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Electroencephalographic activity and plasma ACTH during ethanol-induced euphoria
BlOL PSYCHIATRY 1988;23:141-148
141
Electroencephalographic Activity and Plasma ACTH during Ethanol-Induced Euphoria Scott E. Lukas and Jack H. Mendelson
Covariance of brain electrical activity (EEG), plasma adrenocorticotrophic hormone (ACTH) and cortisol levels, and mood states were determined for healthy adult men during theJirst 2 hr after ingestion of ethanol or ethanol placebo under controlled doubleblind conditions. Analysis of integrated plasma ACTH and cortisol levels at 5-min intervals, EEG power spectral analysis during consecutive 2-min epochs, and continuous assessment of mood states with a nonverbal instrumental device were carried out during the ascending phase of the blood ethanol curve. Ethanol induced rapid changes in brain electrical activity and plasma ACTH levels that were significantly correlated with subjective perception of changes in mood. The paroxysmal short epochs of euphoria associated with electroencephalographic and ACTH responses during the ascending phase of the blood ethanol curve may reflect physiological concomitants of pharmacological and behavioral reinforcers that enhance risk for perpetuation of drinking and alcohol abuse.
Introduction Ethyl alcohol is one of man’s most commonly used and abused substances, but the neural mechanisms underlying intoxication are unknown. The effects of ethanol on mood are paradoxical, as relaxation and pleasurable effects of moderate intoxication may rapidly change to dysphoria and anxiety as drinking progresses. In the chronic ethanol abuser, anxiety and depression are often the sequelae of high-dose intoxication (Mendelson 1964; Nathan et al. 1970; Mello 1972). Although it has been postulated that the way in which ethanol perturbates neural function to alter mood during the ascending phase of the blood ethanol curve may differ from ethanol’s effects during the peak and descending phase of the blood ethanol curve (Goldberg 1943; Mendelson 1970; Jones 1973), it has been difficult to analyze this sequence of events and to establish concordance between physiological processes and mood changes. This article describes the covariance of neurophysiological, neuroendocrine, and behavioral events in human subjects during the first 2 hr after ingesting ethanol or ethanol placebo, administered under controlled double-blind conditions. Analysis of plasma adrenocorticotrophic hormone (ACTH) and cortisol levels at 5-min intervals and EEG power
From Harvard Medical SchooVMcL.ean Hospital, Boston, MA. Supported io pa? by Grant DA00064 from the National InStiNte on Drug Abuse and Grant AA06252 from the National Institute on Alcohol Abose and Alcoholism. Address reprint requests to Dr. Scott E. Lukas, Alcohol and Drug Abuse Research Center, 115Mill Street, Belmont, MA 02178. Received and revised February 7, 1987.
0 1988 Society of Biological Psychiatry
0006-3223/881$03.50
142
BIOL PSYCHIATRY 1988;23:141-148
S. E. i,ukah and .I. H
Mend&w
spectral analysis in multiple 2-min epochs permitted examination of the biobehavioral correlates of intoxication. Data obtained establish that ethanol induces rapid changes in brain electrical activity and ACTH secretion from the pituitary that are correlated with subjective perceptions of positive changes in mood.
Methods Twelve adult male volunteers, ages 21-35 (57-98 kg), provided informed consent for participation in this study. Subjects were recruited via newspaper advertisements and were given a complete medical evaluation, including an electrocardiogram, blood chemistry studies, and urinalysis. Subjects with ethanol or drug abuse-related problems were not permitted to participate in the study. All subjects described themselves as social drinkers who, on the average, consumed ethanol l-3 times/week. Electrophysiological Recording and Blood Withdrawal Procedures Subjects were studied while they were seated in a recliner chair, in a sound- and lightattenuated, electrically shielded chamber, with their eyes closed (Figure I). Scalp electroenceph~ogram (EEG) electrodes were applied using the Intemation~ IO-20 System
Figure 1. Artist’s rendering of a subject in the experimental chamber, demonstrating the multiple components of the study. Movement of the instrumental joystick device is recorded on the polygraph. along with electroencephalographic activity. Ethanol or placebo .~_ solution
EEG power spectral analysis
Instrumental
Btood
withdrawal pump
Experimental
chamber
EEG, ACTH, and Ethanol Euphoria
BIOL PSYCHIATRY 1988;23:141-148
143
(Jasper 1958) over sites C3, C4, P3, and P4. Electrodes were referenced to linked earlobes. A Kowarski-Cormed butterfly needle/catheter was inserted into an antecubital vein of the right arm and threaded bud the chamber wall. The end was attached to a syringe, mounted on a syringe pump, and adjusted to continuously exfuse blood at a rate of 1.O mllmin. Blood samples were collected at 5-min intervals to obtain integrative plasma levels of ACTH, cortisol, and ethanol.
