The effects of ethanol and the role of the spleen during benzene-induced hematotoxicity

Splenectomized and spleen-bearing mice were used to explore the source of nucleated red blood cells (normoblasts) appearing in the peripheral blood of animals treated with both benzene and ethanol and the role of splenic hematopoiesis in compensating for bone marrow stresses by repeated benzene and ethanol exposure. Regardless of operative status, mice exposed to the combined treatment demonstrated a transient appearance of normoblasts in the peripheral blood. Thus, the marrow is the apparent source of the peripheral normoblasts. This condition was not observed in mice treated with only benzene or with only ethanol. Splenectomy significantly influenced bone marrow response to the hematotoxic effects of benzene alone as well as the combined treatment of benzene and ethanol, as evidenced by altered marrow normoblast and granulocyte equilibria.     

In vivo effects of (-)-nicotine on ethanol-induced increase in glucose utilization in the mouse cerebellum

The purpose of this study was to investigate the possible in vivo effects of (-)-nicotine, ethanol, and an adenosine agonist N⁶-cyclohexyladenosine (CHA) when injected individually as well as in various combinations on glucose utilization in the fresh cerebellar slices of mice. Mice received ICV (-)-nicotine or CHA followed 5 min later by a test dose of ethanol (2 g/kg; IP). Animals were killed 20 min postethanol treatment and fresh slices (300 μm) of cerebellum were incubated in a glucose medium in Warburg flasks using ¹⁴C-glucose as a tracer. Trapped ¹⁴CO₂ was counted to estimate glucose utilization. Ethanol treatment markedly accentuated glucose utilization, whereas the pretreatment with (-)-nicotine (125 and 250 ng, ICV) resulted in a significant attenuation in the ethanol-induced increase in glucose utilization. However, ICV (-)-nicotine (125 ng) alone did not produce any change in the cerebellar glucose utilization. The attenuation of ethanol-induced increase in glucose utilization by (-)-nicotine was nearly totally blocked by ICV hexamethonium, a purported nicotinic antagonist, suggesting participation of cholinergic-nicotinic receptors. The (-)-nicotine pretreatment also significantly attenuated both the ICV CHA (25 ng)-induced increase in glucose utilization and the accentuation of ethanol-induced increase in glucose utilization by CHA. The antagonistic effect of (-)-nicotine on CHA- and ethanol-induced increase in glucose utilization indicating an interaction between (−)-nicotine and ethanol and between (-)-nicotine and adenosine may suggest involvement of postreceptor (nicotinic and adenosine) mechanisms including ionic channels.     

The effect of ketotifen in rodent models of anxiety and on the behavioural consequences of withdrawing from treatment with drugs of abuse

Summary Ketotifen was compared to diazepam to inhibit aversive responding of the mouse in a black and white test box and in the rat social interaction test. Both drugs reduced aversive responding in the mouse to the brightly illuminated area of the test box and facilitated social interaction in the rat; ketotifen was approximately 100 times more potent than diazepam. The chronic administration of diazepam, ethanol, nicotine and cocaine in the mouse also reduced aversive responding but their withdrawal was associated with an increased behavioural suppression. The administration of ketotifen during the period of withdrawal from diazepam, ethanol, nicotine and cocaine prevented the exacerbation in aversive responding. It is concluded that ketotifen, like diazepam and 5-HT₃ receptor antagonists, can reduce behavioural suppression in rodent models of anxiety and attenuate the behavioural consequences of withdrawal from treatment with drugs of abuse.Send offprint requests to B. Costall at the above address     

Two distinct propagating regenerative potentials in a single ethanol-treated axon

