Circadian acetylcholine receptor rhythm in rat brain and its modification by imipramine

A circadian rhythm was found in the number of muscarinic acetylcholine receptors of the rat forebrain. The daily rhythm was endogenous and changed throughout the year. Chronic administration of the antidepressant drug imipramine altered the shape (wave form) of the rhythm, amplitude, 24-hr mean, and the timing of its peak (phase). As neuronal transmission is altered by both pre- and postsynaptic receptors, circadian and seasonal rhythms in a number of muscarinic receptors may play a role in the temporal organization of brain synaptic transmission.     

Circadian rhythm of serotonin transport in human platelets

The circadian rhythm of serotonin active transport in human platelets was investigated in ten healthy men, aged 27–35 years. Blood was collected at 08.00, 14.00, 20.00, 02.00 and 08.00 hours the next morning. Simultaneous evaluation of the mean platelet volume, platelet distribution width, platelet distribution skewness and platelet number in whole blood was performed. K _m and V _max for serotonin transport varied considerably among individuals over 24 h. However, the mean values and distribution of these kinetic parameters were reduced at 02.00 hours. All platelet size or number parameters were stable and normal over 24 h; therefore, the reduction in mean K _m and V _max values at 02.00 h is not related to morphological platelet differences but either to platelet intrinsic factors or plasmatic variables. Knowledge of the affinity and capacity of serotonin transport throughout the diurnal cycle is important for future comparisons with depressed patients as well as other hormonal rhythms in patients and healthy humans.     

Circadian rhythm of cyclic nucleotide and GABA levels in the rat brain.

Daily variation in the levels of cyclic nucleotides and GABA was examined in seven brain regions of male Sprague-Dawley rats. Significant daily rhythm of cyclic AMP levels was found in the cerebellum and pons medulla oblongata. Circadian variation of cyclic GMP levels was found in the cerebellum, cerebral cortex, striatum, and hypothalamus. Daily variation of GABA levels was found in the pons medulla oblongata and striatum. Cyclic GMP in the pons medulla oblongata and GABA in the hypothalamus were found to exhibit ultradian variation of levels. These observed daily fluctuations of baseline levels should be considered when examining the duration of action of various drugs upon these substances.     

Circadian rhythm of the renin-angiotensin-aldosterone system in the rat

The 24 h-course of plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma corticosterone concentration (PCC) and of the urinary excretion of sodium, potassium and aldosterone was investigated in male Sprague-Dawley rats under different experimental conditions. The data obtained can be summarized as follows: 1. The renin-angiotensin-aldosterone system (RAAS) of the rat is subject to a circadian rhythm which is largely in phase with the well-known rhythm of the pituitary-adrenal axis. This rhythm can be demonstrated in PRA as well as in plasma concentrations and urinary excretion rates of aldosterone. The rhythm of urinary excretion of electrolytes is unlikely to be due to the rhythm of aldosterone secretion. 2. The light-dark cycle is the main synchronizer for these rhythms: inverting the light-dark cycle for 5 weeks entirely inverts the rhythms of all the parameters cited. 3. A dissociation of the rhythms of PRA and PAC can be observed following sodium restriction or dexamethasone treatment. A role of ACTH IN regulating the rhythmic pattern of aldosterone secretion is suggested by the finding that PAC and PCC follow the same pattern of circadian variations under every experimental condition tested. 4. The responsiveness of the RAAS to stimulation or suppression varies with the time of day. 5. It is suggested that experiments ought to be performed not only during the inactive (light hours) but also during the active (dark hours) phase when investigating the RAAS in the rat. This can conveniently be achieved by the use of an animal room with a reversed lighting regime.     

Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain

The effect of ten daily injections of saline or d-lysergic acid diethylamide (LSD) (260 micrograms/kg i.p.) on serotonin1 (5-hydroxytryptamine1, 5-HT1) and 5-HT2 receptor binding was determined in brain membranes from rats killed 24 h after the last injection. [3H]LSD (3.0 nM) was used with either 30.0 nM 5-HT or 70.0 nM cinanserin to estimate 5-HT1 and 5-HT2 receptors, respectively. LSD administration decreased 5-HT2 binding in cortex, striatum, hippocampus, and diencephalon/midbrain without altering 5-HT1 or total specific binding.     

