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Biomedical subjects

J D Sinclair

Publications and source records attributed to J D Sinclair.

At least 55 records · Page 3Linked to original sources
PubMed1987

Neonatal desipramine or zimeldine treatment causes long-lasting changes in brain monoaminergic systems and alcohol related behavior in rats.

To study the relationship between neonatal antidepressant administration, active (REM) sleep and adult alcohol-related behavior, rat pups were treated daily with 5 mg/kg desipramine (DMI) or 25 mg/kg zimeldine SC from the 6th to the 19th postnatal days. Movement sensitive mattress ("SCSB") measurements showed that zimeldine treatment suppressed active sleep throughout the whole treatment period, but DMI was more effective during the first 8 days than during the last treatment days. At the age of 70 days, the zimeldine-treated rats expressed a selective increase of some components of activity in the open field test, and the DMI rats had a higher defecation score compared to the controls. Furthermore, the zimeldine-rats responded with a decrease in ambulation in the open field to an alcohol dose which generally stimulates locomotion in rats. At the age of 3 months the DMI and zimeldine rats showed increased voluntary intake of 10% (v/v) alcohol. Measurement of brain monoamines revealed that the neonatal treatment with DMI or zimeldine interfered with the normal development and function of the monoamine neuronal systems: the concentrations of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), and their metabolites were altered in several brain regions. The results thus suggest that neonatal treatment with DMI or zimeldine suppresses active sleep and has an influence on later alcohol-related behavior, possibly due to a long-lasting defect in brain monoaminergic transmission.

Alcohol Drinking↗
PubMed1987

Differences in respiratory patterns after acute and chronic pulmonary denervation.

The role of pulmonary vagal information in the control of respiratory patterns was assessed in awake and anaesthetised rats in which pulmonary denervation was effected by bilateral cervical vagotomy or by right cervical vagotomy combined with left pneumonectomy or left intrathoracic vagotomy. Acute denervation led to increases of tidal volume (VT), inspiratory duration (TI) and expiratory duration (TE) in both awake and halothane anaesthetised animals; in awake rats the increase of TE rapidly subsided. Chronic pulmonary denervation produced markedly smaller increases of VT and TI and no change of TE from control values. In hypercapnia, awake animals with combined pneumonectomy and vagotomy consistently increased respiratory frequency by reductions in TI and TE; awake animals with combined intrathoracic and cervical vagotomy showed no increase in f because decreases in TI offset increases in TE; in anaesthetised rats with acute bilateral cervical vagotomy there was a consistent fall in respiratory frequency due to an expiratory pause. The results demonstrate that (1) the role of vagal activity in the production of respiratory patterns is unlikely to be accounted for solely in terms of influences arising from pulmonary stretch receptors; (2) vagal influences of TE are transitory; (3) under halothane anaesthesia hypercapnia induces an expiratory pause; and (4) the combination of pneumonectomy with contralateral vagotomy makes possible studies in awake rats although pulmonary denervation is less complete than with bilateral intrathoracic vagotomy.

Animals↗
PubMed1987

Brain stem projections of the glossopharyngeal nerve and its carotid sinus branch in the rat.

Transganglionic transport of horseradish peroxidase or lectin-conjugated horseradish peroxidase from an application site in the cervical trunk of the glossopharyngeal (IXth cranial) nerve of the rat produced extraperikaryal reaction product characteristic of axon terminal processes in three regions of the brain stem: (1) the nucleus of the tractus solitarius, from approximately 2.5 mm rostral to the obex to approximately 3 mm caudal to the obex; (2) the spinal trigeminal nucleus at the level of obex; (3) the cuneate fasciculus, approximately 3 mm caudal to the obex. In contrast, labelling of the carotid sinus nerve, a branch of the glossopharyngeal nerve which conveys chemoreceptor and baroreceptor afferent fibers from the carotid bifurcation, revealed a restricted central projection to within 1 mm of the obex and corresponding to the intermediate region of the glossopharyngeal nerve projection to the nucleus of the tractus solitarius. Two distinct aggregations of label were observed: (1) rostral to the obex, within the lateral and dorsomedial subnuclei of the nucleus of the tractus solitarius; (2) caudal to the obex, within the commissural and ventrolateral subnuclei of the nucleus of the tractus solitarius. Between these two sites the density of labelling was reduced. Retrogradely labelled neurons were demonstrated in the inferior salivatory nucleus and in the nucleus ambiguus after application of lectin-conjugated horseradish peroxidase to the glossopharyngeal nerve. Of the labelled neurons in the nucleus ambiguus (approximately 100), 25% contributed fibers to the carotid sinus nerve. The concentration of extraperikaryal reaction product located rostral to the obex after labelling of the carotid sinus nerve closely matches descriptions of the region of afferent terminations from carotid and aortic baroreceptors in the cat. The concentration of label caudal to the obex may therefore correspond to the region of afferent terminations from carotid chemoreceptors. This study may therefore provide some basis for a separation of the central synapses of primary afferent fibers from the carotid baroreceptors and chemoreceptors in the rat. The labelled neurons of the nucleus ambiguus provide the anatomical substrate for centrifugal control of carotid chemoreceptor activity.