Subjective Reports of Intoxication As verbal or written reports of perceived mood state changes may compromise the accuracy of EEG measures (Otto 1967; Matousek and Petersen 1983), a custom-made ins~mental joystick device was used to obtain mood status reports. Movement of the handle or depression of the button resulted in a deflection of an event pen located on the polygraph. Thus, behavioral responses were monitored continuously with EEG activity. Details of the device are presented in Lukas et al. (1986a,b). These behavioral measures of mood status do not confound recording of electroencephalographic activity or influence pituitary secretion of ACTH. Subjects were instructed to use their left hand to move the instrumental joystick device as follows: forward when they detected an ethanol effect; left when the effects became intense; backward when the effects disappeared. In addition, they were instructed to press a small button located on the top of the joystick during periods when they perceived feelings of intense pleasure or euphoria.
Endocrine Assays Consecutive 5-min integrated blood samples were subsequently analyzed for plasma ACTH, cortisol, and ethanol levels. ACTH and cortisol were analyzed via radioimmunoassay procedures obtained from Nichols Institute Diagnostics, San Juan Capistrano, CA, and Travenol Laboratories, Cambridge, MA, respectively. The ACTH assay is a double-antibody procedure whereas the cortisol assay utilizes a single-antibody procedure. Intra- and interassay coefficients of variance (CV) for ACTH were 9.04% and 15.1%, respectively, and for cortisol were 4.4% and 13.1%, respectively. Plasma ethanol levels were determined spectrophotometrically using the method of Leric et al. (1970). intraand interassay CVs were 3.0% and 7.4%, respectively.
Experimental Procedure After 30 min of baseline recordings, subjects drank either a placebo or ethanol (0.695 g/kg) solution at a constant rate over a 15min interval. A total of 350 ml was delivered via a drinking tube/peristaltic motor device, which permitted the subjects to drink without opening their eyes or moving their hands. The placebo solution contained only grapefruit juice, whereas the ethanol solution was made with 40% beverage ethanol (vodka). For both doses, a IO-ml reservoir located between the pump and the mouthpiece was tilled with 3 ml of vodka to provide a strong initial taste to mask the two treatments. This practice is an effective placebo that does not produce measurable plasma ethanol levels (Mendelson et al. 1984). Electroencephalographic activity and behavioral responses were monitored continuously for the next 2 hr. Multiple 2-min epochs of EEG activity were subjected to power spectral analysis. Twelve-second epochs were digitized at a rate of 256/set, followed by a fast Fourier Transfo~ation using a Pathfinder II signal processor
144
BIOL PSYCHIATRI 1988;23:141-148
S.E. hkas
and .I H Mendelsot~
(Nicolet Biomedical, Madison, WI). EEG power in the 0.254, 4-X. 8-13, and 13--X) Hz bands was determined and block averaged over 2-min int~~als. Consecutive 5-min integrated plasma samples were removed without disturbing the subject for the duration of the study.
Results After placebo administration, subjects did not report episodes of euphoria, and there were no significant changes in plasma ACTH or cortisol levels or EEG alpha power. In contrast, after ethanol administration, subjects reported several paroxysmal episodes of euphoria. which began within 10 min after drinking and continued for an additional 40 min. Plasma ethanol levels were 32.85 + 5.35 mg/dl within 10 min after drinking began and peaked at 81.79 + 5.35 mg/dl at 115 min after drinking. Plasma ACTH levels increased an average 20 pglml within lo-20 min after drinking began and subsequently declined. Plasma cortisol levels gradually increased and peaked at 30 min. when blood ethanol levels averaged 44.98 rt 6.14 mg/dl. Figure 2 shows regression lines for the linear portion of the time-effect curves for plasma ACTH, cortisol and ethanol levels, EEG alpha power, and the incidence of reported euphoria after placebo (top) and ethanol (bottom) administration. Tests for parallelism (Tallarida and Murray 198 1) revealed that EEG alpha power, subjective reports of euphoria, plasma ACTH levels, and plasma ethanol levels were parallel, and all increased linearly during the first 30 min after ethanol consumption (p < 0.05). Increases in plasma cortisol were not statistically significant. All physiological and behavioral measures decreased linearly within 35-60 min after drinking, even though plasma ethanol levels continued to increase.