Circadian rhythm of brain susceptibility to haloperidol during chronic administration

Circadian fluctuation has been reported to exist to the effects of haloperidol after acute administration. In an attempt to clarify the viability of chronotherapy with haloperidol, the antiapomorphine effect of haloperidol after chronic administration was investigated in the present paper. Haloperidol was administered once daily at the same time for 21 consecutive days to rats which were kept under 12 hr lighting conditions with light onset at 19:30. Then the chronology of the antiapomorphine effect was investigated. The antiapomorphine effect was significantly stronger in the group treated at 19:30 than that treated at 13:30. These data agreed with the results found after the acute administration of the drug. After chronic administration, no difference was found in the plasma and brain level of haloperidol due to the time of administration. These experimental results seem to suggest that a circadian rhythm in the brain susceptibility to haloperidol exists even during chronic administration.     

Circadian rhythm of the in vitro stimulation of adenylate cyclase in rat heart tissue

Adenylate cyclase activity in rat heart ventricles displayed a circadian rhythm with a maximum around 8:00 h and a minimum around 20:00 h. In vitro stimulation with 0.1 mM of isoprenaline, Gpp(NH)p or forskolin increased the 24-h-mean basal adenylate cyclase activity by 1.7-, 2.7- and 10.7-fold, respectively. The magnitude of the drug-induced stimulation varied significantly with the time of day. However, the drugs did not affect the timing of the circadian maximum or the amplitude (as % of 24-h-mean) of the basal rhythm. The data are the first to show that the response to the in vitro stimulation of the cardiac adenylate cyclase also displays a pronounced circadian rhythm.     

Aluminium-induced changes in the rat brain serotonin system

Aluminium exposure, apart from producing cholinotoxicity, can include changes in other neurotransmitter levels since neurotransmitter levels are closely interrelated. Reports of aluminium (Al) effects on brain neurotransmitters are limited. To investigate the effect of Al on the rat brain serotonergic system, the present study was conducted to explore brain region-specific changes and duration-specific changes. Male Wistar albino rats were exposed orally to Al chloride (AlCl₃.6H₂O; 320 mg/kg body weight) daily for up to 60 days and changes in the 5-hydroxytrytamine (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) levels were observed after 4, 14 and 60 days of exposure in olfactory lobe (OLB), cerebellum (CBL), pons (PON), medulla oblongata (MOB), spinal cord (SPI), hypothalamus (HYP), hippocampus (HIP), striatum (STR), midbrain (MBR) and cortex (COR) brain regions. Significantly increased 5-HT levels observed in brain regions OLB (60 days), HIP (4,14 days), STR (14 days), HYP (14, 60 days), MBR (4 and 14 days), PON (4 days), MOB (4 days) and SPI (4, 14 and 60 days) following Al exposure may be due to Al deactivating 5-HT system by decreased release and subsequent breakdown of 5-HT. Decreased 5-HT levels observed in cerebral COR, HIP (60 days) and in CBL after 4 and 60 days of exposure suggest an inhibitory effect of Al on the 5-HT system due to withdrawal of cholinergic input in these brain regions. 5-HIAA level changes correlate with 5-HT level changes in many brain regions studied. The results reveal that the neurochemical changes due to Al were dependent on the duration of exposure and are brain-region-specific. The observed changes may be related to the cholinergic toxicity of Al.     

Circadian rhythm of lithium toxicity in mice

The existence of cyclical (circadian) variations in lithium toxicity in mice was determined. Mice, standardized to a light-dark cycle, were injected with lithium chloride (940 mg/kg) at one of six times (20:00, 24:00, 4:00, 8:00, 12:00, and 16:00) and subsequently observed for mortality over 28 h. A significant (P<0.01) time-of-day effect was found for lithium-induced lethality, with highest lethality following injection at 12:00.     