Afferent Pathways↗
PubMed1987

Dopamine D2 receptor binding in striatal membranes of rat lines selected for differences in alcohol-related behaviours.

The specific binding of 3H-spiperone to striatal membranes was compared within two pairs of rat lines produced by selective breeding for either differences in voluntary alcohol consumption or for differences in acute ethanol-induced motor impairment. Although a significant difference was found between the alcohol-preferring rats and alcohol-avoiding rat lines, the estimate for the Bmax value was only slightly lower in naive alcohol-preferring rats. The small magnitude of the difference suggests it is unimportant for the genetically-determined differences in alcohol preference. No significant differences were found in the estimates for their Kd values. There were no significant differences for either the Bmax and Kd values between the alcohol-sensitive and alcohol-insensitive rat lines, which suggests that striatal dopaminergic D2 receptors are not involved in the genetically-determined factors influencing sensitivity to alcohol (and also barbital and lorazepam).

Alcoholism↗
PubMed1987

Behavioral and color variations between rat lines developed for differential alcohol sensitivity.

The AT and ANT rat lines, outbred for differential sensitivity to ethanol-induced motor impairment, also show a difference in their sober behavior. It is not manifested in an escapable-shock test or an amphetamine-stress test, but is shown as significantly more activity by the alcohol-insensitive ATs in a low-stress (33 degrees C) modification of the forced-swimming test. The correlation between alcohol sensitivity and swimming-test activity is, however, not significant in unselected Long Evans rats. Differences in coat color have also developed in the AT and ANT lines; it was possible to estimate whether these changes are independent of ethanol sensitivity with computer simulations. They showed, for example, that the probability of the observed loss of the agouti color in the ATs being by chance is about 0.53 and the probability is nearly 0.50 for there being a spurious line difference, i.e., unrelated to ethanol sensitivity, in which only line had lost the agouti allele. More generally, these and other simulations showed that permanently maintaining selected lines is not the optimal method for finding genetically-based factors related to ethanol sensitivity or other characteristics for which lines have been developed. Nor is either revitalization or replicate lines optimal. The best method apparently would be perpetual restarting of lines.

Animals↗
PubMed1986

Effect of neonatal clomipramine treatment on adult alcohol drinking in the AA and ANA rat lines.

In order to test further the hypothesis that neonatal active (REM) sleep suppression by means of clomipramine, an inhibitor of monoamine reuptake, is involved in the subsequent increase of voluntary alcohol consumption in rats, the AA (alcohol preferring) and ANA (alcohol avoiding) rat lines were injected daily with 25 mg/kg clomipramine IP from the 7th to the 20th postnatal days. At the age of 3 months the clomipramine AA rats consumed significantly more 10% (v/v) alcohol solution than the control AA rats. Neonatal clomipramine treatment did not, however, affect the drinking patterns of the ANA rats. Secondly, in order to test the alcohol-deprivation effect; i.e., the increase in alcohol consumption after its deprivation, the AA and ANA rats were deprived of alcohol for 17 days. There was a significant difference between the temporal pattern of changes in alcohol drinking produced by alcohol deprivation in the AA rats and the pattern in the ANA rats. Furthermore, the clomipramine treated AA rats tended to show a decrease and the clomipramine ANA rats an increase in their post-deprivation alcohol intake compared to the control AA and ANA rats. The results are interpreted in terms of active sleep being important for later alcohol drinking and other genetically determined differences in behavior.

Alcohol Drinking↗
PubMed1986

Restoration of hypoxic respiratory responses in the awake rat after carotid body denervation by sinus nerve section.

