Alcohol’s Interactions With Circadian Rhythms

A Focus on Body Temperature

Jill A. Wasielewski, Ph.D., and Frank A. Holloway, Ph.D.

The complex interaction between alcohol and the body’s circadian rhythm has become a rapidly expanding area in chronopharmacology. This area has key implications for the field of alcohol research, because understanding alcohol’s effects on the body’s internal clock will aid scientists in designing medications and behavioral interventions for treating alcohol abuse and dependence. A number of studies provide evidence that alcohol sensitivity and preference vary with circadian timing. However, only a few studies support alcohol’s ability to influence the circadian phase directly. This review focuses on studies examining how alcohol and the body’s circadian rhythm interact, using body temperature as an index of circadian rhythm function. Though the research is limited, findings indicate that alcohol sensitivity and preference for drinking do indeed appear to vary with circadian timing and that alcohol may act directly on the central pacemaker to alter circadian functioning. KEY WORDS: circadian rhythm; body temperature; thermoregulation; hyperthermia; hypothermia; physiological AODE (effects of alcohol or other drug [AOD] use, abuse, and dependence); pharmacokinetics; time of day; AOD sensitivity; AOD preference

he complex interaction between studies have likened an alcohol hang- alcohol and the body’s internal over to jet-lag-like circadian disruption JILL A. WASIELEWSKI, PH.D., is an Tcircadian rhythm (CR) or clock is (i.e., phase shifts) of the body’s normal associate study director at MPI Research, a rapidly expanding area of research. The rhythm (Gauvin et al. 1997b). This inter­ Mattawan, Michigan. importance of the interaction between nal jet lag is known to promote alcohol drugs, including alcohol, and CR is ini­ consumption directly by causing these FRANK A. HOLLOWAY, PH.D., is the tially evident in the temporal, or time- phase shifts in the body’s internal clock director of the biological psychology related, restraints on experimentation. (Gauvin et al. 1997a) and could poten­ program in the Department of Psychiatry Pharmacological studies usually are tially promote drinking indirectly through and Behavioral Sciences, University of performed at the same time each day to a disruption of CR caused by alcohol Oklahoma Health Sciences Center, control for the profound effects that CR consumption (Holloway et al. 1993). Oklahoma City, Oklahoma. has over the mammalian system. Further- This review focuses on several vari­ more, this concept often is carried over ants of the alcohol and CR interaction This work was supported by the following into clinical administration, because using body temperature (Tb) as an index grants to Dr. Frank A. Holloway: the many physicians recommend taking of CR output. Tb varies throughout the National Institute on Alcohol Abuse certain drugs at a specific time of day. day in a relatively stable and predictable and Alcoholism (NIAAA) research grant When the circadian effect is applied rhythm. Therefore, examining changes AA–08333, the National Institutes on specifically to alcohol, however, other in the body’s temperature rhythm, Drug Abuse training grant DA–07248, implications arise. For instance, recent which, in people, peaks during late and the NIAAA training grant AA–07222.

