Alcohol Consumption and the Body’s Biological Clock Rainer Spanagel, Alan M. Rosenwasser, Gunter Schumann, and Dipak K. Sarkar This review summarizes new findings on the bidirectional interactions between alcohol and the clock genes, underlying the generation of circadian rhythmicity. At the behavioral level, both adult and perinatal ethanol treatments alter the free-running period and light response of the circadian clock in rodents; genetic ethanol preference in alcohol-preferring rat lines is also associated with alterations in circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, circadian functions of -endorphin– containing neurons that participate in the control of alcohol reinforcement become disturbed after chronic alcohol intake. In turn, per2 gene activity regulates alcohol intake through its effects on the glutamatergic system through glutamate reuptake mechanisms and thereby may affect a variety of physiological processes that are governed by our internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic alcohol intake. Thus, chronic alcohol intake alters the expression of per genes, and, as a consequence, a variety of neurochemical and neuroendocrine functions become disturbed. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control, and, as a final conse- quence, addictive behavior might be triggered or sustained by this cascade. Key Words: Alcohol, Opioid Peptide Rhythm, NK Cell Rhythm, Circadian Activity Rhythm, Period Genes, Genetic Variation of Per 2 Gene. INTRODUCTION C IRCADIAN CLOCKS REPRESENT an adaptation to daily alterations in the environment, and they enable cells (and organisms) to anticipate and prepare for these changes. The synchronization of an organism with both its external and internal environments is critical for its health and well-being. Recently, it has been shown that disruption of normal circadian rhythmicity is associated with various pathologies, including cancer, sleep disorders and depres- sion. Alcohol consumption and abuse interferes with trans- mission processes in the central nervous system, affects the activity of a number of biological systems, and leads to serious health problems. During drinking and withdrawal, an alcoholic often has problems falling asleep and a de- crease in total sleep time as well as disruptions in other daily biological rhythms. Many alcoholics also have depres- sion. To identify the relationship between alcohol-induced alteration of the body’s biological clocks and alcohol drinking-related pathologies, this review evaluates the ef- fects of prenatal and adult alcohol exposure on the core molecular components of the circadian clock mechanism. It also examines the alcohol-induced changes in endogenous rhythmic output signals from the suprachiasmatic nucleus (SCN) and the regulation of neuroendocrine and immune functions, circadian behavior, and alcohol drinking. CIRCADIAN RHYTHMS AND CELLULAR CLOCKS Circadian rhythms (from the Latin circa dies, meaning ap- proximately one day) describe biological phenomena that oscillate within a 24-hour cycle. These rhythms provide a temporal framework necessary for adequate homeostasis. By anticipating both environmental and internal changes, cells (and organisms) can efficiently program their physio- logical tasks and optimize survival. At the cellular level, circadian rhythms are originated by genetic elements (clock genes) organized in autoregulatory transcription- translation feedback loops that form the cellular core os- cillator. This oscillating machinery controls expression of the so-called clock-controlled genes and ultimately gener- ates circadian rhythms in physiology and behavior. The current mammalian clockwork model involves three Per genes (Per1, Per2, and Per3), two cryptochrome genes (Cry1 From the Department of Psychopharmacology (RS) and the Department of Psychiatry and Psychotherapy and Department of Addictive Behaviour and Addiction Medicine (GS), Central Institute of Mental Health, Mannheim, Germany; the Department of Psychology, University of Maine, Orono, ME (AMR); and the Endocrinology Program, Department of Animal Sciences (DKS), Rutgers, The State University of New Jersey, New Brunswick, NJ. Received for publication March 21, 2005; accepted June 6, 2005. Supported by National Institutes of Health grant AA R21 AA013893 (AMR); National Institutes of Health grants R01 AA12642 and AA0875 (DKS); and DFG, BMBF, and EU (Deutsche Forschungsgemeinschaft, Bun- deministerium fu ¨r Bildung und Forschung, and European Union) grants (RS, GS). Reprint requests: Dipak K. Sarkar, Rutgers, The State University of New Jersey, Endocrinology Program and Biomedical Division of the Center of Alcohol Studies, 84 Lipman Drive, New Brunswick, NJ 08901-8525; Fax: 732-932-4134; E-mail: sarkar@aesop.rutgers.edu Copyright © 2005 by the Research Society on Alcoholism. DOI: 10.1097/01.alc.0000175074.70807.fd 0145-6008/05/2908-1550$03.00/0 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 29, No. 8 August 2005 1550 Alcohol Clin Exp Res, Vol 29, No 8, 2005: pp 1550–1557