Discussion In the present study, subjective reports of self-perceived euphoria occurred between 10 and 15 min after drinking ethanol and were accompanied by a significant increase in EEG alpha power and increased plasma levels of ACTH. These data indicate that major physiological and behavioral concomitants of ethanol intoxication occur at relatively low blood ethanol levels (app~ximately 32 mgldl) during the ascending phase of the blood ethanol curve. Previous studies have noted that ethanol intake is associated with activation of the hypothalamic-pituitary-adrenal axis (Mendelson and Stein 1966; Noth and Walter 1984), but we have been unable to locate any report that describes the initiation of such activation after such a short time course and low blood ethanol levels following ethanol intake. Enhanced secretion of ACTH at low blood ethanol levels could be the result of ethanolinduced stimulation of co~ico~opin-releasing factor (CRF). Although subsequent activation of the admnal cortex following ethanol-related ACTH release could media& changes in central nervous system function and behavior, ACTH and probably CRF itself may also directly effect neuronal function in regional portions of the central nervous system {Ehlers 1986). It is also possible that low doses of ethanol may directly stimulate release of ACTH from pituitary corticotrophs (Redei et al. 1986). The acute effects of ethanol on human EEG activity consists of increased voltage and decreased alpha frequency (Engel and Rosenbaum 1945; Holmberg and Martens 1955:
BIOL PSYCHIATRY 1988;23:141-148
EEG, ACTH, and Ethanol Eupho~a
145
Placebo
Ethanol
15
5
0
0 Bi:::::::::::::‘:?J
Drinking L----“---“‘““‘l -30
0
30
60
Time tmin) Figure 2. Regression analysis of changes in plasma ACTH, cortisol, and ethanol levels, EEG alpha power, and incidence of reported euphoria after placebo (top) and ethanot (bonom~ ad~~is~tion. Data are derived from 6 subjects per group.
Varga and Nagy 1960; Dotter et al. 1966). However, most of these studies have examined EEG effects that appear during the “peak” behavioral responses, which typically occur 30-75 min after drinking. Data obtained in this study and our previous study (Lukas et al. 19%~) focused on very early components of the ethanol response and found that neurophysiological and neuroendocrine measures covaried with ethanol-induced intoxication in normal persons. Abrupt increases in EEG alpha power have been associated with specific subjective mood states, generally reported as pleasurable, floating, and extremely relaxed (Lindsley 1952; Brown 1970; Wallace 1970; Matejcek 1982). These data suggest that the reinforcing properties of ethanol intoxication reflect these rapid changes in EEG activity and ACTH secretion. A previous study reported that acute oral administration of 40 mg of ACTH 4-9 analog to human subjects reduced alpha activity
146
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and J.H. Mendelson
(Bonn et al. 1984, 1985). However, this study was conducted to assess selective attention to a dichotic listening task, which may have induced an alpha-suppressing alerting response These positive early effects of ethanol are probably transient and dose-dependent, as high ethanol doses and chronic ethanol abuse are followed by increased anxiety, dysphoria, and depression (McGuire et al. 1966; Alterman et al. 1975; Mello and Mendelson 1978). Yet, it is tempting to speculate that the early positive effects of ethanol may be especially salient for ethanol abusers. Ethanol abusers also have low amounts of spontaneous EEG alpha activity (Davis et al. 1941; Little and McAvoy 1952) and many abnormal endocrine and physiological responses {e.g., impaired adrenocortical responses, regulation of arterial blood pressure) that are reversed or “normalized’ after consumption of small amounts of ethanol (Kissin et af. 1959, 1960). The paroxysmal short epochs of euphoria associated with concomitant neurophysiological and neuroendocrine responses during the ascending phase of the blood ethanol curve may serve as powerful reinforcers for perpetuation of drinking. The rising phase of the blood ethanol curve may produce effects that are comparable to the heroin “rush” and cocaine “high”-intense sensations of intoxication that persist for seconds or minutes and then rapidly disappear. Recent studies have shown that adren~o~ical steroids may enhance or depress neuronal activity (Majewska et al. 1986) and that these changes may covary with positive and negative fluctuations in mood (Gold et al. 1986). Based on these observations, it has been postulated that adrenocortical activation of short-term duration, which induces an acute glucocorticoid response, may facilitate occurrence of positive mood states, whereas long-term adrenocortical activation and associated high levels of glucocorticoids may cause dysphoria (Barnes 1986). Data obtained in the present study are consistent with the notion that eth~ol-induced ACTH secretion during the ascending phase of the blood ethanol curve covaries with subjective reports of euphoria and alterations of electrical activity in the central nervous system. Although chronic ethanol abuse, which is associated with chronic adrenocortical activation, may increase risk for dysphoria, acute low dose ethanol intake clearly induces euphoria. Thus, the biphasic dose-related effects of ethanol on mood may be mediated, in part, by the effects of ethanol on the hypothalamic-pituitary-adrenal axis.
