H. Kalant

Research Advances in Alcohol and Drug Problems

1. Does Acetaldehyde Play a Role in Alcoholism? Behavioral versus Biochemical Analysis.- 2. Critical Explanations-Biological, Psychological, and Social-of Drinking Patterns and Problems from the Alcohol-Related Longitudinal Literature: Critiques and Strategies for Future Analyses on Behalf of the World Health Organization.- 3. Measuring Alcohol Consumption in the United States: Methods and Rationales.- 4. Alcohol and the Family: An International Review of the Literature with Implications for Research and Practice.- 5. The Origins of Modern Research and Responses Relevant to Problems of Alcohol: A Brief History of the First Center of Alcohol Studies.- 6. Drugs, Alcohol, and Aging.- 7. Stress and Coping Factors in the Epidemiology of Substance Use.- 8. Women, Illicit Drugs, and Crime.- 9. The Inverse Relationship between Tobacco Use and Body Weight.- 10. Effects of Abstinence from Tobacco: A Critical Review.

Adverse effects of cannabis on health: an update of the literature since 1996.

Recent research has clarified a number of important questions concerning adverse effects of cannabis on health. A causal role of acute cannabis intoxication in motor vehicle and other accidents has now been shown by the presence of measurable levels of Delta(9)-tetrahydrocannabinol (THC) in the blood of injured drivers in the absence of alcohol or other drugs, by surveys of driving under the influence of cannabis, and by significantly higher accident culpability risk of drivers using cannabis. Chronic inflammatory and precancerous changes in the airways have been demonstrated in cannabis smokers, and the most recent case-control study shows an increased risk of airways cancer that is proportional to the amount of cannabis use. Several different studies indicate that the epidemiological link between cannabis use and schizophrenia probably represents a causal role of cannabis in precipitating the onset or relapse of schizophrenia. A weaker but significant link between cannabis and depression has been found in various cohort studies, but the nature of the link is not yet clear. A large body of evidence now demonstrates that cannabis dependence, both behavioral and physical, does occur in about 7-10% of regular users, and that early onset of use, and especially of weekly or daily use, is a strong predictor of future dependence. Cognitive impairments of various types are readily demonstrable during acute cannabis intoxication, but there is no suitable evidence yet available to permit a decision as to whether long-lasting or permanent functional losses can result from chronic heavy use in adults. However, a small but growing body of evidence indicates subtle but apparently permanent effects on memory, information processing, and executive functions, in the offspring of women who used cannabis during pregnancy. In total, the evidence indicates that regular heavy use of cannabis carries significant risks for the individual user and for the health care system.

Acute tolerance to ethanol in the rat

Male Wistar rats were examined on the moving belt test at approximately 10, 30 and 60 min after administration of ethanol in doses ranging from 1.0–2.8 g/kg. Immediately after the test, each animal was sacrificed and ethanol concentrations were measured. The regression line of impairment as a function of brain alcohol concentration showed a progressive shift toward higher brain levels with increasing time after alcohol administration. The results confirm the existence of acute tolerance to ethanol, as defined by reduced impairment of function for a given blood level on the falling versus the rising arm of the blood alcohol curve. Confusion of interpretation due to arterio-venous differences in alcohol concentration was ruled out by simultaneous measurements in arterial blood and brain. Practice effects were ruled out by testing each animal only once.

Absorption, Diffusion, Distribution, and Elimination of Ethanol: Effects on Biological Membranes

The basic facts of alcohol absorption, distribution, metabolism, and excretion were described clearly many years ago by Nicloux (1900) and Grehant (1907), among others. They showed that alcohol could be absorbed from the stomach or by inhalation in the lungs, distributed throughout the body fluids and tissues via the blood, eliminated only slowly via the lungs, kidneys, and skin, and removed chiefly by slow metabolic oxidation. Later work by a multitude of investigators has clarified the mechanisms, the quantitative relationships, and the influence of various physiological, pathological, and pharmacological factors upon these processes. Many excellent reviews and major studies were written at various stages in the development of knowledge in this field, including those by Mellanby (1919), Kochmann (1923), Miles (1924), Carpenter (1929), LeBreton (1934), Newman (1941), Goldberg (1943), Casier and Delaunois (1947), Elbel and Schleyer (1956), Himwich (1956), Harger and Forney (1963), and Mardones (1963).

Effects of ethanol on Na, K, Mg-stimulated microsomal atpase activity☆

Microsomal fractions containing Na, K, Mg-activated adenosinetriphosphatase activity were prepared from rat and guinea pig brain and from eel electroplaque tissue. This activity was increasingly inhibited by ethanol at concentrations (54 to 218 mM) which produce mild to severe intoxication in vivo. The inhibition was competitive with respect to K+ in all three preparations. Increase in Na+ concentration led to increased inhibition by ethanol. Ethanol intoxication in rats, measured by the inclined-plane test, was less severe when the ethanol was injected in KCl solution than when given in NaCl. This was not due to difference in blood ethanol level, and is taken as evidence that inhibition of active transport of K+ plays an important role in ethanol intoxication in vivo.