94 Alcohol Research & Health Alcohol, Circadian Rhythms, and Body Temperature

afternoon and reaches its lowest point Basic Chronopharmacology and elimination rates of a drug often are during early morning, offers scientists a of Alcohol: Chronokinetics, influenced by the time of day at which way of assessing the circadian system. Chronesthesy, and it enters the system, thereby affecting Body temperature has a unique and Chronergy the relative breakdown of the drug. reciprocal relationship with alcohol and Furthermore, the combination of these the mammalian CR in that a change in This section of the article compiles a processes may differentially alter how one of these components often will variety of CR-related definitions and the drug is used by the body (i.e., the explanations adapted from reviews by bioavailability) depending on the time lead to changes in another. Furthermore, Reinberg (1992) and Bruguerolle (1994). of administration. However, the bioavail­ alcohol and CR have the ability to inter- This short synopsis is intended to pro- ability of alcohol may differ for various act with temperature at both the cellular vide a foundation for discussion of the target organs. Therefore, a person may and behavioral levels. It is important to various topics related to this field of study. be more likely to display the motor note that both CR and alcohol simulta­ The chronopharmacology of alcohol effects of alcohol when it is ingested at neously impose a myriad of behavioral can be divided into two main areas (see noon but may display the greatest ther­ and physiological effects on Tb. With figure 1). The first area focuses on how mal response during the early morning this in mind, temperature serves as a alcohol’s effects (i.e., its efficacy) are hours (Brick et al. 1984). fitting, yet dynamic, variable on which modified according to the time of day to concentrate. at which the alcohol is administered Chronesthesy. The second component This article begins with a summary that is, how alcohol interacts with the of efficacy and time of day is chrones­ of basic chronopharmacology as it body’s physiological components at a thesy. Chronesthesy explains the cyclic relates to alcohol, followed by an analy­ particular time of day. The second area “changes in the susceptibility or the of focus, chronergy, takes a broader sensitivity of a target system” (Reinberg sis of the relationship between alcohol approach, beyond simple time-of-day 1992, p. 57). In many ways, chronesthesy and body temperature. The physiologi­ effects, to determine the influence of a is similar to the field of pharmacody­ cal and behavioral effects of alcohol as a drug on the individual as a whole. These namics, in that it relates to the physio­ function of time of day also are explored, two areas of focus address the complex logical and biochemical changes asso­ followed by a discussion of how alcohol functional interactions between the ciated with a drug depending on the time exerts an influence over the CR of Tb. organism’s CR and how it is influenced of administration. Overall, the field of These distinct, yet related, objectives by or influences the body’s behavioral chronesthesy asserts that the performance reflect the need to better integrate the response to alcohol. of a drug often changes as a result of alcohol and CR fields. variations that occur on a cellular level. In addition to the association between Efficacy and Time of Day For example, alterations in key proteins increased alcohol consumption and on the cell membrane (i.e., receptors CR alteration, alcohol-induced CR Chronopharmacokinetics. Efficacy and on the surface of brain cells) or changes disruption could potentially diminish time of day can be classified into chrono­ in the way the cell membrane responds pharmacokinetics and chronesthesy. to chemicals involved in cellular com­ an individual’s ability to perform at The field of chronopharmacokinetics, munication (that is, the degree of optimum level. At least three interact­ similar to pharmacokinetics, investigates membrane permeability) occur on a ing rhythmic effects exist: the CRs of characteristic properties of the (1) absorp­ relatively predictable time scale. (1) performance efficiency, (2) alcohol tion, (2) distribution, (3) metabolism, consumption, and (3) alcohol’s effects and (4) elimination of a particular sub- Chronergy on performance efficiency. stance related to a specific time course. Depending on the level of responsi­ Absorption, or the rate and extent The second division of chronopharma­ bility of the person (e.g., an air traffic to which a drug (such as alcohol) dis­ cology is that of chronergy. This branch controller or a truck driver), such perses to the bloodstream, can be deter- of study takes into account not only the circadian effects could pose a serious mined by a number of factors (e.g., pH influence that time of day may have on danger to both the affected person levels and the rate of blood flow), all of a drug’s effect, but also the effect that and other people. Therefore, a clearer which may play a part in chronophar­ the drug itself may have on the organ- understanding of how the circadian macology. These factors could be impli­ ism’s biological rhythm. In other words, cated in the variation observed in tem­ chronergy synthesizes information system impacts alcohol consumption poral drug effects. The distribution of obtained from both chronopharmacoki­ and vice versa will most likely provide alcohol within the body also can vary netics and chronesthesy to interpret the a foundation for pharmacological and according to time. For instance, the influence of a drug on the individual as behavioral advances in the treatment degree to which the drug binds to mole­ a whole. This area is far less represented of alcohol abuse and addiction as well cules in the bloodstream (i.e., plasma in the existing literature, but has gained as assist in solving problems related proteins) or to other tissues in the body considerable attention in recent years to public safety. is temporally orientated. Metabolism and is quickly developing into one of