Refer-e:nces AltermanAI, Gottheil E, Crawford DH (1975): Mood changes in an alcoholism treatment program based on drinking decisions. Am J Psychiaty 132:1032-1037. Barnes DM (1986): Steroids may influence changes in mood. Science 232: 1344-1345. Bonn J, Fehm-Wolfsdorf G, Schiebe M, Rock&oh B, Fehm HL, Voight KH (1984): Dishabituating effects of an ACTH 4-9 analog in a vigilance task. F~~rn~oi Biochem Behav 21513-5 19. Bonn J, Fehm-Wolfsdorf G, Schiebe M, Birbaumer N, Fehm HL, Voight KH (1985): An ACTH 4-9 analog impairs selective attention in man. Life Sci 36:2117-2125. Brown BB (1970): Recognition of aspects of consciousness through association with EEG alpha activity represented by a light signal. Psychophysiology 6~442-452. Davis PA, Gibbs FA, Davis H, Jetter WW, Trowbridge LS (1941): Effects of alcohol upon electroencephalogram. Q J Stud Alcohol 1:626-637. Dotter RF, Naitoh P, Smith JC (1966): Elec~~n~ph~o~phic changes and vigilance behavior during experimentally induced intoxication with alcohoiic subjects. Psychosom Ned 28:605-6 15.
EEG, ACTH, and Ethanol Euphoria
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Eblers CL (1986): EEG stability following co~co~pin releasing factor in rats. ~~c~o~u~oendocrinology 11:121-125. Engel GL, Rosenbaum M (1945): Delirium: electroencephalographic changes associated with acute alcoholic intoxication. Arch Neurol Psychiatry 53:44-50. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, Nieman LK, Post RM, Pickar D, Galucci W, et al (1986): Responses to corticotropin-releasing hormone in the hypercortisohsm of depression and Cushing’s disease: Pa~ophysioIogic and diagnostic implications. N Engl J Med 3141329-1335. Goldberg L (1943): Quantitative studies on alcohol tolerance in man. Acta Physiol Scam? S(suppl 16):1-128. Holmberg G, Martens S (1955): Electmencephalographic changes in man correlated with blood alcohol concentration and some other conditions following standardized ingestion of alcohol. Q J Stud Alcohol 16:41 l-424. Jasper HH ( 1958): The 10-20 electrode system of the International Federation. Electroenceph Chin Neurophysiol 10:371-375.
Jones BM (1973): Memory impairment on the ascending and descending limbs of the blood alcohol curve. J Abnorm Psycho1 82:24-32. Kissin B, Schenker V, Schenker A (1959): The acute effects of ethyl alcohol and chiorpromazine on certain physiologic~ functions in alcohohcs. Q J Stud Alcohol 2~:48~92. Kissin B, Schenker V, Schenker AC (1960): The acute effect of ethanol ingestion on plasma and urinary 17-hydroxycorticoids in alcoholic subjects. Am J Med Sci 239:69@-705. Leric W, Kaplan JC, Broun G (1970): Dosage enzymatique de I’alcool sanguin par micromethode colorimetrique. Clin Chim Acta 29:523-528. LindsIey DB (1952): Psychological phenomena and the electroencephalogram. Electroenceph Clin Neuro~hysiol4:443-456.
Little SC, McAvoy M (1952): EI~~~nceph~ographic
studies in alcoholism. Q J Stud Alcohol
13:9-15.
