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Alcohol reverses the proconflict effect of corticotropin-releasing factor
Regulatory Peptides, 16 (1986) 315--320 Elsevier
315
RPT 00547
Alcohol reverses the proconflict effect of corticotropin-releasing factor Karen Thatcher-Britton a and George F. K o o b b Department of Psychiatry, aSan Diego Veterans Administration Medical Center, and UCSD School of Medicine, La Jolla, CA 92161, and bDepartment of Basic and Clinical Research Scripps Clinic and Research Foundation 10666 N. Torrey Pines Road, La Jolla, CA 92037, U.S.A. (Received 29 October 1986; revised manuscript received and accepted 4 November 1986)
Summary Alcohol has tension reducing properties in man that are reflected in a release of punished responding in a rat operant conflict test. In contrast, corticotropin releasing factor (CRF), injected centrally produces a suppression of punished and non-punished responding in the conflict test consistent with its hypothesized role in mediating behavioral responses to stress. Alcohol in a dose of 0.75 g/kg reversed the suppressive effects of 0.5 #g CRF injected intracerebroventricularly on punished responding but augmented the suppression of unpunished responding by CRF. Results suggest that one mechanism for the tension reducing properties of acute alcohol intoxication may involve a suppression of brain CRF systems. corticotropin-releasing factor; alcohol; conflict
Introduction Two behavioral effects of alcohol thought to reflect its acute intoxicating actions are motor ataxia and tension reduction. While ataxia is a relatively common measure of the intoxicating effects of alcohol in animals and man [1], its tension-reducing properties have been more difficult to quantify [2]. Early work showed that these tension-reducing properties of alcohol were weak or Please address correspondence to: Dr. George F. Koob, Department of Basic and Clinical Research (BCR1), Scripps Clinic and Research Foundation, 10666 N. Torrey Pines Road, La Jolla, CA 92037, U.S.A. Telephone: (619) 455-9100 ext. 9736. 016%01 ! 5/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
316 nonexistent when studied in operant conflict paradigms [2]. However, a modification of the Geller-Seifter procedure [3] using incremental shock [4] has proved particularly sensitive to alcohol effects [5-7]. Low doses of alcohol (0.5-1.0 g/kg intraperitoneally) produce a dose-dependent release of punished responding as reflected by an increase in lever pressing in the incremental shock conflict period [5,6]. The same doses of alcohol produce a dose-dependent decrease in responding during the unpunished component which presumably reflects the acute motor debilitating effects of alcohol [5,6]. The purpose of this study was to examine the effects of alcohol on the proconflict actions of centrally administered corticotropin-releasing factor (CRF), a peptide hypothesized to be important in mediating behavioral responses to stress [8]. The present study found that alcohol reverses the proconflict effects of CRF, but alcohol actually potentiates the disruptive effects of CRF on unpunished responding. These results suggest that brain CRF systems might be one possible site of action for alcohol's acute intoxicating effects.
Materials and Methods
Subjects The subjects were male albino Wistar rats weighing 250 g at the beginning of the experiment. All rats were housed in groups of three in a temperature-, humidity- and light-controlled environment.
Conflict training For conflict testing, rats were deprived of food for 24 h and then maintained on 10-15 g of food per day (gradually increasing during the first few weeks of training and then leveling off at 15 g/day). Rats were first trained to lever press for 45 mg Noyes food pellets on a continuous reinforcement schedule in sound-proof chambers (Coulbourn Instruments, Inc.). Continuous reinforcement training was followed subsequently by training on a random interval 30-s schedule. Finally, the rats were trained on a multiple schedule consisting of two cycles of three components: an unpunished component (5 min), a time out component (2 min) and a punished component (2 min). Responses made during the unpunished component were reinforced on a random interval, 30-s schedule in a darkened chamber. During the time out, the chamber was illuminated and responses were not reinforced. The conflict component was signaled by three flashing lights located above the lever (one per second), and responses were both reinforced with food and punished with foot shocks through stainless steel bars on the floor on a continuous reinforcement schedule. Footshock consisted of a scrambled constant current, biphasic square wave produced by a SGS-003 stimulator (BRS/LVE Div. Tech. Serv., Inc.). With each lever press during the conflict period the shock was incremented by 0.15 mA steps to a maximum of 3.3 mA (22 steps).
317
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Fig. 1. The interaction of alcohol (0.75 g]kg) IP and CRF (0.5 #g) ICV on responding during the conflict (top) and unpunished components (bottom) of an operant conflict test. Number of rats in each group is indicated at bottom of each column. Results are expressed as responses/rain (Mean 4- S.E.M.). * Significantly different from ICV saline (main CRF effect, ANOVA). t Significantly different from IP saline (main alcohol effect, ANOVA).