Vol. 25, No. 2, 2001 95 the more popular branches of chrono­ which, in turn, caused a change in how outside temperature is cooler (Kalant pharmacology. easily molecules enter and exit the cell and Le 1991; Alkana et al. 1996). How- (that is, a change in fluidity). Most ever, when mice are given the opportu­ studies now suggest, however, that nity to choose their Ta, they are known Alcohol and Temperature alcohol produces a dysregulation of the to seek out colder temperatures after thermoregulatory system. This thermo­ alcohol is administered (Huttunen dysregulation raises the animal’s tem­ 1990). Similarly, research shows that by perature to higher than normal (i.e., concurrently monitoring the selected Alcohol-Induced Tb Changes causes hyperthermia) when the sur­ Ta and Tb, scientists can observe decreases Numerous reports in the past have rounding or ambient temperature (Ta) in both of these measures after an ani­ asserted that alcohol lowers Tb. Initially is warm and, conversely, decreases the mal receives moderate-to-large doses of this response was thought to be caused animal’s temperature to lower than nor­ alcohol (Crawshaw et al. 1998). Together by a disruption of the cell membranes, mal (i.e., causes hypothermia) when the these findings indicate that in addition

Chronopharmacology

Efficacy and Chronergy time of day

Chronesthesy How the daily rhythm Chronopharmaco• (chronopharmaco• changes alcohol's How alcohol affects the kinetics dynamics on a effects on circadian rhythm target system) the individual

Physiological Changes in Changes to Absorption changes due to sensitivity to preference to Acute effects Chronic effects time of day alcohol alcohol

Period Entrainment Biochemical Distribution changes due to time of day Amplitude Disruption

Phase shifts

Metabolism

Elimination

Figure 1 A representation of the field of chronopharmacology as it relates to alcohol.