Lukas SE, Mendelson JH, Benedikt RA (1986a): Instrumental analysis of ethanol-induced intoxication in human males. Psychopharmacology 89:8-13. Lukas SE, Mendelson JH, Benedikt RA, Jones B (1986b): EEG, physiologic and behavioral effects of ethanof administmtion. In Harris LS (ed), Pr~ie~ of Llnrg Dependence 1985. NIDA Research Mono~aph no. 67. Washington DC: US Government Printing Office, pp 209-214. Lukas SE, Mendelaon JH, Benedikt RA, Jones B (1986c): EEG alpha activity increases during transient episodes of ethanol-induced euphoria. Pharmacol Biochem Behau 25:889-895. Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986): Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232: 1004-1007. Matejcek M (1982): Vigilance and the EEC: PsychoIogic~, physioIogic~ and ph~~oIogic~ aspects‘ In Hermann WM (ed), EEG in Drug Research. Stuttgart: Gustav Fischer, pp 405-508. Matousek M, Petersen I (1983): A method of assessing alertness fluctuations from EEG spectra, Electroenceph Clin Neurophysiol55:108-113.
McGuire MT, Mendelson JH, Stein S (1966): Comparative psychosocial studies of alcoholic and non-alcoholic subjects undergoing experimentally induced ethanol intoxication. Psychosom Med 28:13.
Mello NK f 1972): Behavioral studies of alcoholism. In Kissin B, Begleiter H (eds), The Biology of Alcoholism. Vol II: Physiology and Behavior. New York: Plenum Press, pp 219-291. Mello NK, Mendelson JH (1978): Alcohol atid human behavior. In Iversen LL, Iversen SD, Snyder SH (eds), Handbook of Psychopharmacology, Section III, Chemistry, Pharmacology and Human Use. New York: Plenum Press, pp 235-317. Mendeison JH (1964): Ex~~men~lly induced chronic intoxication and withdrawaf in alcoholics. (2 J Stud Aicohol SuppI 2.
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Mendelson JH (1970): Biological concomitants
of alcoholism,
part 1. N Engl J Med 283:24-32.
Mendelson JH, Stein S (1966): Serum cortisol levels in alcoholic and nonalcoholic experimentally induced ethanol intoxication. Psychosom Med 28:616-626. Mendelson JH, McGuire M, Mello NK (1984): A new device for administering Alcohol 1:417-419.
subjects during placebo alcohol.
Nathan PE, Titler NA, Lowenstein LM, Solomon P, Rossi AM (1970): Behavioral analysis of chronic alcoholism. Interaction of alcohol and human contact. Arch Gen Psychiarry 22:419-430. Noth RH, Walter RM Jr (1984): The effects of alcohol on the endocrine system. Med Clin North Am 68:133-146. Otto E (1967): The effect of instructions influencing the level of alertness of the EEG activity. In Nedecky I (ed), Mechanisms ofOrienting Reaction in Man. Bra&lava: Slovak Acad Sci Pub1 House, pp 351-365. Redei E, Branch B, Taylor AN (1986): Abstracts of the First International docrinology 293:98.
Congress of Neuroen-
Tallarida RJ, Murray RB (1981): Manual of Pharmacologic Calculations. New York: Springer Verlag. Varga B, Nagy T (1960): Analysis of alpha-rhythms Electroenceph Clin Neurophysiol 12:933. Wallace RK (1970): Physiological
in the electroencephalogram
effects of transcendental
meditation.
of alcoholics.
Science 167:1’751-1754.
141
Electroencephalographic Activity and Plasma ACTH during Ethanol-Induced Euphoria Scott E. Lukas and Jack H. Mendelson
Covariance of brain electrical activity (EEG), plasma adrenocorticotrophic hormone (ACTH) and cortisol levels, and mood states were determined for healthy adult men during theJirst 2 hr after ingestion of ethanol or ethanol placebo under controlled doubleblind conditions. Analysis of integrated plasma ACTH and cortisol levels at 5-min intervals, EEG power spectral analysis during consecutive 2-min epochs, and continuous assessment of mood states with a nonverbal instrumental device were carried out during the ascending phase of the blood ethanol curve. Ethanol induced rapid changes in brain electrical activity and plasma ACTH levels that were significantly correlated with subjective perception of changes in mood. The paroxysmal short epochs of euphoria associated with electroencephalographic and ACTH responses during the ascending phase of the blood ethanol curve may reflect physiological concomitants of pharmacological and behavioral reinforcers that enhance risk for perpetuation of drinking and alcohol abuse.
