Marian S. Kafka

Circadian and seasonal rhythms in α- and β-adrenergic receptors in the rat brain

Summary Circadian rhythms in the numbers of α- and β-adrenergic receptors exist in the rat forebrain and hypothalamus. These rhythms are endogenous as they persist in the absence of time cues. The α- and β-receptor rhythms differ both in their shapes (wave form) and in the timing (phase) of the peak numbers. In the course of the year, there are shifts in the timing of both α- and β-receptor peaks. Circadian rhythms in α- and β-adrenergic receptors may modulate synaptic events in brain transmission, synchronizing both the synaptic events and the behaviors related to them to the photoperiod of the natural environment.

Circadian rhythm in rat brain opiate receptor.

To investigate diurnal variations in opiate receptor binding, the amount of specifically bound [3H]naloxone was measured at 4-h intervals across a 24-h period in the forebrains of rats that had been housed under a controlled light--dark cycle (lights on from 07.00 to 19.00 h) for 3 weeks. A significant rhythm with a peak at 22.00 h was found, the amplitude was 46--78%. In the absence of time cues, this circadian rhythm persisted with a peak at 02.00--06.00 h and an amplitude of 88%. Scatchard analysis indicated that the differences in binding throughout the day were due not to changes in affinity, but to changes in the number of binding sites.

Dopamine receptor binding in rat striatum: ultradian rhythm and its modification by chronic imipramine.

To investigate diurnal variations in dopamine receptor binding, the amount of specifically bound 3H-spiroperidol was measured at 4-h intervals over a 24-h period in the striatum of rats which had been housed under a controlled 12-h light-dark cycle (lights on 7 a.m.). A highly significant ultradian rhythm with peaks at 2 a.m. and 2 p.m. was found with an amplitude of about 75%. Chronic imipramine modified the rhythm such that the two peaks occurred 4 h later and amplitude as well as 24-h mean of binding decreased. Scatchard analysis at times of least and greatest binding indicated that the differences in binding were due not to changes in the affinity, but in the number of binding sites. These results are interpreted with regard to the mode of action of psychoactive drugs and to postulated changes of receptor sensitivity in neurological and psychiatric disorders.

Alpha-adrenergic receptors on human platelets.

Abstract [3H] dihydroergocyrptine, an α-adrenergic antagonist, binds specifically to sites on human platelet membranes. Prostaglandin E1 (PGE1) stimulates the production of cyclic AMP (cAMP) in human platelets. Alpha-adrenergic agonists, 1-epinephrine and 1-norepinephrine, and antagonists, phentolamine, phenoxybenzamine, and dihydroergocyrptine inhibit the binding of [3H] dihydroergocryptine. The α-adrenergic agonists inhibit PGE1-stimulated cAMP production and the α-adrenergic antagonists phentolamine and dihydroergocryptine reverse this inhibition. The β-adrenergic agonist 1-isoproterenol and the β-adrenergic antagonists d1-propranolol and 1-alprenolol do not significantly alter binding or PGE1-stimulated cAMP production. Clonidine, dopamine, and serotonin inhibit binding, but clonidine and dopamine are weak inhibitors of PGE1-stimulated cAMP production, and serotonin is without effect. Tyramine, an amine without direct adrenergic activity fails to inhibit binding. Alpha-adrenergic agonists decrease the apparent affinity of a PGE1-receptor activating cAMP production. The inhibition of PGE1-stimulated cAMP production is a physiological measure of α-adrenergic agonist binding to the α-receptor.

Effect of Lithium on Circadian Neurotransmitter Receptor Rhythms

Chronic lithium administration significantly changes characteristics of the circadian rhythms in rat brain alpha- and beta-adrenergic, muscarinic acetylcholine, dopamine, opiate, and benzodiazepine receptors. There are changes in the timing of the peak number of receptors (phase-position), in the amplitude of the rhythms, and in the 24-hour mean number of receptors. The circadian rhythm in the number of forebrain alpha- and beta-adrenergic and benzodiazepine receptors is abolished. The phase-position of forebrain acetylcholine and opiate receptors and striatal benzodiazepine receptors is delayed. As the rhythms of the dopamine receptor number and alpha-melanocyte-stimulating hormone secretion become bimodal, their phase positions are difficult to evaluate. The mean number of forebrain alpha- and beta-adrenergic, acetylcholine, opiate, and striatal benzodiazepine receptors increases. The mean number of forebrain benzodiazepine and striatal dopamine receptors and the mean concentration of alpha-melanocyte-stimulating hormone decreases. Lithium has profound effects on each of the receptor rhythms measured. Slowing and altering circadian rhythms may contribute to the therapeutic effects of chronic lithium treatment in affective disorders.

Circadian rhythms in rat brain alpha- and beta-adrenergic receptors are modified by chronic imipramine

Abstract Circadian rhythms of α- and s-adrenergic receptor number, with different wave forms, as well as differences in timing of maximal binding, are present in rat brain. Chronic treatment with the tricyclic antidepressant drug imipramine modifies these rhythms: peak binding of both receptors occurs 4–12 hours later than in controls, the 24-hour mean is decreased by 15–30%, and the amplitude is increased by 20–30%. Delaying of the phase position of neurotransmitter receptor rhythms by a tricyclic antidepressant may be relevant to its clinical mode of action, since depressive patients appear to have abnormally phase-advanced circadian rhythms.

Sleep deprivation: Effects on circadian rhythms of rat brain neurotransmitter receptors

Specific binding of ligand to rat forebrain alpha- and beta-adrenergic, muscarinic cholinergic, opiate, benzodiazepine, and striatal dopamine receptors was measured at 4-hour intervals during the last 13 hours of a 24-hour sleep deprivation period, and during the first 11 hours of the recovery sleep period. In non-sleep-deprived controls a 24-hour rhythm in binding was evident. The minor differences between the sleep deprivation group and the control group consisted mainly in a reduced amplitude of the 24-hour rhythm under the sleep deprivation schedule. The results indicate that neither the 24-hour forced locomotion nor the subsequent prominent sleep rebound is accompanied by marked changes in the number of neurotransmitter receptors and their circadian rhythms.

Ionophores X537A and A23187. Effects on the permeability of lipid bimolecular membranes to dopamine and calcium

X537A carries dopamine across lipid bimolecular membranes. The rate of transport increases linearly with the X537A concentration and is independent of an electric field across the membrane. The evidence suggests that the permeating species is a neutral 1:1 complex between dopamine and X537A. A23187 does not transport dopamine. The permeability of the membrane to calcium increases as the square of the X537A concentration; the transport of calcium is also increased by A23187. With both ionophores, calcium is probably transported as an uncharged complex. Neither desmethylimipramine nor cocaine alters the transport of dopamine with X537A.

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

Abstract 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.

Clorgycline delays the phase-position of circadian neurotransmitter receptor rhythms

The number of alpha- and beta-adrenergic, muscarinic cholinergic, opiate, and benzodiazepine receptors in rat forebrain, and dopamine and benzodiazepine receptors in striatum, change throughout the day. The diurnal rhythms of these receptors were altered by treatment with the monoamine-oxidase inhibitor clorgyline: following treatment some or all rhythm characteristics of wave form, amplitude, 24-h mean, and phase, were affected. One common effect of treatment was a delay in phase-position of binding to alpha- and beta-adrenergic, opiate and benzodiazepine receptors. Additionally, the nocturnal elevation in pineal melatonin which normally returns to baseline at light onset, persisted 3 h into the light period after clorgyline administration. These biochemical observations extend behavioural findings that clorgyline can delay the phase-position of rodent nocturnal activity onset, and does so by slowing the central circadian pacemaker.