The restoration of ventilatory responses to hypoxia after carotid body denervation was studied in twenty-eight awake rats. The respiratory depression seen in moderate hypoxia (partial pressure of inspired O2, PI,O2, 80-100 mmHg) 3 days after bilateral carotid sinus nerve section disappeared by day 10. By day 17 respiratory stimulation occurred at all levels of PI,O2 below 125 mmHg. The largest restored response, in severe hypoxia (PI,O2 50-60 mmHg), was approximately 55% of the pre-denervation response. The response showed little further change from day 17 to day 192. A comparison of the effect of bilateral section of the glossopharyngeal nerve and of the abdominal vagus 1 and 28 days after carotid sinus nerve section demonstrated that the restoration of hypoxic response resulted in part from an enhanced effect of the inputs from the secondary glomus tissue served by these nerves. A comparison of the effect of bilateral section of glossopharyngeal, abdominal vagal and aortic depressor nerves 1 and 28 days after carotid sinus nerve section demonstrated an increase of a residual hypoxic response which must result either from inputs from unidentified peripheral chemoreceptors or from central mechanisms. Bilateral sectioning of the aortic depressor nerves produced no additional effect on restored responses to sectioning glossopharyngeal and abdominal vagal nerves, providing further evidence against significant aortic body function in the rat. The studies support the hypothesis that central neural reorganization provides compensation for loss of carotid body function by enhancement of effects of normally subsidiary inputs.

Abdomen↗
PubMed1986

Arguments against tighter restrictions on the use of animals and in favor of experimenter-regulated research.

There are several potential problems with stronger animal welfare legislation. Partly because there are no simple logical rules separating what most people would consider acceptable and what is inhumane, it may not be possible to stop the program before the restrictions become so strict that science is harmed. Provisions should at least be included that improve animal welfare without threatening science. The researcher is often best at deciding whether to do an experiment because he can best estimate the benefits. The time and effort spent meeting the bureaucratic requirements and administering the program may be largely wasted in many countries because the cruel experiments never would have been conducted in the first place. Military research is likely to be exempt from the restrictions and may become a haven for prohibited civilian research to the detriment of both the animals and science. The legislation provides legal means by which some people are given the right to impose their moral beliefs upon others, by essentially creating and administering new laws, and judging and penalizing offenders, all outside of the existing legal structure.

Animal Welfare↗
PubMed1985

Enhancement of respiratory response to carbon dioxide produced by lesioning caudal regions of the nucleus of the tractus solitarius.

Bilateral lesions of the caudal region of the nucleus of the tractus solitarius produced a significant enhancement of the ventilatory response to carbon dioxide in awake rats. The result indicates release of an inhibitory influence normally operating at hindbrain level. Respiration in air or oxygen was not affected while hypoxic responses were depressed insignificantly.

Animals↗
PubMed1985

Analysis of respiratory patterns in the awake and in the halothane anaesthetised rat.

Respiratory patterns have been studied in awake and halothane anaesthetised rats. Tidal volume (VT) was shown to be age-sensitive over 44-200 days; failure to account for this gave the appearance of an increased ventilatory sensitivity to CO2 with age. Inspiration of CO2 (0-10.5%) produced linear responses of VT whereas frequency responses stabilised at 6% CO2. Initially expiratory duration (TE) decreased more than inspiratory duration (TI) and both decreased linearly relative to increased VT; above 6% CO2, increases in VT occurred with only minor changes in TI and TE. Halothane anaesthesia dominantly depressed the frequency response to CO2. We conclude that the rat shows a great influence of vagal control on breathing in the awake state and in halothane anaesthesia; that TE is controlled independently of TI; and that respiratory frequency is more rigorously controlled than VT.

Aging↗
PubMed1985

Respiratory effects of sectioning the carotid sinus glossopharyngeal and abdominal vagal nerves in the awake rat.

Normoxic and hypoxic respiration has been measured in awake rats after denervation procedures designed to eliminate the regulatory input from the carotid bodies, from all chemosensory tissue supplied by the glossopharyngeal nerve (n. IX), and from abdominal chemoreceptors. Studies were made 1 day after section of the carotid sinus nerve (c.s.n.), n. IX (at a level including c.s.n.), the abdominal vagus (n. Xa) and combinations of these nerves. Results were compared with those found in normal controls. C.s.n. section led to hypoventilation in both normoxia and hypoxia, reductions in respiratory frequency being consistent and substantial, and reductions in tidal volume varying with the degree of hypoxia. By comparison, section of n. IX produced significantly greater reductions of both normoxic and hypoxic ventilation. Section of n. Xa produced no significant change in normoxic ventilation but in hypoxia produced a significant small reduction in ventilation, mostly from an effect on tidal volume. Denervation of all the associated chemosensory tissue by combined section of n. IX and n. Xa demonstrated a summation of effects but left two distinct residual responses, one to mild hypoxia, and one to severe hypoxia, both associated mainly with increases of tidal volume. The experiments demonstrate that glomus tissues at different sites in the rat produce significant and distinct contributions to respiratory regulation. Denervation of all known receptors shows that significant ventilatory responses to hypoxia are still produced, either by unrevealed peripheral chemoreceptors, or by central neural mechanisms.