Introduction Ethyl alcohol is one of man’s most commonly used and abused substances, but the neural mechanisms underlying intoxication are unknown. The effects of ethanol on mood are paradoxical, as relaxation and pleasurable effects of moderate intoxication may rapidly change to dysphoria and anxiety as drinking progresses. In the chronic ethanol abuser, anxiety and depression are often the sequelae of high-dose intoxication (Mendelson 1964; Nathan et al. 1970; Mello 1972). Although it has been postulated that the way in which ethanol perturbates neural function to alter mood during the ascending phase of the blood ethanol curve may differ from ethanol’s effects during the peak and descending phase of the blood ethanol curve (Goldberg 1943; Mendelson 1970; Jones 1973), it has been difficult to analyze this sequence of events and to establish concordance between physiological processes and mood changes. This article describes the covariance of neurophysiological, neuroendocrine, and behavioral events in human subjects during the first 2 hr after ingesting ethanol or ethanol placebo, administered under controlled double-blind conditions. Analysis of plasma adrenocorticotrophic hormone (ACTH) and cortisol levels at 5-min intervals and EEG power
From Harvard Medical SchooVMcL.ean Hospital, Boston, MA. Supported io pa? by Grant DA00064 from the National InStiNte on Drug Abuse and Grant AA06252 from the National Institute on Alcohol Abose and Alcoholism. Address reprint requests to Dr. Scott E. Lukas, Alcohol and Drug Abuse Research Center, 115Mill Street, Belmont, MA 02178. Received and revised February 7, 1987.
0 1988 Society of Biological Psychiatry
0006-3223/881$03.50
142
BIOL PSYCHIATRY 1988;23:141-148
S. E. i,ukah and .I. H
Mend&w
spectral analysis in multiple 2-min epochs permitted examination of the biobehavioral correlates of intoxication. Data obtained establish that ethanol induces rapid changes in brain electrical activity and ACTH secretion from the pituitary that are correlated with subjective perceptions of positive changes in mood.
Methods Twelve adult male volunteers, ages 21-35 (57-98 kg), provided informed consent for participation in this study. Subjects were recruited via newspaper advertisements and were given a complete medical evaluation, including an electrocardiogram, blood chemistry studies, and urinalysis. Subjects with ethanol or drug abuse-related problems were not permitted to participate in the study. All subjects described themselves as social drinkers who, on the average, consumed ethanol l-3 times/week. Electrophysiological Recording and Blood Withdrawal Procedures Subjects were studied while they were seated in a recliner chair, in a sound- and lightattenuated, electrically shielded chamber, with their eyes closed (Figure I). Scalp electroenceph~ogram (EEG) electrodes were applied using the Intemation~ IO-20 System
Figure 1. Artist’s rendering of a subject in the experimental chamber, demonstrating the multiple components of the study. Movement of the instrumental joystick device is recorded on the polygraph. along with electroencephalographic activity. Ethanol or placebo .~_ solution
EEG power spectral analysis
Instrumental
Btood
withdrawal pump
Experimental
chamber
EEG, ACTH, and Ethanol Euphoria
BIOL PSYCHIATRY 1988;23:141-148
143
(Jasper 1958) over sites C3, C4, P3, and P4. Electrodes were referenced to linked earlobes. A Kowarski-Cormed butterfly needle/catheter was inserted into an antecubital vein of the right arm and threaded bud the chamber wall. The end was attached to a syringe, mounted on a syringe pump, and adjusted to continuously exfuse blood at a rate of 1.O mllmin. Blood samples were collected at 5-min intervals to obtain integrative plasma levels of ACTH, cortisol, and ethanol.
Subjective Reports of Intoxication As verbal or written reports of perceived mood state changes may compromise the accuracy of EEG measures (Otto 1967; Matousek and Petersen 1983), a custom-made ins~mental joystick device was used to obtain mood status reports. Movement of the handle or depression of the button resulted in a deflection of an event pen located on the polygraph. Thus, behavioral responses were monitored continuously with EEG activity. Details of the device are presented in Lukas et al. (1986a,b). These behavioral measures of mood status do not confound recording of electroencephalographic activity or influence pituitary secretion of ACTH. Subjects were instructed to use their left hand to move the instrumental joystick device as follows: forward when they detected an ethanol effect; left when the effects became intense; backward when the effects disappeared. In addition, they were instructed to press a small button located on the top of the joystick during periods when they perceived feelings of intense pleasure or euphoria.
