Circadian rhythm of cerebral perfusion pressure and intracranial pressure in head injury.

The aim of the study was to determine if Cerebral Perfusion Pressure (CPP) and Intracranial Pressure (ICP), in patients with head injury, has a circadian rhythm. CPP and ICP data of 13 patients were analysed using the Regressive and Iterative Cosinor methods. The Regressive Cosinor method did not detect a strong 24-hour rhythm. Therefore, the Iterative Cosinor method was used to seek rhythms with period not necessarily equal to 24 hours. Studying consecutive patient days by the Iterative cosinor method showed that rhythm is present but the rhythm period was often not 24 hours. A significant rhythm in the range of 20-30 hours was detected in eight patients for CPP (62%) and in six patients for ICP (46%). To validate the results real and surrogate time series were compared. The clinical implications of rhythmic data analysis are discussed.

Effects of corticotropin-releasing factor on circadian locomotor rhythm in the golden hamster.

Stress produces a reduction in the amplitude of some circadian rhythms. The neurochemical mechanisms underlying stress-induced changes in circadian rhythms are not known. To investigate a possible role of corticotropin-releasing factor (CRF) in this phenomenon, three related experiments were carried out: activity rhythms of male golden hamsters (10/14 hours light/dark entrained, lights on at 0800 h) were measured 1) following the intracerebroventricular administration of CRF (0.5, 1.0, 2.0, or 4.0 microg) at two different times of day, 2) following social stress (30-min resident-intruder confrontation), 3) and following the administration of the CRF-antagonist alpha-helical CRF9-41 (2.0 microg) prior to a 15-min resident-intruder confrontation. CRF produced a significant, dose-related decrease in circadian rhythm amplitude following administration in the morning hours, but not in the afternoon. CRF also induced transient increases in activity post injection concomitant with an activation of the hypothalamic-pituitary-adrenocortical (HPA) system. Stress similarly reduced the amplitude of activity patterns and stimulated the HPA system. The stress-induced depression of circadian rhythm amplitude was significantly attenuated following alpha-helical CRF9-41. These data suggest a role for CRF in the stress-related modulation of circadian locomotor rhythm amplitude.

Neonatal scopolamine or antidepressant treatment: effect on development of hamster circadian rhythms.

Chronic treatment of young rodents with drugs altering monoamine metabolism has been reported to produce lasting effects on behavior that resemble human affective disorders. To test the generality of this finding, scopolamine, imipramine, or clomipramine was injected daily between the ages of 8 and 21 days in golden hamsters. Wheel-running rhythms were monitored continuously from the age of 4 to 20 weeks of age to test the hypothesis that neonatal treatments would lower the amplitude of biological activity rhythms in adults. Of these three neonatal treatments only scopolamine altered running rhythms, significantly increasing the amplitude of running rhythms in adult hamsters under both entrained and free-running conditions. Hamsters treated neonatally with scopolamine were also more sensitive to the hypothermic effects of the muscarinic agonist, oxotremorine, as adults. These data indicate that neonatal exposure to cholinergic receptor blockade may produce long-lasting changes in biological rhythm characteristics related to upregulation of muscarinic receptors.

Cardiovascular actions of neuropeptide Y and social stress.

The role of central neuropeptide Y (NPY) in the cardiovascular response to social stress was evaluated in freely moving rats using telemetry. In unstressed rats, intracerebroventricular (ICV) administration of NPY and the selective Y1 receptor agonist [Leu31, Pro34]-NPY decreased blood pressure and heart rate, while the selective Y2 agonist NPY13-36 transiently raised blood pressure. NPY and [Leu31, Pro34]-NPY blunted elevations in blood pressure and pulse rate following exposure to the resident-intruder procedure, an established social stress paradigm. In contrast, the Y2 agonist significantly augmented stress-induced pressor effects. These observations indicate that the hypotensive effects of ICV NPY appear to be mediated by the Y1 receptor subtype and the NPY receptor subtypes may mediate opposing cardiovascular actions in response to stressful stimuli.

Antimanic drugs stabilize hamster circadian rhythms.

The circadian wheel-running rhythm of golden hamsters was monitored during chronic oral treatment with four mood-stabilizing drugs in doses relevant for treatment of manic-depressive disorder. Carbamazepine and verapamil shortened the duration of locomotor activity and improved the stability of the pattern of running activity. At comparable doses, valproate had no clear effect on any rhythm variable tested. None of these drugs consistently altered the phase of light-synchronized running rhythms or the period of the rhythm in constant darkness. The results are compared to data showing that lithium, which delays entrained phase and lengthens circadian period in hamsters, also shortens activity duration and increases the stability of wheel-running rhythms. Stabilization of circadian rhythms may be a key action of clinically effective mood-stabilizing drugs.

