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John M. Littleton

Bio: John M. Littleton is an academic researcher from University of Cambridge. The author has contributed to research in topics: In vivo & Acetaldehyde. The author has an hindex of 11, co-authored 11 publications receiving 401 citations.

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Journal ArticleDOI
TL;DR: The results suggest that acetaldehyde may play a role in some of the biochemical and behavioural changes associated with ethanol dependence.
Abstract: After chronic exposure to ethanol or acetaldehyde vapour in concentrations which depress locomotor activity, mice show similar behavioural changes during withdrawal, and there is some degree of cross dependence. Mice exposed to acetaldehyde vapour had blood acetaldehyde concentrations similar to those of ethanol-treated mice, but brain acetaldehyde concentrations were apparently lower. There was no accumulation of acetaldehyde in blood or brain in either group during chronic administration. Chronic ethanol or acetaldehyde administration to mice is associated with an increase in the concentrations of the brain monoamines noradrenaline, dopamine and 5-HT. Withdrawal of ethanol or acetaldehyde is associated with a further, rapid, transient rise in the brain catecholamines, noradrenaline and dopamine. These results suggest that acetaldehyde may play a role in some of the biochemical and behavioural changes associated with ethanol dependence.

78 citations

Journal ArticleDOI
TL;DR: Evidence was obtained that similar age and strain differences may exist with respect to tolerance to the hypothermic effects of ethanol, and in relation to current concepts of ethanol sensitivity, tolerance and physical dependence.
Abstract: The time course of development of functional tolerance to ethanol was investigated in mice during the inhalation of ethanol vapour, using loss of righting reflex as the behavioural end-point. In male mice of the TO Swiss strain, weanling mice (18 days) showed no development of tolerance during continuous or repeated exposure to ethanol vapour for 6 h. Adolescent TO Swiss mice (35–40 days) showed rapid development of functional tolerance, reaching a state where 2x the original effective concentration of ethanol in blood was required to produce loss of righting reflex within 5 h. Older adult mice (150–200 days) showed some development of tolerance during continuous or repeated exposure to ethanol for 5 h but this was much less than that seen in adolescent mice. When adolescent males of the C57BL, TO Swiss and DBA2 strains were compared, marked differences were observed. C57BL mice showed very rapid development of functional tolerance to ethanol in which more than 2 × the original effective dose was required to produce loss of righting reflex after about 3 h of ethanol exposure. TO Swiss mice showed somewhat slower development of ethanol tolerance. DBA2 mice showed little evidence of development of functional tolerance over the time course of these experiments. Evidence was also obtained that similar age and strain differences may exist with respect to tolerance to the hypothermic effects of ethanol. These results are discussed in relation to current concepts of ethanol sensitivity, tolerance and physical dependence.

53 citations

Journal ArticleDOI
TL;DR: It is suggested that the genetically determined capacity to adapt rapid to the presence of ethanol (rapid cellular tolerance) is related to the ability to adapt rapidly to the removal of the drug, and that this limits the duration and severity of the ethanol withdrawal syndrome.

48 citations

Journal ArticleDOI
TL;DR: It is demonstrated that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 × the original effective blood ethanol concentration is required to produce the behavioural end‐point, can develop in 3–5 h.
Abstract: A method is described in which the development of tolerance to ethanol in individual mice can be measured during the inhalation of ethanol vapour. This method has been used with two behavioural end-points, loss of righting reflex and loss of rotarod performance. It demonstrates that, in the adult male, TO Swiss mouse, peak tolerance, in which approximately 2 X the original effective blood ethanol concentration is required to produce the behavioural end-point, can develop in 3--5 h. After this time the ability of the animals to perform normally in the presence of continued high concentrations of ethanol in blood begins to fall. The results are discussed in relation to current concepts of tolerance to central nervous system depressant drugs.

