Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice

 The route of drug delivery is an important consideration in studies that evaluate the long-term biobehavioral adaptations that occur in response to chronic drug administration. Continuous infusions (intravenous or subcutaneous) or intermittent intraperitoneal (or subcutaneous) injections are the most commonly utilized routes of chronic drug delivery in these studies. The purpose of the present study was to determine the effects of chronic oral nicotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57Bl/6 mice. Mice were randomized to different treatment groups that received 2% saccharin, containing 0–200 μg/ml nicotine (free base). In preliminary experiments, radiotelemetry devices were implanted in the mice; consumption of the nicotine-containing drinking solution caused a significant increase in home-cage nocturnal (but not diurnal) activity and also altered circadian alterations in body temperature. Oral nicotine exposure resulted in dose-related elevations in plasma levels of cotinine, a primary nicotine metabolite. Continuous exposure (30 days) to oral nicotine (200 μg/ml) resulted in the expression of significant tolerance to the locomotor depressant and hypothermic actions of acute nicotine challenge. This tolerance was accompanied by a significant increase in brain nicotinic receptor number assessed by quantitative autoradiography using [³H]-cytisine (α4 nAChr) and [¹²⁵I]-α-bungarotoxin (α7 nAChr) as radioligands. These results suggest that chronic oral nicotine delivery to female C57Bl/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery. Received: 30 January 1998 / Final version: 25 June 1998     

Early nocturnal blood pressure changes in diabetic autonomic neuropathy assessed by Fourier series

The 24 h periodic pattern of blood pressure was studied in 44 patients with diabetes mellitus (14 type 1, 30 type 2; mean duration of disease 6.5 ± 1.8 years) in good metabolic control but with abnormal cardiovascular reflex responses; of these 21 were normotensive and 23 hypertensive. All had abnormal responses to at least two out of four tests: deep breathing, lying to standing, Valsalva manoeuvre and postural hypotension. Two sex- and agematched groups, consisting of 20 normotensive and 20 hypertensive diabetic patients without dysautonomia, were studied as controls. Each patient underwent ambulatory blood pressure monitoring for at least 24 h, using an auscultatory automatic device. Data were analysed using the sum of three periodic functions (Fourier partial sum). In the diabetic normotensive groups, the absolute blood pressure fell to its night-time minimum more rapidly, and increased to its morning maximum more slowly, in those with abnormal cardiovascular reflexes than in the controls (nightly blood pressure decrease –5.8/–4.7 vs. –3.8/–4.0 mmHg/h; increase 4.7/3.6 vs. 5.9/6.1 mmHg/h). The same behaviour was found in both hypertensive groups but the amplitude of the differences was more marked (blood pressure nocturnal decrease –7.7/–7.1 vs. –4.3/–3.9 mmHg/h; increase 3.2/2.1 vs. 5.8/4.3 mmHg/h). This analysis of 24 h ambulatory blood pressure data may be of value in diagnosis and evaluation of autonomic deficits.     

Antagonism by chlorisondamine and propranolol,but not by atenolol,of the circadian phase-dependent phentolamine-induced changes in the cardiac noradrenaline turnover in the rat

Summary The effects of phentolamine alone or in combination with propranolol, atenolol and chlorisondamine were studied on the concentration and turnover of noradrenaline in the heart of light-dark (L:D=12:12h) synchronized rats. In order to detect possible circadian phase-dependent variations in the drug effects, the same experiments were performed in the light-period and dark-period, respectively. The parameters of the turnover were calculated from the exponential decline of i.v. injected ³H-(-)-noradrenaline. Phentolamine significantly decreased the noradrenaline concentration during L, but not during D. Reduction in ³H-noradrenaline accumulation by phentolamine was 42.3% during L and 22.2% during D. Phentolamine increased the turnover rate of cardiac noradrenaline more than 3-fold in either photoperiod. Chlorisondamine reversed all the effects of phentolamine studied. Propranolol, but not atenolol, antagonized the effects of phentolamine in a dose-dependent and stereospecific way, being more effective when applied during D. Thus, the chronopharmacological studies in unrestrained rats show a circadian phase-dependency of the effects of adrenoceptor blocking drugs. It is concluded that a central site of action is responsible for the antagonism by propranolol of the phentolamine-induced increase in the turnover of the cardiac noradrenaline in vivo.Parts of this work were presented at the 18th Spring Meeting of the German Pharmacological Society, Mainz 1977 (Lemmer and Charrier, 1977) and at the 7th International Congr. of Pharmacology, Satellite Symposium on chronopharmacology, Paris 1978 (Lemmer and Charrier, 1978)     

