The preventive paradox: a critical examination.
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Alcohol Drinking↗
Biomedical subjects
J D Sinclair
Publications and source records attributed to J D Sinclair.
Responding for oral ethanol after naloxone treatment by alcohol-preferring AA rats.
The present study examined the effect of a relatively nonselective opioid antagonist, naloxone, on lever pressing for oral ethanol by the alcohol-preferring AA rats. The AAs, housed continually in operant chambers with free access to food and water, learned to respond for 10% oral ethanol during daily 60-min alcohol access periods indicated by a stimulus light. The rats developed stable ethanol responding, resulting in mean ethanol intakes of 1.2 g/kg/60 min and measurable blood alcohol levels. In the first experiment, single systemic injections of naloxone (0.05-2.5 mg/kg) had no effect on the initial rate of responding; dose-dependent decreases were observed later during the alcohol access. The second experiment examined the effects of repeated injections of 0.5 and 2.5 mg/kg naloxone on 5 consecutive days. Naloxone suppressed responding dose-relatedly over the treatment days. In contrast to the effects of single injections, repeated injections with 2.5 mg/kg naloxone produced progressive decreases within the first minutes of access. The results suggest that naloxone may attenuate the reinforcing actions of ethanol.
Alcohol Drinking↗
Localization of the primary sites of genetic influence.
When studying the nervous system of animal lines developed for specific genetically-determined behavioral differences, how does one tell whether a difference between the lines found at one specific location was caused by a direct genetic interaction at that location or by an interaction at some distant site which was then imposed on the tested location? The form of the line difference can help to answer this question. One particular form, called an inverse line difference, is shown to have a higher probability of being close to the location of the direct gentic interaction.
Alcohol Drinking↗
Alcohol elimination and the regulation of alcohol consumption in AA and ANA rats.
Previous studies have usually found that animals with either higher alcohol elimination rates or ADH (alcohol dehydrogenase, EC1.I.I.I) activities have higher voluntary intakes of alcohol than ones with lower elimination rates. This relationship has now been studied in the AA and ANA rat lines genetically developed, respectively, for high and low alcohol consumption. Female AA and ANA rats had their alcohol elimination rate measured before being given a free choice between 10% (v/v) alcohol and water for 3 weeks. The elimination rate was then measured again and liver ADH activity was determined. The alcohol elimination rate was significantly higher in AA than ANA rats before drinking and was increased by alcohol drinking in AA but not ANA rats. ADH activity was similar in both lines and unrelated to either alcohol drinking or elimination rates, suggesting that the enzyme activity is not a rate-limiting factor in the alcohol metabolism of these two lines. The present results support the conclusion that alcohol elimination and alcohol consumption are partially determined by genetics. Furthermore, although alcohol elimination itself probably does not have direct control over drinking, some factor related to the alcohol elimination rate appears to be among the mechanisms influencing the level of alcohol drinking.
Alcohol Dehydrogenase↗
Respiratory patterns in anesthetised rats before and after anemic decerebration.
Experiments were undertaken to test the comparability of changes in respiratory frequency and tidal volume during hypoxia and hypercapnia in rats with and without intact peripheral chemoreceptors and with intact vagi. Neural organisation of respiratory control was perturbed by anemic decerebration, achieved by ligation of the common carotid and basilar arteries. Ischemia of the brain was produced as far candal as the rostral pontine nuclei involved in respiratory control but left the medulla well perfused. The dominant respiratory effect in animals breathing air or oxygen was polypnea with hypocapnia (mean PaCO2 when breathing air 24.7 mmHg, when breathing oxygen 29.6 mmHg). After decerebration the increase of ventilation produced by breathing 10% O2 in N2 was reduced compared with responses in the intact state but levels of ventilation (V1) in hypoxia were similar to those before decerebration. After decerebration, the increase of ventilation produced by breathing 5% CO2 was greatly reduced and the level of V1 in animals breathing CO2 was significantly less than in the intact state. Intermediate changes were seen in animals breathing 2-3% CO2 which converted the hypocapnia (PaCO2 30.9 mmHg) to eucapnia (PaCO2 46.4 mmHg). In the intact state, hypoxia dominantly caused increased frequency (f) and hypercapnia caused increased tidal volume (VT); after decerebration, hypoxia produced reduction of VT while hypercapnia produced reduction of f. Bilateral carotid sinus nerve section in decerebrate animals eliminated the ventilatory response to hypoxia but left the responses to hypercapnia unaltered. The results point to differences in the mechanisms by which hypoxia and hypercapnia influence respiration in both intact and decerebrate animals with carotid sinus and vagus nerves functional. The differences can now be interpreted in terms of specific neural features of respiratory control.
