Alcohol, antidepressants, and circadian rhythms. Human and animal models

Abstract

Alcohol consumption (both acute and chronic) and alcohol withdrawal have a variety of chronobiological effects in humans and other animals. These effects are widespread, altering the circadian rhythms of numerous physiological, endocrine, and behavioral functions. Thus, some of alcohol's negative health consequences may be related to a disruption of normal physiological timing. Most studies of alcohol's chronobiological effects have been conducted under natural conditions in which environmental stimuli, such as regular cycles of light and darkness, act to coordinate circadian rhythms with the environment and with each other. However, such studies cannot distinguish between effects occurring directly on the circadian pacemaker and those occurring "downstream" from the pacemaker on the physiological control systems. Studies using animals have enabled researchers to begin to examine the effects of alcohol on circadian rhythms under so-called free-running conditions in experimental isolation from potential environmental synchronizers. These studies have provided preliminary evidence that alcohol's chronobiological effects are indeed the result of direct influences on the circadian pacemaker itself. Furthermore, the effects of alcohol on animal circadian rhythms appear similar to the effects seen during administration of antidepressant drugs. Taken together with evidence that the chronobiological effects of alcohol withdrawal in human alcoholics are reminiscent of those described in depressed patients, these observations suggest that alcohol may produce antidepressantlike effects on the circadian pacemaker. One theory suggests that the effects of alcohol on the circadian pacemaker are mediated in part by alterations in serotonin, an important chemical involved in cellular communication within the circadian system. However, other neurochemical systems also are likely to be involved.

Figure 1

Panels show the circadian water-intake rhythms in four rats before, during, and after free-choice access to both a 10-percent alcohol solution and water. Time of day (a 48-hour span) is indicated along the horizontal axis, and successive days of the experiment are represented from top to bottom along the vertical axis (as shown by the breaks in the lines). The period of time the rats had access to alcohol is indicated by the label along the vertical axis. Dark areas in the charts show the times when the rats had the highest drinking activity. The animals were maintained in constant darkness to allow for the expression of free-running circadian rhythms—that is, in experimental isolation from any potential environmental synchronizer. Note that all four rats showed shortening of a free-running circadian period during the period of alcohol access as indicated by the relative decrease in rightward drift and/or increase in leftward drift of the times of highest activity during the alcohol access.

Figure 2

Schematic representation of the neural circuitry underlying the control of circadian rhythms. The circadian pacemaker resides just above the base of the brain in a distinct region of the hypothalamus called the suprachiasmatic nucleus (SCN). Cells of the SCN mutually interact and contain a number of chemicals important in cellular communication, including the neurotransmitter gamma-aminobutyric acid (GABA) and one or more neuropeptides (NP). The SCN receives incoming information from three primary sources: (1) the retina of the eye, which sends signals about environmental lighting to the SCN along a direct pathway that uses glutamate (GLU) as its primary transmitter, along with at least two different NPs; (2) the intergeniculate leaflet (IGL) of the visual thalamus, which receives retinal signals and sends signals to the SCN via a pathway that employs both GABA and neuropeptide Y (NPY) as transmitters; and (3) the raphe cell groups of the midbrain, which use the monoamine serotonin (5 HT) as the primary neurotransmitter and also send signals to the IGL. As indicated, the serotonin pathways to the SCN (and IGL) are most likely involved in mediating, at least in part, the effects of alcohol on the circadian pacemaker in the SCN. However, alcohol also is known to interact with GLU, GABA, and NP signaling elsewhere in the brain. Thus, these systems also may be important for the circadian effects of alcohol.