Endocrine Assays Consecutive 5-min integrated blood samples were subsequently analyzed for plasma ACTH, cortisol, and ethanol levels. ACTH and cortisol were analyzed via radioimmunoassay procedures obtained from Nichols Institute Diagnostics, San Juan Capistrano, CA, and Travenol Laboratories, Cambridge, MA, respectively. The ACTH assay is a double-antibody procedure whereas the cortisol assay utilizes a single-antibody procedure. Intra- and interassay coefficients of variance (CV) for ACTH were 9.04% and 15.1%, respectively, and for cortisol were 4.4% and 13.1%, respectively. Plasma ethanol levels were determined spectrophotometrically using the method of Leric et al. (1970). intraand interassay CVs were 3.0% and 7.4%, respectively.
Experimental Procedure After 30 min of baseline recordings, subjects drank either a placebo or ethanol (0.695 g/kg) solution at a constant rate over a 15min interval. A total of 350 ml was delivered via a drinking tube/peristaltic motor device, which permitted the subjects to drink without opening their eyes or moving their hands. The placebo solution contained only grapefruit juice, whereas the ethanol solution was made with 40% beverage ethanol (vodka). For both doses, a IO-ml reservoir located between the pump and the mouthpiece was tilled with 3 ml of vodka to provide a strong initial taste to mask the two treatments. This practice is an effective placebo that does not produce measurable plasma ethanol levels (Mendelson et al. 1984). Electroencephalographic activity and behavioral responses were monitored continuously for the next 2 hr. Multiple 2-min epochs of EEG activity were subjected to power spectral analysis. Twelve-second epochs were digitized at a rate of 256/set, followed by a fast Fourier Transfo~ation using a Pathfinder II signal processor
144
BIOL PSYCHIATRI 1988;23:141-148
S.E. hkas
and .I H Mendelsot~
(Nicolet Biomedical, Madison, WI). EEG power in the 0.254, 4-X. 8-13, and 13--X) Hz bands was determined and block averaged over 2-min int~~als. Consecutive 5-min integrated plasma samples were removed without disturbing the subject for the duration of the study.
Results After placebo administration, subjects did not report episodes of euphoria, and there were no significant changes in plasma ACTH or cortisol levels or EEG alpha power. In contrast, after ethanol administration, subjects reported several paroxysmal episodes of euphoria. which began within 10 min after drinking and continued for an additional 40 min. Plasma ethanol levels were 32.85 + 5.35 mg/dl within 10 min after drinking began and peaked at 81.79 + 5.35 mg/dl at 115 min after drinking. Plasma ACTH levels increased an average 20 pglml within lo-20 min after drinking began and subsequently declined. Plasma cortisol levels gradually increased and peaked at 30 min. when blood ethanol levels averaged 44.98 rt 6.14 mg/dl. Figure 2 shows regression lines for the linear portion of the time-effect curves for plasma ACTH, cortisol and ethanol levels, EEG alpha power, and the incidence of reported euphoria after placebo (top) and ethanol (bottom) administration. Tests for parallelism (Tallarida and Murray 198 1) revealed that EEG alpha power, subjective reports of euphoria, plasma ACTH levels, and plasma ethanol levels were parallel, and all increased linearly during the first 30 min after ethanol consumption (p < 0.05). Increases in plasma cortisol were not statistically significant. All physiological and behavioral measures decreased linearly within 35-60 min after drinking, even though plasma ethanol levels continued to increase.