Anemia↗
Effects of hypoxia and cold acclimation on thermoregulation in the rat.
The effects of hypoxia (inspired O2 fraction = 0.12) on thermoregulation and on the different sources of thermogenesis were studied in rats before and after periods of 1-4 wk of cold acclimation. Measurements of metabolic rate (VO2) and body temperature (Tb) were made at 5-min intervals, and shivering activity was recorded continuously in groups of rats subjected to three protocols. In protocol 1, rats were exposed to normoxia to an ambient temperature (Ta) of 5 degrees C for 2 h. In protocol 2, at Ta of 5 degrees C, rats were exposed for 30 min to normoxia, then for 45 min to hypoxia, and finally for 30 min to normoxia. In protocol 3, in the non-cold-acclimated (NCA) rats, Ta was decreased from 30 to 5 degrees C in steps of 5 degrees C and of 30-min duration while in cold-acclimated (CA) rats at 5 degrees C for 4-wk, Ta was increased from 5 to 30 degrees C in steps of 5 degrees C and of 30-min duration. Recordings were made in normoxia and in hypoxia on different days in the same animals. The results showed that 1) in NCA rats, cold exposure in normoxia induced increases in VO2 and shivering that were proportional to the decrease in Ta; 2) in CA rats in normoxia, for a given Ta, VO2 and Tb were higher than in NCA rats, whereas shivering was generally lower; and 3) in both NCA and CA rats, hypoxia induced a transient decrease in shivering and a sustained decrease in nonshivering thermogenesis associated with a marked decrease in Tb that was about the same in NCA and CA rats. We speculate that hypoxia acts on Tb control to produce a general inhibition of thermogenesis. Nonshivering thermogenesis is markedly sensitive to hypoxia, especially demonstrable in CA rats; a recovery or even an increase in shivering can compensate for the decrease in nonshivering thermogenesis.
Acclimatization↗
Determinants of alcohol preference in the AA and ANA rat lines selected for differential ethanol intake.
A selective breeding program conducted in this laboratory has resulted in the establishment of the alcohol-preferring AA (Alko Alcohol) and alcohol-avoiding ANA (Alko Nonalcohol) rat lines. These lines have been used as a tool for attempting to identify the behavioral, neurochemical, and biochemical correlates of differential voluntary ethanol consumption. Some of the differences that have been found between the lines involve differential reinforcement: AA rats, but not ANA rats, rapidly acquire an ethanol-reinforced operant response. The AA's greater development of tolerance to the depressant effects of ethanol and their faster ethanol metabolism would also allow them to drink more. Neurochemical studies have suggested differential functioning of brain monoaminergic mechanisms. The activity of tyrosine hydroxylase and dopa decarboxylase, and the brain dopamine concentrations are higher in the AA rats than in the ANA rats, and the maximal number of dopamine D2 receptors is lower in the AA rats. The concentration of noradrenaline is higher in the brain of ANA rats than in that of AA rats, while the 5-hydroxytryptamine levels do not seem to differ greatly. The importance of these differences to the line difference in ethanol intake is not, however, clear, since there appears to be no difference in the sensitivity of monoamine systems of the two lines to ethanol.
Alcohol Drinking↗
Clinicians wanted.
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Education, Medical, Undergraduate↗
Medical research in New Zealand.
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Humans↗
Kainic acid on the rat ventral medullary surface depresses hypoxic and hypercapnic ventilatory responses.