Predominantβ-adrenoceptor blocking effect of xamoterol averaged over the day in patients with mild to moderate heart failure: insight into the mechanism of its long-term clinical efficacy

Summary Xamoterol acts as a ₁-adrenoceptor agonist at low sympathetic activity and as an antagonist at high activity. Although its long-term efficacy has been proven in patients with mild to moderate heart failure, it remains unclear which effect, agonism or antagonism, accounts for its long-term activity.To clarify the effect of xamoterol on cardiac sympathetic activity in daily life, 24-h R-R interval histograms were obtained during administration of xamoterol 100 mg b. d. for 1 week to 10 patients with mild to moderate heart failure. Eight normal subjects were also studied as controls. To examine the relation between the effect of xamoterol and sympathetic activity, plasma noradrenaline (NA) levels were measured under 5 graded conditions simulating daily living.Xamoterol administration significantly decreased the standard deviation of the R-R interval, both in patients with heart failure and in normal subjects. The mean R-R interval, however, was increased in patients with heart failure, relative to normal subjects.In both groups, the R-R interval histograms had two peaks, i. e. a short daytime peak and a long night-time peak. Xamoterol decreased the median of the night-time peak without changing the daytime peak in normal subjects. In contrast, it increased the median of the daytime peak without producing a significant change in the nighttime peak in patients with heart failure. Levels of plasma NA were significantly higher in patients than in normal subjects under all conditions.Thus, in normal subjects xamoterol predominantly increased the slower heart rate at night with only a minor effect on the higher heart rate in the daytime, whereas it predominantly attenuated the daytime tachycardia induced by sympathetic stimulation in patients with heart failure.It is concluded that xamoterol tends overall to act as a-adrenoceptor antagonist during the day, especially in the daytime in patients with mild to moderate heart failure. Its antagonist rather than its agonist effect may account for the long-term efficacy of xamoterol in patients with mild to moderate heart failure.     

The circadian rhythm of atrial natriuretic peptide,vasoactive intestinal peptide,beta-endorphin and cortisol in healthy young and elderly subjects

Atrial natriuretic peptide, vasoactive intestinal peptide, beta-endorphin and cortisol are humoral variables characterized by a 24-h periodicity. We evaluated the circadian rhythm of these peptides and hormones in healthy subjects who were young (between 20–25 years) or elderly (between 65–75 years). All were on controlled diets. Blood samples were collected six times during a 24-h period (at 06.00, 08.00, 12.00, 18.00, 20.00 and 24.00 h) beginning 8-h after start of recumbency. The time-related data were analysed by the Cosinor method in order to validate the circadian rhythm and to quantify rhythmometric parameters which included the midline estimate of rhythm (mesor). In contrast to the young subjects, Cosinor analysis failed to reveal a significant circadian rhythm in elderly subjects, for plasma cortisol. In elderly subjects oscillation (mesor) of atrial nutriuretic peptide was higher, while that of vasoactive intestinal peptide and beta—endorphins was lower. The results suggest changes in the physiological secretion of these three peptides in healthy elderly subjects.     

"Hyperfrontal" distribution of the cerebral grey matter flow in resting wakefulness; on the functional anatomy of the conscious state

Regional cerebral blood flow was measured with the intra-arterial 133 Xenon clearance technique using a multidetector device in 11 patients undergoing carotid angiography (with normal findings). During the flow studies the patients were awake and strict resting conditions were observed. The patients did not move or speak, and sensory stimulation were kept at a minimum. It was confirmed that the distribution of the grey matter blood flow showed a hyperfrontal pattern, the flow in frontal regions being significantly (20-40%) higher than in postcentral, occipital and temporal regions. There were no technical factors or morphological features of the telencephalon which could explain this difference. It was also shown that the distribution of the white matter flow and the relative weight of the grey matter corresponded in general to hemisphere morphology. Since in normal nervous tissue the blood flow is regulated by the neuronal activity, the following interpretation is given of the main finding. The hyperfrontal flow distribution of the grey matter (cortical) flow during resting wakefulness shows that there is a high activity in frontal "efferent" (motor-behavior) regions. At the same time there is a low activity in post-central and temporal "afferent" (sensory-gnostic) cortical areas. The high frontal activity suggests that in the resting conscious state--unaccompanied by movements, speech or behavioral reactions--the brain is active with an anticipatiory "simulation of behavior". The low postcentral flow, on the other hand, may possibly be related to a global inhibition of the sensory input. Several clinical as well as general biologic arguments are forwarded to support this interpretation. It is further pointed out that the hyperfrontal distribution of the resting activity in the cerebral cortex correlates to the resting EEG, in which lower frequencies (the alpha rhythm) predominate in postcentral and temporal regions where there is a low flow/activity, and high frequencies in frontal areas where the blood flow is high. This is in agreement with the finding that the blood flow and metabolism of the brain correlate to the EEG frequency content.     

