Circadian rhythms in mammalian neurotransmitter receptors.

At the present time, the following summary statements can be made as to 24-hour changes in receptor binding. In all receptors studied in homogenates from whole rat forebrain (alpha 1, alpha 2, beta-adrenergic, muscarinic cholinergic, dopaminergic, 5HT-1, 5HT-2, adenosine, opiate, benzodiazepine, GABA, imipramine), significant variations over 24 hours have been documented. The receptor rhythms measured change in wave form, amplitude, and phase throughout the year, even though the animals have been kept on a defined and constant LD cycle. Whether these rhythms are truly seasonal requires further investigation. The rhythms are circadian: i.e. they persist in the absence of time cues, and the unimodal rhythms do not persist after lesion of the putative circadian pacemaker in the suprachiasmatic nuclei. The rhythms can be uni- or bimodal, and each brain region shows a particular pattern. The pattern can be different for the same ligand in different nuclei of a given brain region (e.g. hypothalamus). Nearly all studies of receptor rhythms have been carried out in rats; the results vary according to strain and even within the same strain from different breeding lines. Receptor rhythm characteristics are modified by age: e.g. the amplitude, phase, as well as the 24-hour mean of binding to a given ligand in a defined brain region. The changes in number of binding sites over 24 hours can be correlated with amine turnover, second messenger, or function of that brain region; however these relationships, although consistent within a region, do not hold for all regions. If gradual changes in CNS neurotransmitter receptor function are considered important in the pathogenesis of schizophrenia and affective disorders and the mode of action of psychopharmacological agents, then consideration of the short term rapid change over 24 hours is equally necessary. Chronic treatment with a number of psychoactive drugs known to induce up- or down-regulation of receptor number, also induces marked changes in circadian rhythm parameters of wave form, amplitude, phase and 24-hour mean. This is of methodological importance for single time-point studies, since the interpretation of the results will depend on time of day. Preliminary evidence supports the assumption that the significant variation in receptor binding throughout the day may underlie the well-known circadian rhythms of susceptibility to many CNS drugs. New findings of circadian rhythms in receptors on blood cells indicate the relevance of these changes also in human physiology.