Experimental procedure After establishing stable responding ( + 10% o f average for three successive days), 46 rats were anesthetized with pentobarbital and implanted with lateral ventricular cannulae. A 7 m m 23-gauge stainless steel guide cannula was lowered to within 1 m m o f the lateral ventricle and secured with two stainless steel screws and dental cement. The stereotaxic coordinates, with the t o o t h b a r 5 m m above interaural zero, were: - 0 . 6 m m posterior to bregma, 4-2.0 m m lateral, and - 3 . 2 m m below the skull surface at the point o f entry. Cannulae were equally distributed between the left and right ventricles. After a m i n i m u m o f five days recovery f r o m surgery the rats were divided r a n d o m l y into four g r o u p s in a 2 x 2 factorial design. One g r o u p (n = 10) received saline injected infraventricularly (ICV) and saline intraperitoneally (IP). A second g r o u p (n = 11) received 0.5 #g C R F injected I C V and saline IP. A third g r o u p (n = 13)
318
received saline ICV and alcohol 0.75 g/kg IP. A fourth group (n = 12) received 0.5 /~g CRF ICV and alcohol 0.75 g/kg 1P. Rat CRF was synthesized by Jean Rivier (Clayton Foundation Laboratories for Peptide Biology, The Salk Institute) and dissolved in 0.9% saline in a concentration of 0.25 /~g/#l. Two ~tl of CRF were injected 30 min prior to the test by gravity. Alcohol was dissolved in saline in a concentration of 10% (w/v) and injected 15 min prior to the test in a volume according to body weight sufficient to produce a dose of 0.75 g/kg.
Data analysis Response rates were computed for each rat in each condition by obtaining the mean rate across replications within a given session. 'lhe drug effects were analyzed with a two-factor (Alcohol x CRF) analysis of variance (ANOVA). This analysis procedure permitted the assessment of the main effects for each drug treatment as well as any statistical interaction between the drug/saline combinations.
Experimental Results The effects of alcohol alone and in combination with CRF are illustrated in the top portion of Figure 1 for the conflict condition and in the bottom portion of Figure 1 for the unpunished condition. During the conflict component, response rates were increased when alcohol was administered for both the saline and CRF treatment conditions to produce a significant main effect for the presence of alcohol .(F = 9.31, df = 1,42, P < 0.01). However, response rates were decreased when CRF was administered for both the saline and alcohol treatment conditions to produce a significant main effect for the presence of CRF (F 13.92, df = 1,42, P < 0.01). No interaction between these factors was obtained (F < 1). During the unpunished component, response rates were decreased when alcohol was administered for both the saline and CRF treatment conditions to produce a significant main effect for the presence of alcohol (F = 5.80, df = 1,42, P < 0.01). Response rates were decreased in the unpunished component as well by CRF for both the saline and alcohol treatment conditions to produce a significant main effect for the presence o f C R F (F = 18.09, df = 1,42, P < 0.01). No interaction between these factors was obtained (F > 1).
Discussion Alcohol produced a release of punished responding in an operant test of conflict as previously demonstrated [5-7], while CRF produced a suppression of both punished and unpunished responding as previously reported [10]. However, alcohol reversed the suppression of punished responding produced by CRF but failed to reverse the suppression of unpunished responding produced by CRF. Indeed, alcohol actually augmented this suppression of unpunished responding. The differential effects
319 of alcohol on the different schedule components are not likely due to the reinforcement scheduling per se, since similar effects were observed with other schedules. For example, if the unpunished component consists of a signalled fixed internal schedule, alcohol reduces the rate of responding but fails to alter the number of reinforcers earned. Alcohol, however, still causes a release of punished responding in the conflict component (reinforcement density was equal in both components) (Koob and Thatcher-Britton, unpublished results). The suppression of unpunished responding produced by CRF is consistent with previous investigations showing that CRF produces behavioral responses in aversive situations suggestive of increased 'stress' [8,11,12]. In addition, systemically administered benzodiazepine (chlordiazepoxide) attenuated the response suppressing effects of CRF [10]. Taken together, these results suggest that exogenous administration of CRF can produce behavioral results consistent with an increase in the aversiveness of the punishing stimulus. Of particular interest is the observation that the alcohol/CRF drug effects in the conflict component reflect the addition of a treatment that releases punished responding (alcohol) and suppresses punished responding (CRF). At the same time, however, these effects also demonstrate the addition of two treatments that suppress unpunished responding. Thus, it seems that the effects of CRF on unpunished responding do not necessarily indicate a generalization of its proconflict effect, since alcohol, if this was the case, should reverse the rate-decreasing effects of CRF on both components. However, as was observed with other alcohol/stimulant effects [5], CRF actually potentiated the disruptive influence of alcohol on operant responding. The reversal of the proconflict effects of CRF on punished responding suggests that at some neuronal level CRF and alcohol may be interacting to produce changes in conflict behavior. This is not a true classic antagonist action in that alcohol and CRF both have effects that are additive in the conflict component which cancel each other out. However, such a clearcut antagonist action is difficult to establish in any system where the antagonist or agonist interacts with an endogenous substrate. For example, both naloxone - the opiate antagonist and FG 7142 - a benzodiazepine ligand can reverse agonist actions but also have actions on their own. Thus, while alcohol's reversal of the proconflict effect of CRF by no means proves a central nervous system interaction, a failure to observe such a reversal would effectively rule out such a possibility. While the cellular and molecular mechanisms [7,15] underlying the biological effects of alcohol are largely unknown, there is evidence to support the hypothesis that alcohol modulates the benzodiazepine GABA receptor ionophore complex via the picrotoxin site [13]. Both biochemically and pharmacologically, alcohol can facilitate GABA function in the central nervous system [14]; the GABA antagonist, picrotoxin, also reverses the anti-conflict effects of alcohol. Whether brain CRF systems might be a particularly sensitive substrate for these neuronal actions of alcohol in producing its acute intoxicating effects remains to be determined.