Abdomen↗
PubMed1984

Fitness tests.

Explore the source record for details and available documents.

Exercise Test↗
PubMed1984

Effects of neonatal treatment with clomipramine on adult ethanol related behavior in the rat.

Male rat pups were deprived of active (REM) sleep by giving daily injections of clomipramine between 8 and 21 days after birth. At the age of 55 days their ambulation and defecation in the open-field were tested. Thereafter, beginning at the age of 66 days, the voluntary ethanol consumption of the rats was tested for 4 weeks. Compared to saline-treated rats, the CLM rats consumed more ethanol, tended to be more active in the open-field, and responded with a decrease in ambulation to an ethanol dose which stimulated locomotion in control rats. These results indicate that neonatal treatment with clomipramine has an influence on later ethanol-related behavior in rats.

Alcohol Drinking↗
PubMed1984

Diabetes and the alcohol consumption of AA and ANA rats.

Some earlier results have suggested a link between diabetes and voluntary ethanol consumption. Measurement of blood glucose levels now showed, however, that the AA line of rats developed for high alcohol intake is not diabetogenic. The alcohol-avoiding ANA line was somewhat more susceptible to streptozotocin-induced diabetes. Streptozotocin greatly increased blood glucose levels, water intake, and food consumption, but had no effect on the voluntary alcohol drinking of either AA or ANA rats. Normalization of blood glucose levels with insulin from osmotic minipump implants also failed to change their ethanol drinking. Thus, although the evidence from some other lines of rats and mice suggests that alcohol drinking is related to some forms of diabetes, the present results indicate that it is independent of the diabetes induced by streptozotocin and also of water and food intake regulation in this situation.

Alcohol Drinking↗
PubMed1982

Cerebroventricular tetrahydropapaveroline infusions and ethanol consumption in the rat.

Discrepant results have been reported from different laboratories on the effects of tetrahydropapaveroline (THP) and related compounds. In order to try to explore the discrepancy, an independent researcher participated in a partial replication attempt at the laboratory from which reports had previously come that THP markedly increased ethanol consumption by rats and produced withdrawal-like behavior. Withdrawal-like signs were observed after several once-daily bilateral ventricular infusions of 1.0 microgram THP. These abnormal behaviors varied in frequency and intensity but continued up to the last day of infusion and were rated independently by up to 5 judges. The mean ethanol intake, however, during THP treatment remained virtually the same as before THP (mean g ethanol per kg body wt. +/- SE: 1.60 +/- 0.29 before THP, 1.69 +/- 0.45 during THP). Control rats drank similar amounts of ethanol (1.60 +/- 0.33 before vehicle infusions, 1.65 +/- 0.42 during vehicle infusions). The individual THP animals tended to show greater variations than the controls from their own pre-treatment levels, but none of them showed a mean increase of greater than 2.0 g/kg in ethanol intake. Injections of THP or noreleagnine into cannulae aimed at hippocampal and periventricular grey sites also failed to increase alcohol drinking; however because histology was not available, it is not known whether or not the sites of injection were located in these structures. In comparison to the previously published report of Myers and Oblinger (25), this experiment differed in several variables. It is concluded that the precise experimental parameters necessary for once-daily THP reliably to increase ethanol consumption remain to be determined.

Alcohol Drinking↗
PubMed1981

Suppression of alcohol drinking with brain aldehyde dehydrogenase inhibition.

Calcium cyanamide, an aldehyde dehydrogenase (ALDH) inhibitor used in the treatment of alcoholism, strongly suppressed voluntary ethanol drinking by rats. Such inhibitors have generally been believed to act primarily by limiting drinking through acetaldehyde accumulation after ethanol consumption. Administration of a low dose of 4-methylpyrazole (4-MP) that abolished acetaldehyde accumulation did not, however, remove the suppression produced by cyanamide. 4-MP alone did not affect the unsuppressed alcohol intake by Long Evans rats or the drinking by rats of the ANA strain developed for low levels of ethanol consumption. When given from the start with cyanamide, 4-MP did affect the development of the suppression, but probably by its effect in lessening the degree of brain ALDH inhibition: a high correlation (r = +0.825, p less than 0.001) was found between brain ALDH activity and ethanol consumption. The results suggest that cyanamide suppresses alcohol drinking also in the absence of acetaldehyde accumulation probably by some action related to its direct inhibition of brain ALDH.

Acetaldehyde↗