CDP was the dependent measure. During tolerance testing, rats from both Experiments I and II were given CDP in one of three environments, CS+, CS-, or a novel environment (CSnov). In Experiment I, rats were equally tolerant in all three test environments when duration of sleep was assessed. However, when inactivity was used as the measure of tolerance, rats showed tolerance in CS+ and CS-, and significantly less tolerance in CSnov. Drug-naive controls showed similar nontolerant responses to CDP in all environments, thus ruling out the possibility that the effect of sedation was mediated nonassociatively. In Experiment II, drug-experienced rats showed tolerance to CDP-induced hypothermia in CS+ and CS- but less tolerance in CSnov. A compensatory hyperthermia was observed when these rats were given saline in CS+. There was some evidence for a generalization gradient in the conditional control of tolerance in both experiments.

Analysis of Variance↗
PubMed1993

Chronic spinal infusion of dexmedetomidine, ST-91 and clonidine: spinal alpha 2 adrenoceptor subtypes and intrinsic activity.

The antinociceptive effect (hot plate test) and behavioral changes produced by the continuous 7-day i.t. infusion of alpha 2 adrenoceptor agonists dexmedetomidine (10 and 3 nmol/hr), clonidine (100 and 30 nmol/hr) and 2-(2,6-diethylphenylamino)-2-imidazoline (ST-91) (30 and 10 nmol/hr) were examined in rats. The highest doses of each agonist produced an equivalent increase in hot plate latency on day 1 of infusion. These effects diminished to near base line by 5 to 7 days. In separate groups, i.t. dose-response curves were obtained with dexmedetomidine, clonidine and ST-91 in groups of rats which had received a 7-day infusion of saline or the equianalgesic concentrations of dexmedetomidine (10 nmol/hr) or ST-91 (30 nmol/hr). Dose-response curves in drug-infused animals showed a right shift as compared to the vehicle-infused rats. Calculation of the ratio of the ED50 values (tolerance ratio: drug vs. control) in animals receiving the continuous infusion of dexmedetomidine vs. saline indicated: 8- (6-12), 36- (19-54) and 1.0- (0.6-1.5) (ratio with 95% Cl) fold rightward shifts of dexmedetomidine, clonidine and ST-91 dose-response curves, respectively. Chronic infusion of ST-91 resulted in 62- (36-127), 22- (13-46) and 0.9- (0.7-1.1) fold rightward shift of the ST-91, clonidine and dexmedetomidine dose-response curves, respectively. Previously, we have shown that dexmedetomidine and clonidine act upon spinal alpha 2 adrenoceptor, which appeared distinguishable from that acted upon by ST-91.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1978

Biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes.

Oral glucose tolerance was examined in five maturity-onset diabetics during the infusion of somatostatin or saline. Somatostatin inhibited glucose-stimulated insulin release and reduced plasma glucagon by 50%--65%. The rise in plasma glucose after glucose ingestion was initially (at 30--120 min) reduced by somatostatin. However, beyond 3 hr, plasma glucose levels were 50--200 mg/100 ml higher, with somatostatin reaching concentrations at 6 hr that were twofold higher than those observed with saline ( p less than 0.005). The degree of late glucose intolerance was inversely related to postglucose plasma insulin concentrations (p less than 0.01). These findings demonstrate a biphasic effect of somatostatin on oral glucose tolerance in maturity-onset diabetes. The exaggerated later hyperglycemia is related to suppression of insulin secretion. The initial blunting of postprandial hyperglycemia may reflect decreased carbohydrate absorption and/or hypoglucagonemia-mediated enhancement of glucose disposal.

Adult↗
PubMed1987

Cocaine disposition in the brain after continuous or intermittent treatment and locomotor stimulation in mice.