Kainic acid, topically applied to the ventral surface of the medulla immediately caudal to the trapezoid body in the urethane/chloralose anaesthetised rat, led to a depression of ventilation and a sustained rise in blood pressure; ventilatory responses to hypercapnia (10% carbon dioxide) and hypoxia (11% oxygen) were slightly depressed. Widespread application of kainic acid to an area at and slightly rostral to the rootlets of the hypoglossal nerve produced a stimulation of ventilation and an unsustained rise in blood pressure. Apnea ensued 12-28 min after application. Ventilatory responses to hypercapnia and hypoxia were markedly attenuated; more discrete bilateral application revealed two regions, one immediately rostral and lateral to the hypoglossal rootlets and the other over the point of exit of the hypoglossal nerve rootlets, which specifically contributed to the diminution of the chemosensory responses. These results raise questions about the medullary circuitry which mediates the chemoreflex regulation of breathing.
Animals↗
Differential reinforcement and diurnal rhythms of lever pressing for ethanol in AA and Wistar rats.
High-drinking AA (Alko, Alcohol) and moderate-drinking Wistar rats, after ethanol drinking experience in their home cages, were housed continually in operant chambers with free access to water and food. Ethanol and water could be obtained by lever pressing on a concurrent FR1:FR1 schedule. The AA rats readily learned the operant response for oral ethanol, responded significantly more for ethanol than water, and increased ethanol responding when the fixed-ratio schedule for it was increased from FR1 to FR2 and FR4. This indicates that ethanol was serving as a reinforcer for the AAs. In contrast, the Wistars showed little evidence for ethanol reinforcement. Both AAs and Wistars had a three-peak pattern of ethanol responding during the dark phase, but peaks for the Wistars preceded those for the AAs by 1 or 2 hr. The patterns were similar when on an FR4 schedule, which greatly reduced the amount of alcohol, suggesting that they are not controlled by blood alcohol levels. The difference between the AA and Wistar patterns may, however, be related to the differential ethanol reinforcement.
Alcohol Drinking↗
Drugs to decrease alcohol drinking.
A wide variety of drugs have been tested in experimental animals and several have been found that reduce voluntary alcohol drinking. The available evidence suggested that the same drugs also reduce alcohol drinking in alcoholics. Various factors limited or prevented the clinical use of the these drugs. Our working hypothesis has been that alcohol drinking is a learned response, reinforced primarily from alcohol in the brain, and that an alcoholic is a person in which this response and the related craving have become so strong that they dominate the behaviour and interfere with normal functioning. Learned responses are extinguished if they are made repeatedly while the reinforcement is blocked, and opiate antagonists appear to block the reinforcement from alcohol. A series of experiments support the hypothesis that drinking alcohol while an antagonist is present extinguishes the alcohol-drinking response in rats. The antagonists are non-addictive and at least naloxone appears to be safe. Clinical trials are now needed, but the present results suggest that this extinction procedure might be a useful adjunct to the treatment of alcoholism.
Alcohol Drinking↗
The AA and ANA rat lines, selected for differences in voluntary alcohol consumption.
The offspring of rats that voluntarily select larger quantities of alcohol are heavier consumers of alcohol than the offspring of rats that tend to avoid it. Such selective breeding, repeated over many generations, was used to develop the AA (Alko, Alcohol) line of rats which prefer 10% alcohol to water, and the ANA (Alko, Non-Alcohol) line of rats which choose water to the virtual exclusion of alcohol. In addition to demonstrating the likely role of genetic factors in alcohol consumption, these lines have been used to find behavioral, metabolic, and neurochemical correlates of differential alcohol intake. Some of the line differences that have been found involve the reinforcing effects of ethanol, the changes in consumption produced by alcohol deprivation and nutritional factors, the behavioral and adrenal monoamine reactions to mild stress, the development of tolerance, the accumulation of acetaldehyde during ethanol metabolism, and the brain levels of serotonin. It is hoped that these studies will lead to a better understanding of the genetically-determined mechanisms that influence the selection of alcohol.
Alcohol Drinking↗
Biological control systems in health and disease.
Research into mammalian organ systems remains essential to proving the significance of new advances at the molecular level. Computational analysis, histology, controlled experimental conditions, require skills lying outside those of the traditional medical sciences. Medical graduates who want partnership in the research teams of the future will need formal training in science.
Disease↗
Hangover hyperthermia in rats: relation to tolerance and external stimuli.