Discussion In the present study, subjective reports of self-perceived euphoria occurred between 10 and 15 min after drinking ethanol and were accompanied by a significant increase in EEG alpha power and increased plasma levels of ACTH. These data indicate that major physiological and behavioral concomitants of ethanol intoxication occur at relatively low blood ethanol levels (app~ximately 32 mgldl) during the ascending phase of the blood ethanol curve. Previous studies have noted that ethanol intake is associated with activation of the hypothalamic-pituitary-adrenal axis (Mendelson and Stein 1966; Noth and Walter 1984), but we have been unable to locate any report that describes the initiation of such activation after such a short time course and low blood ethanol levels following ethanol intake. Enhanced secretion of ACTH at low blood ethanol levels could be the result of ethanolinduced stimulation of co~ico~opin-releasing factor (CRF). Although subsequent activation of the admnal cortex following ethanol-related ACTH release could media& changes in central nervous system function and behavior, ACTH and probably CRF itself may also directly effect neuronal function in regional portions of the central nervous system {Ehlers 1986). It is also possible that low doses of ethanol may directly stimulate release of ACTH from pituitary corticotrophs (Redei et al. 1986). The acute effects of ethanol on human EEG activity consists of increased voltage and decreased alpha frequency (Engel and Rosenbaum 1945; Holmberg and Martens 1955:
BIOL PSYCHIATRY 1988;23:141-148
EEG, ACTH, and Ethanol Eupho~a
145
Placebo
Ethanol
15
5
0
0 Bi:::::::::::::‘:?J
Drinking L----“---“‘““‘l -30
0
30
60
Time tmin) Figure 2. Regression analysis of changes in plasma ACTH, cortisol, and ethanol levels, EEG alpha power, and incidence of reported euphoria after placebo (top) and ethanot (bonom~ ad~~is~tion. Data are derived from 6 subjects per group.
Varga and Nagy 1960; Dotter et al. 1966). However, most of these studies have examined EEG effects that appear during the “peak” behavioral responses, which typically occur 30-75 min after drinking. Data obtained in this study and our previous study (Lukas et al. 19%~) focused on very early components of the ethanol response and found that neurophysiological and neuroendocrine measures covaried with ethanol-induced intoxication in normal persons. Abrupt increases in EEG alpha power have been associated with specific subjective mood states, generally reported as pleasurable, floating, and extremely relaxed (Lindsley 1952; Brown 1970; Wallace 1970; Matejcek 1982). These data suggest that the reinforcing properties of ethanol intoxication reflect these rapid changes in EEG activity and ACTH secretion. A previous study reported that acute oral administration of 40 mg of ACTH 4-9 analog to human subjects reduced alpha activity
146
BIOL PSYCHIATRY 1988;23:141-148
S.E.
hkas
and J.H. Mendelson
(Bonn et al. 1984, 1985). However, this study was conducted to assess selective attention to a dichotic listening task, which may have induced an alpha-suppressing alerting response These positive early effects of ethanol are probably transient and dose-dependent, as high ethanol doses and chronic ethanol abuse are followed by increased anxiety, dysphoria, and depression (McGuire et al. 1966; Alterman et al. 1975; Mello and Mendelson 1978). Yet, it is tempting to speculate that the early positive effects of ethanol may be especially salient for ethanol abusers. Ethanol abusers also have low amounts of spontaneous EEG alpha activity (Davis et al. 1941; Little and McAvoy 1952) and many abnormal endocrine and physiological responses {e.g., impaired adrenocortical responses, regulation of arterial blood pressure) that are reversed or “normalized’ after consumption of small amounts of ethanol (Kissin et af. 1959, 1960). The paroxysmal short epochs of euphoria associated with concomitant neurophysiological and neuroendocrine responses during the ascending phase of the blood ethanol curve may serve as powerful reinforcers for perpetuation of drinking. The rising phase of the blood ethanol curve may produce effects that are comparable to the heroin “rush” and cocaine “high”-intense sensations of intoxication that persist for seconds or minutes and then rapidly disappear. Recent studies have shown that adren~o~ical steroids may enhance or depress neuronal activity (Majewska et al. 1986) and that these changes may covary with positive and negative fluctuations in mood (Gold et al. 1986). Based on these observations, it has been postulated that adrenocortical activation of short-term duration, which induces an acute glucocorticoid response, may facilitate occurrence of positive mood states, whereas long-term adrenocortical activation and associated high levels of glucocorticoids may cause dysphoria (Barnes 1986). Data obtained in the present study are consistent with the notion that eth~ol-induced ACTH secretion during the ascending phase of the blood ethanol curve covaries with subjective reports of euphoria and alterations of electrical activity in the central nervous system. Although chronic ethanol abuse, which is associated with chronic adrenocortical activation, may increase risk for dysphoria, acute low dose ethanol intake clearly induces euphoria. Thus, the biphasic dose-related effects of ethanol on mood may be mediated, in part, by the effects of ethanol on the hypothalamic-pituitary-adrenal axis.
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