96 Alcohol Research & Health Alcohol, Circadian Rhythms, and Body Temperature

to impairing thermoregulation, alcohol such as Tb. Rather, this nucleus works Collins (1987) hypothesized that after may alter the set point for Tb (Kalant at a higher level to control the overall repeated alcohol administration, the and Le 1991; Crawshaw et al. 1992). generation of the CR, which constantly behavioral tolerance observed might Currently, researchers believe that underlies these important body func­ actually be a development of tolerance alcohol exerts its effects both on the brain tions (Refinetti 1995a, 1995b). to the depressant effects of hypothermia, (i.e., centrally) and on the peripheral which, in turn, increases the metabolism body (i.e., peripherally) (Huttunen of alcohol. Studies such as these reiter­ 1990). Centrally, alcohol-induced ther­ ate the important influence that alco­ moregulation, or dysregulation, is thought hol has on thermoregulation and lead to occur in a part of the brain responsi­ Recent studies have to the idea that alcohol-induced ble for processing incoming sensory found that behavioral hypothermia is a tailored, or adaptive, signals (i.e., the anterior hypothalamic response most likely found within a preoptic area, or AH/POA) (Kalant and and brain sensitivity variety of organisms (Crawshaw et al. Le 1991; Alkana et al. 1996). Almost 1992; Alkana et al. 1996). all nerve-cell-communication chemicals to alcohol are are thought to be involved in alcohol- indirectly dependent induced hypothermia (Kalant and Le Physiological and 1991; Crawshaw et al. 1992). However, on the environmental Behavioral Effects the AH/POA shows a particularly temperature. of Alcohol as a increased release of one chemical (i.e., Function of Time of Day norepinephrine) with the administra­ tion of alcohol, which, in turn, appears to cause a decrease in Tb (Huttunen 1990). Changes in Sensitivity to Alcohol This same release of norepinephrine is Temperature-Induced observed peripherally and may result Changes in Alcohol Sensitivity to alcohol also is altered from signals (i.e., afferent pathways) Elimination and according to the time of day that the to the portion of the brain (i.e., the Intoxication alcohol is consumed. In rats, sensitivity hypothalamus) that induces produc­ (as measured by hypothermia) is com­ monly thought to increase at nighttime tion of this hormone. Tb has been reported as a major factor Scientists also have reported that in the rate in which alcohol is broken (i.e., the dark phase) compared with alcohol-induced hypothermia is corre­ down and eliminated from the body daytime (i.e., the light phase) (Crawshaw lated with a decreased release of another (Romm and Collins 1987). Specifically, et al. 1992; Brick et al. 1984). The key chemical involved in nerve-cell com­ alcohol-induced hypothermia decreases absorption, distribution, and metabolism munication (i.e., serotonin) (Huttunen the rate of chemical reactions, thereby of alcohol were reported to be unal­ 1990; Alkana et al. 1996). Conversely, slowing the rate of elimination. Through tered in these studies, implying that the other studies have associated drops in various metabolic mechanisms, Tb has differences which occur result from cir­ Tb with higher serotonin levels in the reportedly affected the rate of alcohol cadian changes in brain sensitivity and brain (Crawshaw et al. 1992). Admittedly, elimination by up to 50 to 60 percent not from changes in the peripheral the neurochemical relationship between (Romm and Collins 1987). body (Alkana et al. 1996). alcohol and Tb needs additional clarifi­ As previously mentioned, alcohol However, other, more straightforward cation (Kalant and Le 1991; Crawshaw has the ability to induce hypothermia explanations may account for these cir­ et al. 1992). Nonetheless, these findings or hyperthermia, depending on the cadian effects. For instance, the sedative suggest that alcohol produces direct temperature in the environment. effects of alcohol may cause a decrease alterations on specific nerve cells in the Therefore, to include alcohol in the in the normally high levels of activity brain that produce Tb changes in addi­ equation, one must consider the influ­ seen in these animals during nighttime tion to the widespread cellular effects it ence of Tb on the elimination of alcohol (which therefore reduces Tb), or a “base­ produces throughout the central ner­ (see figure 2). Recent studies have found ment” effect of Tb may occur, whereby vous system. that behavioral and brain sensitivity to the already low