Intermittent s.c. and i.p. injections of cocaine (20 mg/kg; total 430 mg/kg for each animal) for 18 days resulted in locomotor stimulation of mice upon challenge with cocaine on the 25th or 26th day, compared with no locomotor stimulation in a saline-pretreated group. In contrast to the sensitization by intermittent cocaine administration, tolerance was found upon challenge after continuous administration of cocaine by minipumps (25 mg/kg/day; total 450 mg/kg for each animal) on a similar schedule. No differences were found between the sensitized and tolerant groups in the levels of cocaine and benzoylecgonine in plasma and brain 12 min after i.p. administration of a challenge dose of cocaine, suggesting that in these chronic experiments the changes in the locomotor response are not accounted for by dispositional effects. In contrast, in animals treated daily for 2 or 3 days i.p. with cocaine and challenged with cocaine 1 day later, there was both a greater locomotor stimulation and a higher level of brain cocaine than in saline-pretreated animals, suggesting a dispositional effect. Among individual animals there was a positive correlation between their locomotor stimulation by the challenge dose and their brain cocaine concentration.

Animals↗
PubMed1986

Subchronic treatment of rats with nicotine: effects on tolerance and on [3H]acetylcholine and [3H]nicotine binding in the brain.

The effects of subchronic nicotine treatment on the development of tolerance and on two nicotinic ligand binding sites were investigated. After subcutaneous injection of nicotine (0.45 mg nicotine base/kg) or saline twice a day for 14 days the body weight of rats was significantly lower than that of control animals. A significant tolerance to the acute effects of nicotine on locomotor activity and body temperature was observed after the treatment period. Nicotine treatment also resulted in a significant increase in [3H]acetylcholine (3H-ACh) binding in the midbrain (48.3% increase in comparison with controls) and hippocampus (38.3% increase), whereas the binding of [3H]nicotine (3H-NIC) was unaffected in all brain areas investigated. These results indicate that subchronic s.c. injections of nicotine can differentially affect the binding of two different nicotinic ligands in the brain. It is also concluded that the development of tolerance to the acute effects of nicotine on locomotor activity and temperature is not directly dependent upon changes in binding of [3H]nicotine to the brain.

Acetylcholine↗
PubMed2002

Effect of acetaldehyde on acute tolerance and ethanol consumption in drinker and nondrinker rats.

OBJECTIVE: Acetaldehyde (AcH) has been shown to have aversive or reinforcing actions in relation to ethanol consumption. We have previously observed that a pharmacological dose of AcH (50-150 mg/kg) administered intraperitoneally (i.p.) produced a dose-dependent flavor aversion in low-ethanol drinker (UChA) rats, whereas high-ethanol drinker (UChB) rats appeared to be insensitive to AcH. Both strains of rats differ innately in their brain aldehyde dehydrogenase (ALDH) activity and in their capacity to develop acute tolerance to ethanol. The present study evaluates the effects of AcH, in UChA and UChB rats, on rats' behavior, their voluntary ethanol consumption and the development of acute functional tolerance to motor impairment induced by a dose of ethanol. METHOD: Subjects were rats selectively bred for high (UChB; n = 48) and low (UChA; n = 40) voluntary ethanol consumption. Rats were treated with either saline or doses of AcH (50 or 100 mg/kg, i.p.), and examined for effects on motor activity, on voluntary alcohol consumption with free access to a 10% alcohol solution and on acute tolerance to motor impairment induced by an ethanol dose (2.3 g/kg, i.p.), using the tilting plane test. RESULTS: AcH, 50 or 100 mg/kg, caused a dose-dependent loss of the righting reflex in UChA rats, whereas in UChB rats with same dose, a slight excitement was observed. There was significant increase of voluntary ethanol consumption in UChB rats (p < .001) 17 hours after the AcH injection, compared with saline-treated and control rats; in UChA rats, no change in voluntary ethanol consumption was produced. AcH produced a faster acute tolerance-to-ethanol development in UChB rats (p < .001) as compared with saline-treated and control rats, and no change in acute tolerance in UChA rats. Acetaldehyde injection did not change total mitochondrial ALDH2 activity. CONCLUSIONS: These results show that, 17 hours later, treatment of rats with pharmacological doses of acetaldehyde alters the voluntary ethanol consumption and acute tolerance development in UChB but not UChA rats. One of the factors involved may be a different sensitivity to AcH in these rat strains.

Acetaldehyde↗