Effects of nutritional lithium deficiency on behavior in rats.

To demonstrate whether nutritional lithium deficiency is associated with behavioral changes, male Sprague-Dawley rats were placed on a lithium-deficient diet (Li content < .01 ppm). A lithium-deprived group, receiving drinking water containing 31 microM NaCl, were compared to a control group receiving drinking water containing 31 microM LiCl. Growth and general appearance were the same in both groups. However, lithium-deficient animals demonstrated decreased aggression in social interactions with other rats and also in response to handling. The phase of wheel-running activity was delayed by 0.8 h and exhibited decreased amplitude (p < .05). Other behaviors, including acquisition and retention of a passive avoidance response, were unaffected by lithium deprivation.

Dietary potassium effects on lithium concentration and toxicity in hamsters.

Lithium can be toxic in rodents and human patients at concentrations within the therapeutic range for treatment of affective disorders. Diet containing supplemental potassium reduced lithium-induced weight loss in hamsters following daily injections of 3 mmol LiCl/kg for 7-10 days. Potassium supplementation also decreased lithium concentrations in peripheral tissues; but not in brain, after repeated lithium administration. Repeated lithium injection lowered the concentration of potassium in peripheral tissues, but tissue potassium was not restored by dietary potassium supplementation. Toxic effects of single injections of 1-10 mmol LiCl/kg were unaffected by dietary potassium. Lithium concentrations in plasma, brain, or peripheral tissues 6-hr after injection of 5 mmol LiCl/kg were also not altered by potassium diet. These data suggest that interactions between lithium and potassium diet differ in peripheral tissues compared to the central nervous system, and after acute versus chronic lithium administration.

Antidepressant and depressogenic drugs lack consistent effects on hamster circadian rhythms.

The circadian wheel-running rhythm of golden hamsters was monitored during chronic oral treatment with four antidepressants and two potentially depressogenic agents. Desmethylimipramine shortened the circadian period (tau) by 0.1 hour. In contrast, clorgyline lengthened tau by 0.1 hour and delayed light-synchronized wheel-running rhythms by 1.4 hour. Phenelzine, fluoxetine, clonidine, and propranolol did not significantly alter light-entrained phase or free-running period over a range of doses. Other rhythm parameters were also unaffected by antidepressant or depressogenic drugs. These data suggest that mood-altering drugs do not consistently influence circadian rhythms in the hamster.

Potassium, rubidium, and 4-aminopyridine effects on the circadian running rhythm in the hamster.

The period of the circadian rhythm of wheel-running was shortened when golden hamsters were given supplemental dietary potassium or rubidium for two weeks. Treatment with 4-aminopyridine, a potassium channel blocker, significantly increased circadian period. These period changes (0.17 h for potassium treatment, 0.14 h for rubidium, and 0.07 h for 4-aminopyridine) support previous data indicating that potassium is a component of the mammalian biological clock mechanism.

Dietary calcium blocks lithium toxicity in hamsters without affecting circadian rhythms.

Lithium can be toxic to rodents at plasma concentrations (0.6-1.2 mmol/L) that also phase delay circadian rhythms. In hamsters, raising the concentration of calcium in the diet from 0.1%-3% reduced weight loss and polydipsia caused by 0.4% lithium carbonate. Calcium ingestion did not affect plasma lithium concentration or the phase of the circadian wheel-running rhythm in lithium-treated animals. Calcium ingestion did not alter weight gain, salt or water intake, or circadian rhythms in hamsters not receiving lithium. Dietary calcium supplementation may prevent some toxic effects of lithium without interfering with other central nervous system actions.

Rhythms and the pharmacology of lithium.

Lithium is the treatment of choice for bipolar affective disorder (manic-depression) and is useful in other recurrent affective and nonaffective illnesses. This review discusses lithium's actions on period, phase, amplitude and coupling of biological rhythms that may relate to its therapeutic effectiveness. Alternatively, lithium might interact with environmental light to influence circadian rhythms by an action on the retina. The mechanisms responsible for lithium's chronopharmacological actions are not known, but cellular cations, phosphoinositide or adenylate cyclase second messenger systems, hormones and neurotransmitters may all be involved.

Potassium affects actigraph-identified sleep.

