Harry Klemfuss

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 lithiums 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 lithiums chronopharmacological actions are not known, but cellular cations, phosphoinositide or adenylate cyclase second messenger systems, hormones and neurotransmitters may all be involved.

Seeking tau: A comparison of six methods

Abstract Six methods for measuring the period of circadian rhythms (tau) have been compared using real and artificial data. The modified periodogram technique estimates tau by fitting a data‐specific form estimate to time series data with a period that minimizes the variance of data around the form estimate. The onset periodogram converts raw data to new values that reflect rapid increases of data magnitude, then fits a form estimate to these new values. Iterative cosinor determines the period of the single cosine curve that best describes the data. The iterative harmonic derives a form estimate, consisting of a cosine function plus a series of true harmonics, which most closely describes the data. Other methods measure the slope of the line fitting each days acrophase (regressive cosinor) or subjectively selected phase markers (eyefitting). Our analyses indicate that the estimated value of tau can vary depending on the method used. Periodogram and iterative harmonic methods provided the most consistentl...

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.

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.

Diurnal rhythm of core body temperature is phase advanced ina 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.

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.

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.

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.

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.

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.