Superfusion of the cockroach (Periplaneta americana) giant axon by ethanol (0.5–2%) produces conditions which allow the generation and active propagation of two kinds of regenerative potentials. (a) The classical action potential with a threshold at about 30 mV above resting potential, an amplitude of about 105 mV, a duration of 1–2 ms, and a conduction velocity of 3–6 m/s. (b) A smaller depolarizing potential (SDP) with a threshold of 5–15 mV above resting level, an amplitude of 10–30 mV, a duration of several hundred ms and a conduction velocity of 0.1–0.6 m/s. The SDP is associated with a small increase in conductance (10–15%), and is abolished by tetrodotoxin (10⁻⁶ M) or by removing extracellular sodium. The amplitude of the SDP slightly increases when the extracellular Ca²⁺ concentration is elevated and is reduced at low (Ca²⁺)₀ concentration; however, it is not blocked in a solution containing high Mg²⁺ (19 mM), low Ca²⁺ (1 mM) concentrations, indicating that inward Ca²⁺ current is not required for the generation of SDP.     

Effects of the self-administration of ethanol and ethanol/sucrose on rates of local cerebral glucose utilization in rats

In a previous study, the voluntary ingestion of ethanol by rats was found to be associated with a discrete pattern of changes in functional activity that included the nucleus accumbens, medial prefrontal cortex, basolateral and central nuclei of the amygdala, as well as the ventral midbrain. Rats in this study, however, consumed a combination of ethanol in a sucrose vehicle. The purpose of the present experiment was to characterize the role of sucrose in determining the effects of orally self-administered ethanol using the quantitative autoradiographic 2-[¹⁴C]deoxyglucose (2DG) method for measurement of rates of local cerebral glucose utilization. A modified sucrose-substitution procedure was employed to train three groups of Wistar rats to self-administer either water, 10% ethanol (10E), or a 10% ethanol/2% sucrose solution (10E/2S) in daily sessions. An additional group of rats was trained using a modified acclimation procedure (home cage) in order to determine if any exposure to sucrose would alter rates of glucose utilization. Once stable rates of consumption were established, the 2DG method was applied immediately following completion of the final test session. Rats received a dose of ethanol equivalent to 0.5 g kg⁻¹ on the day of the procedure or a comparable volume of water. Rates of energy metabolism were significantly increased in all three groups of rats that consumed ethanol (10E/2S, 10E, and home cage), as compared to rates in rats that consumed water. The areas of significant change included the rostral pole and posterior shell of the nucleus accumbens, medial prefrontal cortex, the basolateral and central nuclei of the amygdala, the ventral tegmental area, and the substantia nigra pars compacta. Thus, the pattern of changes in functional brain activity that accompanies voluntary ingestion of ethanol is independent of the vehicle in which the ethanol is presented or the procedures used to initiate consumption. Furthermore, these data demonstrate that it is the simultaneous activation of an interrelated network of limbic brain regions that serves as the substrate of the effects of ethanol self-administration.     

Percutaneous ethanol injection into parathyroid adenomas: mid- and long-term results

The aim of this study was to evaluate mid- and long-term results of ultrasonically guided ethanol injection into parathyroid adenomas. From 1988 to 1996, 27 patients (mean age 77 ± 13 years) were treated for parathyroid adenomas by percutaneous ethanol injection. The survey included clinical information, plasma calcium, phosphorus and PTH (1–84) evaluation. Follow-up lasted 22.6 ± 10 months. No major complications were observed for 63 ethanol injections. Biochemical recovery was 58 %, biochemical improvement at 3 months was 33 %, and failure was 7 %. Four of 15 cured patients presented a recurrence of the disease 1 or 2 years after the first treatment. Ultrasonically guided ethanol injection can be useful in the treatment of parathyroid adenomas when surgery is not possible. The immediate results are interesting but not as good as those obtained with surgery. A regular biochemical survey is necessary so that recurrences can be recognized and treated at an early stage. Received 14 July 1997; Revision received 26 February 1998; Accepted 3 March 1998     

Effects of Prenatal Ethanol Exposure and Stress in Adulthood on Lymphocyte Populations in Rats