Circadian system response to night work in relation to the individual circadian phase position

Summary In 6 night nurses the daily course of body temperature and pulse rate was measured under strict resting conditions immediately after a 7 to 18-day period with night work as well as after a 10-day period of recovery under normal life conditions. Three of the subjects were morning types and three evening types according to the Horne-Östberg-Questionnaire as well as to the phase position of the body temperature cycle.In order to quantify the changes in amplitude, phase position, and frequency a flattening index, a circadian deformation index, and according to the calculated phase shift a corrected deformation index were used. While the evening types reacted with a flattening of their circadian amplitude and thus gained a greater tolerance, the morning types hyper reacted when exposed to the inverse life pattern, developing an increased amplitude and adding to the circadian deformation by ultradian periods. No significant differences could be detected in phase shift. Higher amounts of subjective complaints and deficit of sleep as well as differences in the additionally controlled vigilance functions demonstrated the lower tolerance of the morning types to night work.The discussion concerns the methological basis of a quantitative evaluation of disturbance of the circadian system, and shows off, that the greater tolerance of evening types to night work is based on a lower reagibility of the vegetative functions to changes in the outer environment.     

Phase shift in temperature rhythm ffter transmeridian flight,as related to pre-flight phase angle

Summary Further analysis of temperature rhythms obtained in an earlier study of 38 subjects subjected to an 8-h eastward transmeridian flight showed that the extent to which the phase of the rhythm was shifted after the flight was related to the phase angle of the pre-flight rhythm. Late peakers shifted more than early peakers, and this difference between the two types was still as large after 12 days in the new time zone as on the first day. Because the phase-shift was an advance one, this meant that the pre-flight individual differences in phase-angle were abolished by the flight, and had not re-appeared by the end of the observation period. It is suggested that this may have been due to an increase in the rigidity of the routine in the post-flight stage of the study, and that a similar effect may also occur in a switch from day to shiftwork.     

The active phase-related increase in corticosterone and aggression are linked

Recently we demonstrated that corticosterone exerts an acute facilitatory effect on aggression in male rats. Corticosterone production reaches a maximum at the onset of the dark period, while male rats are more aggressive in the dark. Here we present evidence demonstrating that the corticosterone increase at the beginning of the dark period is causally linked to the increase in aggressiveness. We measured plasma corticosterone and quantified aggressive behaviour of male territorial rats at various time points of the day-night transition. Low aggression levels were observed in the full light period when plasma concentrations of corticosterone were low. An increase in plasma corticosterone occurred just prior to the dark phase, when aggressive responding was the highest. Aggressive behaviour remained high in the early dark period when corticosterone was still high. We found that blocking the high affinity mineralocorticoid receptor (MR) with spironolactone (5 or 10 mg/kg) during the early dark period dramatically and specifically reduced territorial aggression.     

Metabolic influences on circadian rhythmicity in Siberian and Syrian hamsters exposed to long photoperiods

Calorie restriction and other situations of reduced glucose availability in rodents alter the entraining effects of light on the circadian pacemaker located in the suprachiasmatic nuclei. Siberian and Syrian hamsters are photoperiodic species that are sexually active when exposed to long summer-like photoperiods, while both species show opposite changes in body mass when transferred from long to short or short to long days. Because metabolic cues may fine tune the photoperiodic responses via the suprachiasmatic nuclei, we tested whether timed calorie restriction can alter the photic synchronization of the light-entrainable pacemaker in these two hamster species exposed to long photoperiods. Siberian and Syrian hamsters were exposed to 16 h:8 h light:dark cycles and received daily hypocaloric (75% of daily food intake) or normocaloric diet (100% of daily food intake) 4 h after light onset. Four weeks later, hamsters were transferred to constant darkness and fed ad libitum. The onset of the nocturnal pattern of locomotor activity was phase advanced by 1.5 h in calorie-restricted Siberian hamsters, but not in Syrian hamsters. The lack of phase change in calorie-restricted Syrian hamsters was also observed in individuals exposed to 14 h:10 h dim light:dark cycles and fed with lower hypocaloric food (i.e. 60% of daily food intake) 2 h after light onset. Moreover, in hamsters housed in constant darkness and fed ad lib., light-induced phase shifts of the locomotor activity in Siberian hamsters, but not in Syrian hamsters were significantly reduced when glucose utilization was blocked by pretreatment with 500 mg/kg i.p. 2-deoxy-D-glucose. Taken together, these results show that the photic synchronization of the light-entrainable pacemaker can be modulated by metabolic cues in Siberian hamsters, but not in Syrian hamsters maintained on long days.