daytime Tb cannot be Another portion of the hypothalamus, alcohol are indirectly dependent on the reduced any further. Furthermore, the the suprachiasmatic nucleus (SCN), is environmental temperature (Alkana et review by Alkana and colleagues (1996) the main timekeeping center of the al. 1996). Specifically, Alkana’s review concluded that when baseline Tbs were body and is responsible for the develop­ discusses a number of studies that taken into account, the major hypother­ ment, maintenance, and coordination describe how increases in external tem­ mic and hyperthermic responses actually of bodily CRs. Significant for this dis­ perature result in hypersensitivity of were observed during the light-to-dark cussion, the SCN does not assert a direct rodents to alcohol, as indicated by vari­ and dark-to-light transition times, role in maintaining normal body func­ ous behavioral measures, including respectively. All of these factorscirca­ tion (that is, maintaining homeostasis), higher levels of mortality. Romm and dian, peripheral, direct, and indirect

Vol. 25, No. 2, 2001 97 need to be assessed individually to the greatest increase occurring on the possibly as a means of self-medicating determine the role that time of day second day. This animal model resembles the desynchronosis or rhythm disruption. plays in sensitivity to alcohol’s effects. the various symptoms of jet lag seen in humans, in that it may take 2 to 3 days before the maximal effects of phase shift­ Influence of Alcohol Alcohol Preference as a Function on the CR of Body of Time of Day ing are displayed. Conversely, a phase delay of the same magnitude produced Temperature As nocturnal animals, many rodents only minimal changes in drinking engage in a greater degree of activity behavior, with increases occurring only Investigators have often stated that in during the nighttime than in the day- on the day of the shift (Gauvin et al. most situations alcohol produces time. Studies have reported that rats 1997a). These findings appear to con­ “rebound” hyperthermia, a response by and other rodents prefer alcohol to a tradict Geller and Purdy’s findings, in the body to counter the hypothermia greater degree when in a dark environ­ which a greater degree of drinking initially produced by alcohol. This ment, in that these animals drink more occurred after increasing the light por­ interpretation, however, was challenged alcohol during the dark period of an tion of the cycle on the first day (i.e., by Gallaher and Egner (1987), who alternating light-dark (i.e., L:D) sched­ phase advance). proposed that in certain situations the ule. Likewise, animals placed in con­ Repeated daily shifts in the amount hyperthermia observed may not be a stant dark (i.e., D:D) environments of light and dark (i.e., photoperiod) homeostatic rebound effect, but rather will drink significantly more than ani­ during a 2-month period (similar to “an abolition of the normal circadian mals placed on L:D schedules (Geller long-term rotating shift work in humans) temperature rhythm” (p. 38). Supporting and Purdy 1979). It seems likely, then, also produced significant increases in this proposal, Gauvin and colleagues that a synergistic effect of CR and typi­ alcohol intake (Gauvin et al. 1997a). (1993) found that the “hyperthermia” cal rodent behavior occurs. Gauvin and colleagues have suggested exhibited by animals after a bout of The release of the hormone mela­ that these photoperiod shifts serve as alcohol-induced hypothermia did not tonin from the pineal gland appears to stressors, which may result in alcohol use, exceed normal circadian fluctuations. play a role in the development of such “dark preferences.” A few observations support this hypothesis. First, animals kept in dark environments reportedly Alcohol have larger pineal glands, the gland responsible for melatonin production. Second, daily melatonin administration Ambient Thermoregulation produces a preference for alcohol in temperature (T ) animals that previously preferred water. a Third, artificially increased levels of serotonin, which is depleted at night because of its conversion to melatonin, Sensitivity Body Alcohol decrease an individual’s preference for and temperature (T ) elimination alcohol. However, the findings sur­ tolerance b rounding melatonin and serotonin are largely circumstantial and require fur­ ther investigation to confirm such a relationship (Geller and Purdy 1979). Behavioral SCN Shifts in an organism’s normal CR effects also have been found to induce alcohol consumption (Gauvin et al. 1997a).