Behavioral augmentation of tolerance to ethanol in the rat

Three groups of rats were trained on a circular maze task, then were tested under the influence of ethanol. Thereafter, all three groups received ethanol daily, on different schedules. One group (“psychological”) received ethanol (1.2 g/kg i.p.) just before each treatment session; another group (“physiological”) received the same dose immediately after the session; and the control group received only saline. All three groups were tested under ethanol every fourth day. The psychological group showed significant tolerance by the second test day, and maximal tolerance by the fourth. The physiological group reached the same maximum tolerance by the sixth test day, while the controls showed no increase in tolerance. Addition of daily gavage with ethanol (6 g/kg) did not modify the level of tolerance in the psychological or physiological groups, but raised the controls to the same level as the others. None of the changes in tolerance were attributable to increased rate of ethanol elimination. It is concluded that production of tolerance by these various techniques is distinguishable only with respect to rate.

Motivational properties of ethanol in naive rats as studied by place conditioning.

The reinforcing properties of ethanol were examined in naive adult male rats by means of a place conditioning paradigm that has previously demonstrated the positive reinforcing properties of food, water and some drugs, and the aversive properties of punishers such as electric shock and lithium chloride. Only doses of 0.8-1.0 g/kg and higher produced clear place conditioning, and this was only conditioned place aversion; rats spent significantly more time on the side of the place conditioning box in which they received the vehicle than on the side in which they received ethanol. Doses between 0.1 g/kg and 0.8 g/kg produced increases in general activity, but did not produce any place conditioning. Control experiments indicated that the pattern of effects was not specific to the route of ethanol administration (intravenous or intragastric), rate of infusion, concentration, or vehicle. It was concluded that ethanol, in the doses used here, has only punishing or neutral motivational effects in naive rats and does not serve as a primary positive reinforcer in this model. The conclusions are discussed in relation to the relative difficulty encountered in attempts to produce ethanol self-administration, and the findings are viewed as consistent with a proposal that prolonged training and experience with ethanol are important for ethanol self-administration by the rat.

Acquisition and loss of behaviorally augmented tolerance to ethanol in the rat

The phenomenon of behavioral augmentation of tolerance (BAT) to ethanol (EtOH) in the rat was replicated in studies using the moving belt test of intoxication. Rats performing the test daily under the influence of EtOH (2.2 or 2.5 g/kg i.p.) developed tolerance more rapidly than those receiving the same dose after each daily session on the belt. However, both groups reached the same maximum level of tolerance. Acceleration of tolerance by BAT was proportional to the frequency of performance under the influence of EtOH when total exposure to EtOH was held constant. The degree of tolerance produced by BAT could not be increased by daily gavage with a large dose (6 g/kg) of EtOH. After termination of EtOH administration, tolerance produced by BAT was lost at the same rate, whether or not daily alcohol-free sessions on the belt test were given. These findings are consistent with the hypothesis that BAT and conventionally produced tolerance differ only in rate.

Generalization of behaviorally augmented tolerance to ethanol, and its relation to physical dependence

Adult rats, required to perform a motor coordination task while under the influence of ethanol (2.2 g/kg) daily for 12 days, developed significant tolerance to the effects of ethanol, not only on this test but also on a food-motivated maze task. At the same time, they showed reduced shock threshold for production of a startle response, and reduced open field test scores 23 hrs after the last dose of ethanol. Other animals receiving the same dose of ethanol immediately after each training session on the coordination task, and others performing the task and receiving no ethanol, showed no tolerance on either test and no change in shock threshold or open field behavior. The results suggest that behaviorally augmented tolerance depends on basic neuronal adaptive changes indistinguishable from those accompanying physiological tolerance and dependence.

Quantitative relationships among measures of morphine tolerance and physical dependence in the rat

Abstract The influence of treatment dose on a number of characteristics of opiate tolerance was studied in male Sprague-Dawley rats treated with daily intraperitoneal (IP) injections of morphine sulfate. Zero, 7.5, 15, 25 or 45 mg/kg/day was given for 34 consecutive days and the degree of morphine effect on four different tests was periodically assessed. Dose-related effects on tailflick latency (tail immersion test, 1.5 hr post injection), swimming test (2 hr post injection), and body weight gain revealed the development of tolerance; there was a non-dose-related hyperthermia (1.5 hr post injection) to which rapid sensitization occurred. All changes reached asymptote and the rate and extent of change varied with the test. Plots of log response vs test day for tailflick and swimming indicated an early steep component and a later less steep component of decline. Subsequent testing indicated that the log-dose/response (LDR) curves for tailflick latency and time to maximum hyperthermia shifted to the right by an amount dependent on the treatment dose; there was no change in the curve for hyperthermia duration. In high dose groups no further shift occurred, but the tailflick LDR curves became flattened. The tailflick LDR curve changes were replicated in rats treated for 24 days with 0, 8, 24, 48, 96, or 240 mg/kg/day. Subsequently, a constellation of withdrawal signs precipitated by naloxone HCl (1 mg/kg, IP) was measured. On the basis of the relation between treatment dose and the magnitude of the various measures, there was a parallel between analgesia tolerance and some, but not all, signs of physical dependence.