The present study examines the effects of potassium supplementation on sleep quality and phase, as indirectly inferred from wrist actigraphy and sleep logs, in normal young males on a low-potassium diet. A randomized, double-blind, placebo-controlled, counterbalanced crossover design compared 1 wk of oral potassium chloride supplements (96 meq/day) to 1 wk of identical placebo capsules. Outcome measures were taken from sleep logs and wrist actigraphy. Sleep was indirectly inferred from wrist-actigraph data using a computer algorithm. Potassium supplementation significantly delayed sleep-log-identified Bedtime (p less than 0.001). Potassium reduced Sleeping Interval for both sleep-log (p less than 0.01) and wrist-actigraph (p less than 0.1) data. Potassium significantly increased actigraphic Sleep Efficiency (p less than 0.05) due to a reduction in actigraphic Wake after Sleep Onset (WASO) (p less than 0.05). No effect of potassium on actigraphic sleep phase was observed. Side effects were minimal and not significantly different between treatment conditions. The results may indicate an improvement in sleep consolidation with potassium supplementation. Further studies using standard polysomnography are required to define potassium's effects on human sleep.

Diurnal rhythm of core body temperature is phase advanced in a rodent model of depression.

We examined the diurnal rhythm of core body temperature in a strain of rats with an upregulated central muscarinic receptor system. The Flinders-Sensitive Line (FSL) was derived by selectively breeding rats for sensitivity to cholinergic agonists. When compared to control rats, the FSL rats showed a remarkably strong phase advance of the acrophase in body temperature during a standard light-dark schedule. Some patients with some types of depression also show phase advances in a number of circadian rhythms, including temperature. Our finding of a phase advance in a rodent model with a known upregulated muscarinic receptor system is compatible with both the phase advance and the muscarinic overdrive theories of depression. These findings also further validate the usefulness of the FSL rats in the study of depression.

Potassium advances circadian activity rhythms: interactions with lithium.

Lithium delays the circadian rhythm of wheel-running in Syrian hamsters at plasma concentrations (0.59-0.74 mM) that also cause toxic weight loss. A moderate elevation of dietary potassium (up to 6 times normal intake) prevented lithium-induced weight loss in a dose-dependent manner, but had no effect on the delay of activity rhythms caused by lithium. Without lithium, the highest level of potassium intake advanced activity rhythms by 1 h relative to an entraining light:dark cycle. These results suggest that lithium's toxic, but not behavioral, actions involve an interaction with potassium ion. Furthermore, dietary potassium supplementation might have independent uses as treatment for chronobiological disorders.

Acute ultrastructural and behavioral effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice.

Acute actions of MPTP on behavior and on neostriatal ultrastructure were examined in young C57 Black mice. Autonomic, motor, and toxic effects of MPTP exhibited dependence on dose (20-40 mg/kg) and time during the first 4 h after subcutaneous injection. The ultrastructure of the neostriatum was altered very quickly (2-24 h) after single injections of MPTP. Darkened glial processes were found within 2-8 h, followed by dark degeneration of synaptic boutons, especially those making small symmetric synapses. More rarely, swollen axons and postsynaptic degeneration were also observed.

Potassium reduces lithium toxicity: circadian rhythm actions are maintained.

We tested whether a high potassium diet alters lithium's effects on locomotor activity rhythms to the same extent as it prevents lithium toxicity. Rats fed a standard diet containing 0.47% potassium lost weight after subcutaneous implantation of an osmotic pump delivering 1.35 mg of lithium chloride per hour, and most died or became sick within three weeks after implantation. In contrast, all rats fed a diet containing 4.1% potassium gained weight at the same rate regardless of whether they had received lithium infusions or placebo. In a second experiment, lithium administration by either diet or osmotic pump delayed wheel running rhythms, showing that lithium's central nervous system action did not depend on potassium intake or method of lithium administration. Dietary potassium supplementation may provide a useful strategy for improving the therapeutic index of lithium treatment.

Do antidromic latency jumps indicate axonal branching in nigrostriatal and hypothalamo-neurohypophysial neurons?

Neurons in many brain regions exhibit discontinuous decreases in antidromic latency with small increases in stimulating current. We used an electrophysiological test requiring a single stimulating electrode to determine whether these 'latency jumps' are due to shifts in the site of spike initiation to the same or different axon branches. Latency jumps in response to stimulation of the striatal terminal fields of substantia nigra, pars compacta neurons represent spike initiation on different branches while those seen in paraventricular neurons with pituitary stalk stimulation usually reflect a change in site on a single branch.