The recent finding of rebound hyperthermia in rats on the day after a single IP injection or oral intubation of ethanol was confirmed. In our studies, body temperature measured by rectal probe was significantly decreased for 8 h after 2.5 g/kg ethanol IP and was then significantly elevated 16-24 h after injection; increased vocalization during handling at 24 h was also found. However, rats isolated in a sound-attenuation chamber with remote temperature measurement showed no hyperthermia even though they were hypothermic during intoxication. The results do not support the hypothesis that rebound hyperthermia was caused by either a disruption of circadian rhythms, or by a mild abstinence syndrome alone. Instead, it appears that external stimuli, perhaps related to stress or associated with ethanol administration, are necessary on the day after a moderate dose of ethanol to produce the hyperthermia. Like hangover in humans, hyperthermia was reduced in rats made tolerant to ethanol: both the hypothermia and the rebound hyperthermia were significantly lower on the day after the 12th alternate-day ethanol injection than after the first injection. The aftereffects in rats of acute intoxication are, by definition, hangover signs, and they resemble hangover in humans in several ways, but their relevance as an animal model of hangover remains to be determined.
Animals↗
The effect of adenosine on respiratory chemosensitivity in the awake rat.
The effect of adenosine on respiration and respiratory chemosensitivity in awake animals was studied in rats, intact and chemodenervated, before and after intra-peritoneal injection of L-phenylisopropyladenosine (PIA). Respiration was measured by barometric plethysmography. The administration of PIA depressed respiration substantially, in a dose-related manner, the maximum effect occurring after 30-80 min; PIA also depressed body temperature but over a slower time course. In both intact and chemodenervated animals, the characteristic responses to hypoxia were maintained after the administration of PIA, but at depressed respiratory levels. There was no interaction between effects. Administration of PIA produced enhancement of the ventilatory response to hypercapnia, in both intact and peripherally chemodenervated animals. The results do not support the hypothesis that hypoxic effects on respiration are related to the accumulation of adenosine in brain tissues. Enhancement of the hypercapnic response represents evidence for disinhibition of the mechanism concerned.
Adenosine↗
Multiple t-tests are appropriate in science.
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Data Interpretation, Statistical↗
Localization by kainic acid lesions of neurones transmitting the carotid chemoreceptor stimulus for respiration in rat.
1. An attempt has been made to test the hypothesis that in the nucleus of the tractus solitarius (NTS) in the rat, the most caudal region of synaptic terminals of the carotid sinus nerve, just caudal to the obex, represents mainly the site of synapse of chemoreceptor fibres from the carotid body. 2. Under halothane anaesthesia, the neurotoxin kainic acid was used to lesion this region and a second region, immediately rostral to obex, where terminals are thought to arise mainly from baroreceptor fibres of the carotid sinus nerve. 3. Measurements based on the distribution of fluorescent dye co-injected with the kainic acid showed that the two groups of 100 nl microinjections were centered 0.82 mm apart and that the injectate spread through mean distances of 0.57 mm (caudal microinjections) and 0.52 mm (rostral microinjections). Nissl staining was used to determine cellular degeneration. The caudal lesions mostly involved ventrolateral and commissural subnuclei of NTS and the rostral lesions involved lateral and dorsolateral subnuclei. 4. Ventilatory sensitivity to hypoxia was tested under light halothane anaesthesia, 1 day after lesioning. To enhance the responses, the contralateral carotid sinus nerve was sectioned prior to experiments. Caudal lesions reduced the ventilatory response to inspired oxygen (20.9-9.6% O2) by a mean of 67% and rostral lesions by 18% of the effect produced by carotid sinus nerve section on that side. Subsequent section of the carotid sinus nerve on the side of the NTS lesion confirmed that caudal lesions produced effects comparable to those of carotid body denervation; rostral lesions did not. 5. These results strongly support the hypothesis that chemoreceptor and baroreceptor afferent fibres in the carotid sinus nerve synapse at substantially separable sites in the nucleus of the tractus solitarius. The identification of the site in NTS caudal to the obex as the principal site of carotid chemoreceptor synapses places them close to but not upon respiratory premotor neurones of the same nucleus.
Animals↗