Those shifts include phase delays in Figure 2 Body temperature (Tb) can be significantly influenced by environmental which the peak of a body rhythm (such or ambient temperature (Ta) in the presence of alcohol. Alcohol-induced as a peak in temperature) occurs at, disruption of normal thermoregulatory mechanisms results in hyper­ or shifts, to a point later in the cycle. thermia or hypothermia in response to higher or lower Ta, respectively. Likewise, a phase advance causes a shift A lower Tb appears to be protective of the system, because hypother­ in the cycle to an earlier time. mia causes the body to be less sensitive to the central depressant The study by Gauvin and colleagues effects of alcohol. Initial sensitivity or tolerance to alcohol also may (1997a) found that a single large phase play a part in the overall behavioral effects. The circadian rhythm influences Tb or behavior (e.g., amount of activity) via an area of the advance produced significant increases brain involved in regulating bodily rhythms (i.e., the suprachiasmatic in the amount of alcohol consumed by nucleus [SCN]). rats for 3 days following the shift, with

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Therefore, alcohol appears to shift the and colleagues requires further support, erence vary with circadian timing. circadian Tb cycle, but not the absolute they suggested that their findings endorse However, studies supporting alcohol’s magnitude of Tb. In other words, the the Gallaher and Egner theory pre­ ability to influence the circadian phase delayed hyperthermic rebound effect is sented previously, which interprets this are limited. not a physiological response at all, but change in temperature as a phase shift Our laboratory is continuing to rather an effect that results from the in the Tb rhythm rather than as a examine the interaction of alcohol and absence of the normal low in the circadian homeostatic response to the alcohol- CRs, including the attenuation of the rhythm of Tb (Holloway et al. 1993). induced hypothermia. circadian phase shifts engendered by The involvement of SCN in Tb reg­ Third, several acrophase (i.e., the alcohol. In addition to the acute alcohol ulation was touched on in an earlier time it takes to reach the peak Tb of exposure studies, we are investigating section of this article. Research has sug­ the rhythm from an arbitrary reference alcohol’s ability to serve as an entrainer gested that although this section of the point, usually midnight) changes were of the circadian Tb rhythm. This find­ brain does not respond directly to indi­ uncovered in response to alcohol admin­ ing would support a direct relationship vidual homeostatic fluctuations of Tb, istration. The study conducted by with the circadian system. Elucidating it does act as an overall regulator, ensur­ Baird and colleagues (1998) found that this relationship will provide the basis ing that the organism can adapt to phase delays were produced when alcohol for developing techniques (e.g., bright fluctuations in the environmental cycle. was administered at 11:00 p.m. Those light therapy) and medications (e.g., This interpretation does not necessarily delays were believed to result from the melatonin) to prevent or treat alcohol provide support for the interconnec­ initial hypothermia typically induced abuse and addiction as well as the per­ tion between alcohol and CR through by alcohol—that is, alcohol-induced formance deficits associated with alco­ direct mechanisms. Instead, indirect hypothermia prevented the normal cyclic hol-induced CR disruption. modulation, by way of alcohol’s disrup­ increase in Tb observed at that time. Because of the differences between tive effects on the hormonal and chem­ However, when alcohol was adminis­ species that are active at night, such as ical communication networks involved tered at 1:00 a.m., phase advances were rodents, and species that are active during in maintaining the body’s temperature observed. Those advances cannot be the day, such as humans, it is difficult balance, also must be considered in explained in the same way as the phase to speculate how these rodent models studies such as the following. delays—that is, as an indirect result of will translate for human application. Few experiments have taken a sys­ alcohol-induced hypothermia. This Recent technological advances in human- tematic approach toward elucidating finding further strengthens the theory circadian-monitoring devices, which alcohol’s direct effects on CR. Recently, that alcohol acts directly on the central can be worn on the wrist much like a however, Baird and colleagues (1998) pacemaker. Baird and colleagues pro- watch, may soon clarify this point. We examined the effects produced when posed that alcohol alters the overt Tb hope that such investigations, along alcohol was administered at various times rhythm, not the peripheral system, which, with the rapidly growing body of research throughout the day. Under a 12:12 in turn, might alter the SCN. presented, will provide a clearer under- L:D cycle (that is, 12 hours of daylight It should be taken into account, how- standing of the unique interplay between and 12 hours of nighttime, with lights ever, that to separate phase advances or alcohol and CR. on at 6:00 a.m.), a number of time- and delays from the acute effects of alcohol, dose-dependent alterations in circadian the shift must be enduring. In an L:D Tb parameters were demonstrated. paradigm, such as the one used by Baird Acknowledgments First, alcohol-treated animals showed and colleagues, the animals were being significantly shorter (i.e., less than 24 reconditioned to the light each day. To The authors would like to thank Ms. hours) Tb rhythm periods or cycles. Baird disentangle these circadian effects, we Lynn Montgomery for her excellent and colleagues (1998) suggested that have conducted a followup study repli­ administrative assistance and Drs. this patterning may signify that CR is cating this systematic approach under a Theodore Baird and David Gauvin for susceptible to initial temperature-lowering D:D schedule. Preliminary results appear the invaluable guidance and consulta­ effects of alcohol (i.e., indirect pathways) to support a similar phase-response curve tion they provided. or that alcohol is able to alter the length in free-running, dark-adapted animals. of the period of the Tb rhythm directly. Second, animals exhibited a dose- References dependent decrease in Tb rhythm (i.e., Summary amplitude) when alcohol was adminis­ ALKANA, R.; DAVIES, D.; AND LE, A. Ethanol’s acute effects on thermoregulation: Mechanisms and tered at 7:00 p.m. The hypothermic The areas of chronopharmacokinetics consequences. In: Deitrich, R., and Erwin, V., eds. response of alcohol administered at this and chronopharmacodynamics are now Pharmacological Effects of Ethanol on the Nervous time also might be countered by the stable pillars in the foundation of alco­ System. New York: CRC Press, 1996. hyperthermic rebound effect brought hol chronopharmacology. Furthermore, BAIRD, T.; BRISCOE, R.; VALLET, M.; ET AL. Phase- on by the animal’s increased nighttime in the area of chronergy, it is becoming response curve for ethanol: Alterations in circadian activity. Although the assertion by Baird clearer that alcohol sensitivity and pref­ rhythms of temperature and activity in rats.