The present study was undertaken to assess the possible interactive effects of prenatal ethanol exposure and stress in adulthood on lymphocyte populations in rat offspring, and to examine differential vulnerability of males and females to these challenges. Male and female offspring from prenatal ethanol-exposed (E), pair-fed, and ad libitum-fed control conditions were exposed to a 3-week chronic intermittent stress regimen in adulthood. Animals were exposed to two of six different stressors daily, one each at random times in the morning and afternoon, with the same pair of stressors being repeated every 4 days. Following the 3-week stress period, lymphocytes from four compartments (peripheral blood, spleen, thymus, and cervical lymph nodes) were analyzed for expression of differentiation antigens. Data demonstrate that, whereas a number of the effects of prenatal ethanol on lymphocyte populations appeared to be nutritionally mediated, the additional challenge of exposure to stressors differentially affected animals exposed to ethanol prenatally and appeared to have effects primarily in male offspring. Stressed E males had a greater reduction in the number of pan T-cells in the thymus and peripheral blood, compared with nonstressed E males, but showed an increased peripheral blood pan T-antigen expression. Stressed E males also had reduced numbers of peripheral blood CD4⁺ T-cells and thymic CD4⁺CD8⁺ T-cells, compared with controls. In addition, several effects of stress were observed in animals in all three prenatal treatment groups, including decreased numbers of lymph node pan T- and CD4⁺ T-cells and decreased numbers of total peripheral blood lymphocytes in males, increased numbers of total splenic and thymic lymphocytes in females, and increased numbers of splenic CD8⁺ T-cells, as well as a decreased ratio of CD4⁺:CD8⁺ T-cells in the lymph node and spleen in both males and females. These findings indicate that, although exposure to chronic intermittent stress in adulthood may have marked effects on lymphocyte populations across all treatment groups, specific deficits in the immune system of fetal E animals may become apparent only when these animals are subjected to the additional challenge of stress. Moreover, male and female offspring may be differentially affected by the two challenges of ethanol and stress.     

Learned tolerance to ethanol in the spinal cord

Learning has been claimed to be of major importance in the development of tolerance to ethanol. In the present study we investigated the influence of learning on tolerance to ethanol-induced inhibition of a spinal reflex (tail-flick response) in intact and spinal rats. On day 1 and 9, groups of rats were injected with either ethanol 2.5 g/kg IP or saline 30 min prior to tail-flick testing. On days 2–8 the groups were treated differently in order to reveal the importance of the drug alone, the test alone and the combination of the two on development of tolerance. On day 10, the rats rendered tolerant in the home room were transferred to a new test room to be tested. Both in intact and spinal rats development of tolerance was observed only if the animals were repetitively tested while intoxicated. Tolerance acquired in the home room was not attenuated by transfer to a new environment. Results in the spinal rats suggested that adaptive mechanisms leading to tolerance may also be located in the spinal cord. The tolerance observed may be regarded as learned from practice while intoxicated.     

Polymorphism of aldehyde dehydrogenase and ethanol elimination

The influence of polymorphism of aldehyde dehydrogenase (ALDH) on ethanol elimination was investigated. Japanese healthy male volunteers were divided into two groups, i.e., a normal ALDH group of 52 subjects with the low Km isozyme of ALDH, and a deficient group of 48 subjects without it. The subjects of the normal group were given 0.4, 0.8, 1.2, 1.6 or 2.0 g/kg of ethanol, while those in the deficient group ingested 0.4, 0.8 or 1.2 g/kg of ethanol. Widmark's factors (beta 60, Co and r) and ethanol elimination rate (ER) were compared between the two groups. In the deficient group, beta 60 and ER were not clearly elevated with the increase of ethanol dose, while those in the normal ALDH group increased depending on the blood ethanol level. Blood acetaldehyde level was elevated with the increase of the ethanol dose in the deficient group, but not in the normal group. In the experiment of the repeated ingestion of ethanol in the deficient group, the second peak of blood acetaldehyde level was lower than that of the first one.