Circadian rhythm of apomorphine-induced stereotypy in rats

The existence of circadian variations of apomorphine-induced stereotypy was determined. Male Wistar rats, standardized to a light-dark cycle (lights on from 7:00–19:00) for three weeks, were injected with apomorphine hydrochloride (1 mg/kg or 3 mg/kg) at one of six times (9:00, 13:00, 17:00, 21:00, 1:00 and 5:00). A significant time-of-day effect was found for apomorphine-induced stereotypy, with highest stereotypic score following injection at 13::00 or 17:00. The circadian rhythm of apomorphine-induced stereotypy was significantly fitted to a single cosine curve with a 24-hr cycle using the least squares method.     

Circadian rhythm of [3H]imipramine binding in the rat suprachiasmatic nuclei

High affinity imipramine binding undergoes circadian variations of ca. 35% amplitude in many rat brain nuclei. The suprachiasmatic nuclei of the anterior hypothalamus (considered to be the circadian pacemaker driving many overt rhythms) has highest imipramine binding at the end of the dark and lowest at the end of the light phase. A similar circadian rhythm has previously been observed for serotonin uptake in the suprachiasmatic nuclei. In conjunction with other findings, these data indicate that serotonergic turnover in the suprachiasmatic nuclei decreases at lights on and increases at lights off.     

Characterization of the receptor subtype involved in alpha-adrenoceptor-mediated modulation of serotonin release from rat brain cortex slices

Rat brain cortex slices preincubated with 3H-5-hydroxytryptamine and superfused with physiological salt solution were stimulated electrically at a frequency of 3 Hz. 1. The electrically evoked 3H-overflow was decreased by clonidine, noradrenaline and B-HT 920 in a concentration-dependent manner (negative logarithms of the IC30 values: 6.66, 6.55 and 4.40, respectively) 2. Phenylephrine 10-5 M (which increased basal 3H-efflux) and methoxamine 10-4 M decreased the impulse-evoked 3H-overflow by less than 25% whereas lower concentrations were ineffective. 3. Yohimbine produced a shift to the right of the concentration-response curves of noradrenaline (apparent pA2: 6.93) and clonidine (apparent pA2: 7.06) for their inhibitory effects on evoked 3H-overflow. Rauwolscine also shifted the concentration-response curve of noradrenaline to the right (apparent pA2: 7.29), whereas prazosin (10-6 and 3.2 x 10-6 M) was ineffective in this respect. These results suggest that the alpha-adrenoceptors on the serotoninergic nerve fibres belong to the alpha2-subtype.     

Circadian rhythm of rat liver dihydropyrimidine dehydrogenase. Possible relevance to fluoropyrimidine chemotherapy

The activity of dihydropyrimidine dehydrogenase (DPD), the initial, rate-limiting enzyme in pyrimidine catabolism, was measured at various times over a 24-hr period in the livers of rats housed under standardized conditions of light and dark. Under "normal" conditions, i.e. lights on from 6:00 a.m. to 6:00 p.m. and off from 6:00 p.m. to 6:00 a.m., a circadian rhythm of DPD activity was observed (P less than 0.0001, Cosinor analysis) with the peak of activity at 4:00 p.m. (2.96 nmol catabolites/min/mg) and the trough at 4:00 a.m. (0.40 nmol catabolites/min/mg). Maximum enzyme activity exceeded minimum activity by more than 7-fold. Reversing the light-dark cycle (i.e. lights on from 6:00 p.m. to 6:00 a.m. and off from 6:00 a.m. to 6:00 p.m.) resulted in a corresponding shift in enzyme activity. Under these "reverse" conditions, a circadian rhythm was observed (P less than 0.0001, Cosinor analysis) with the peak of activity at 6:00 a.m. (2.87 nmol catabolites/min/mg) and the trough at 6:00 p.m. (0.92 nmol catabolites/min/mg). These studies demonstrated that DPD activity in rat liver varies over a 24-hr period in association with the light-dark cycle.     

No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC₅₀ = 10^− 7.96 M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 μM. Furthermore, substance P as well as Sar⁹Met(O₂)¹¹SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.