Vol. 25, No. 2, 2001 99 Pharmacology Biochemistry and Behavior 61:303− GAUVIN, D.; BAIRD, T.; VANECEK, S.; ET AL. Effects HUTTUNEN, P. Effect of ethanol on the processes of 315, 1998. of time-of-day and photoperiod phase shifts on vol­ thermoregulation. Acta Physiologica Polonica 41:1− untary ethanol consumption in rats. Alcoholism: 3, 25−31, 1990. BRICK, J.; POHORECKY, L.; FAULKNER, W.; AND Clinical and Experimental Research 21:817−825, 1997a. ADAMS, M. Circadian variations in behavioral and KALANT, H., AND LE, A. Effects of ethanol on ther­ biological sensitivity to ethanol. Alcoholism: Clinical GAUVIN, D.; BRISCOE, R.; BAIRD, T.; ET AL. Cross- moregulation. In: Schonbaum, E., and Lomax, P., and Experimental Research 8:204−211, 1984. generalization of an EtOH “hangover” cue to eds. Thermoregulation: Pathology, Pharmacology and BRUGUEROLLE, B. Chronopharmacology. In: endogenously and exogenously induced stimuli. Therapy. New York: Pergamon Press, 1991. Touitou, Y., and Haus, E., eds. Biological Rhythms Pharmacology Biochemistry and Behavior 57:199− in Clinical and Laboratory Medicine. New York: 206, 1997b. REFINETTI, R. Effects of suprachiasmatic lesions on Springer-Verlag, 1994. temperature regulation in the golden hamster. GAUVIN, D.; CHENG, E.; AND HOLLOWAY, F. Brain Research Bulletin 36:81−84, 1995a. CRAWSHAW, L.; O’CONNOR, C.; AND WOLLMUTH, Biobehavioral correlates. Recent Developments in L. Ethanol and the neurobiology of temperature Alcoholism 11:281−304, 1993. REFINETTI, R. Rhythms of temperature selection regulation. In: Watson, R., ed. Alcohol and and body temperature are out of phase in the Neurobiology: Brain Development and Hormone GELLER, I., AND PURDY, R. Interrelationships golden hamster. Behavioral Neuroscience 109:523− Regulation. Ann Arbor: CRC Press, 1992. between ethanol consumption and circadian 527, 1995b. rhythm. In: Majchrowicz, E., and Noble, E., eds. CRAWSHAW, L.; WALLACE, H.; AND CRABBE, J. Biochemistry and Pharmacology of Ethanol. Vol. 2. REINBERG, A. Concepts in chronopharmacology. Ethanol, body temperature and thermoregulation. Annual Review of Pharmacology & Toxicology Clinical and Experimental Pharmacology and New York: Plenum Press, 1979. Physiology 25:150−154, 1998. 32:51−66, 1992. HOLLOWAY, F.; MILLER, J.; KING, D.; AND GALLAHER, E., AND EGNER, D. Rebound hyper­ BEDINGFIELD, J. Delayed ethanol effects on physio­ ROMM, E., AND COLLINS, A. Body temperature thermia follows ethanol-induced hypothermia in logical and behavioral indices in the rat. Alcohol influences on ethanol elimination rate. Alcohol rats. Psychopharmacology (Berlin) 91:34−39, 1987. 10:511−519, 1993. 4:189−198, 1987. Are these NIAAA Research Monographs in your collection? Each monograph presents research by noted scientists, reviews research progress, and offers a glimpse of future research in key areas. Scientists, clinicians, and others with an interest in alcohol research will find these volumes a welcome addition to their library.

Alcohol and Intracellular Signaling (No. 35) presents research on alcohol’s effects on intracellular signaling pathways and their implications for alcohol- induced organ injury and the development of alcoholism. Topics include: • Biochemical mechanisms of alcoholic liver disease • The role of genetics in alcoholism vulnerability • The use of animal models to study alcohol’s effects on cellular protein synthesis • Alcohol’s effects on the inflammatory process • Intracellular effects that contribute to fetal alcohol syndrome

Alcohol Epidemiology of Small Geographic Areas (No. 36) reviews progress made over the past decade in the study of alcohol consumption and prob­ lems in small geographic areas. Topics include: • Estimating rates of alcohol problems within demographic and geographic subgroups • Measuring the severity of psychiatric and addictive disorders • Determining the effectiveness of local prevention programs • Evaluating the relative need for alcoholism treatment services in different communities • Predicting alcohol-related risks on a geographic basis

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