46 citations

Journal ArticleDOI
TL;DR: It is concluded that the combination of pyrazole and ethanol is probably not capable of separating primary effects of chronic ethanol administration from secondary (metabolic) effects, and that inhibition of alcohol dehydrogenase is unlikely to be the sole reason for the potentiation of the ethanol withdrawal syndrome by pyrazoles.
Abstract: Daily administration of an inhibitor of alcohol dehydrogenase (pyrazole, 1 m mol kg−1, i.p.) appeared to prevent the development of metabolic tolerance to ethanol administered chronically to mice by inhalation, but increased the duration and intensity of the behavioural change associated with ethanol withdrawal, despite the absence of any marked difference in blood or brain ethanol and acetaldehyde concentrations during ethanol administration in the two groups. (Pyrazole-treated mice were exposed to lower concentrations of ethanol.) Changes in brain monoamine concentrations which occur in mice during chronic ethanol administration were not prevented by pyrazole, but differed in time course under these conditions. Repeated administration of pyrazole intraperitoneally caused weight loss and hypothermia in mice, whether or not ethanol was also given. It is concluded that the combination of pyrazole and ethanol is probably not capable of separating primary effects of chronic ethanol administration from secondary (metabolic) effects, and that inhibition of alcohol dehydrogenase is unlikely to be the sole reason for the potentiation of the ethanol withdrawal syndrome by pyrazole.

45 citations


Cited by
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Journal ArticleDOI
TL;DR: Developmental changes in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems likely contribute to the unique characteristics of adolescence.

4,985 citations

Journal ArticleDOI
TL;DR: It is concluded that myopathy of skeletal muscle and cardiomyopathy are common among persons with chronic alcoholism and that alcohol is toxic to striated muscle in a dose-dependent manner.
Abstract: To determine the prevalence of alcoholic myopathy and cardiomyopathy, we studied a group of 50 asymptomatic alcoholic men (mean age, 38.5 years) entering an outpatient treatment program. Studies performed included an assessment of muscle strength by electronic myometer, muscle biopsy, echocardiography, and radio-nuclide cardiac scanning, with comparison to healthy control subjects of similar age. The patients' mean (±SEM) daily alcohol consumption was 243± 13 g over an average of 16 years. These patients had no clinical or laboratory signs of malnutrition or electrolyte imbalance. Forty-two percent of the patients, as compared with none of the controls, had strength of less than 20 kg as measured in the deltoid muscle. Muscle-biopsy specimens from 23 patients (46 percent) had histologic evidence of myopathy. In the cardiac studies, when the alcoholic patients were compared with 20 healthy controls, the patients had a significantly lower mean ejection fraction (59 vs. 67 percent), a lower mean sho...

608 citations

Journal ArticleDOI
TL;DR: The FHP subjects (at elevated risk for the development of alcoholism) reported less intense feelings of subjective intoxication after drinking, especially during the two hours following the peak blood alcohol concentration (BAC).
Abstract: • We matched 23 nonalcoholic male drinkers who were aged 21 to 25 years and had alcoholic close relatives (FHP) with 23 control subjects with negative family histories (FHN) for demographic characteristics and drinking and smoking histories. The subjective feelings of intoxication for the 46 men were studied on three occasions using placebo, 0.75 mL/kg of ethanol, and 1.1 mL/kg of ethanol. The FHP subjects (at elevated risk for the development of alcoholism) reported less intense feelings of subjective intoxication after drinking, especially during the two hours following the peak blood alcohol concentration (BAC). Group differences were most marked with the 0.75-mL/kg dose. The two groups did not differ significantly on their BACs nor on the expectation of how they would feel under the influence of alcohol.

395 citations

Journal ArticleDOI
TL;DR: It is concluded that serotonin mediates ethanol intake as a part of its larger role in behavior modulation, such that increases in serotonergic functioning decrease ethanol intake, and decreased serotonergy functioning increases ethanol intake.

350 citations

01 Jan 1994
TL;DR: In this article, the effects of serotonergic manipulations on the intake of alcohol, and the effect of acute and chronic alcohol intake, as well as the withdrawal of chronic alcohol, on the Serotonergic system were investigated.
Abstract: Despite a relatively large body of literature on the role of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-liT) in the regulation of alcohol intake, the functional significance of serotonergic neurotransmission and its relationship to alcohol intake, abuse, and dependence remains to be fully elucidated. In part two of this review, the experimental (animal) data is summarized along two lines: the effects of serotonergic manipulations on the intake of alcohol, and the effects of acute and chronic alcohol intake, as well as the withdrawal of chronic alcohol, on the serotonergic system. It is concluded that serotonin mediates ethanol intake as a part of its larger role in behavior modulation, such that increases in serotonergic functioning decrease ethanol intake, and decreased serotonergic functioning increases ethanol intake. Ethanol produces transient increases in serotonergic functioning that activate the mesolimbic dopaminergic reward system. The results are discussed in light of recent theories describing the regulatory role of serotonin in general behavior.

343 citations