320
Acknowledgements This work was supported in part by a Merit Review Grant from the Veterans Administration, La Jolla, CA, Alochol Research Center Grant AA06420 and NIH Grant P01 AM26741. We thank Ms. Gin Lee for excellent technical assistance, Dr. Jean Rivier (The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute) for providing the corticotropin-releasing factor, and Dr. John Polich for statistical advice and help on the manuscript. We thank the Basic and Clinical Research Word Processing Center for manuscript preparation. This is publication number 4433BCR from the Research Institute of Scripps Clinic, La Jolla, CA, U.S.A.
References 1 Wallgren, H. and Barry, H., Ili (Eds.), Actions of Alcohol, Elsevier, Amsterdam, 1970. 2 Barry, H., Alcohol. In S.N. Pradhan and S.M. Dutta (Eds.), Drug Abuse: Clinical and Basic Aspects, Mosby, St. Louis, MO, 1977. 3 Geller, I. and Seifter, J., The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in rat, Psychopharmacologia, 1 (1960) 482-492. 4 Pollard, G.T. and Howard, J.L., The Geller-Seifter conflict paradigm with incremental shock, Psychopharmacology, 62 (1979) 117-121. 5 Aston-Jones, S., Aston-Jones, G. and Koob, G.F., Cocaine antagonizes anxiolytic effects of alcohol, Psychopharmacology, 84 (1984) 28-31. 6 Koob, G.F., Thatcher-Britton, K., Britton, D., Roberts, D.C.S. and Bloom, F.E., Destruction of the locus coeruleus or dorsal noradrenergic bundle does not alter release of punished responding by ethanol and chlordiazepoxide, Physiol. Behav., 33 (1984) 479-485. 7 Koob, G.F., Braestrup, C. and Thatcher-Britton, K., The effects of FG7142 and RO15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol, Psychopharmacology, 90 (1986) 173-178. 8 Koob, G.F. and Bloom, F.E., Corticotropin releasing factor and behavior. Fed. Proc., 44 (1985) 259-263. 9 Winer, B.J., Statistical Principles in Experimental Design, McGraw-Hill, New York, 1971. 10 Thatcher-Britton, K., Morgan, J., Rivier, J., Vale, W. and Koob, G.F., Chlordiazepoxide attenuates CRF-induced response suppression in the conflict test, Psychopharmacology, 86 (1985) 170-174. 11 Britton, D.R., Koob, G.F., Rivier, J. and Vale, W., Intraventricular corticotropin releasing factor enhances behavioral effects of novelty, Life Sci., 31 (1982) 363-367. 12 Sutton, R.E., Koob, G.F., LeMoal, M., Rivier, J. and Vale, W., Corticotropin releasing factor produces behavioral activation in rats, Nature, 297 (1982) 331-333. 13 Ticku, M.K., Burch, T.P. and Davis, W.C., The interactions of ethanol with the benzodiazepine GABA receptor ionophore complex, Pharmacol. Biochem. Behav., 18 (1983) Suppl 15-18. 14 Ticku, M.K. and Burch, T., Alterations in GABA receptor sensitivity following acute and chronic ethanol treatment, J. Neurochem. 34 (1980) 417-423. 15 Liljequist, S. and Engel, J.A., Effects of GABAergic agonists and antagonists on various ethanolinduced behavioral changes, Psychopharmacology, 78 (1982) 71-75.
315
RPT 00547
Alcohol reverses the proconflict effect of corticotropin-releasing factor Karen Thatcher-Britton a and George F. K o o b b Department of Psychiatry, aSan Diego Veterans Administration Medical Center, and UCSD School of Medicine, La Jolla, CA 92161, and bDepartment of Basic and Clinical Research Scripps Clinic and Research Foundation 10666 N. Torrey Pines Road, La Jolla, CA 92037, U.S.A. (Received 29 October 1986; revised manuscript received and accepted 4 November 1986)
Summary Alcohol has tension reducing properties in man that are reflected in a release of punished responding in a rat operant conflict test. In contrast, corticotropin releasing factor (CRF), injected centrally produces a suppression of punished and non-punished responding in the conflict test consistent with its hypothesized role in mediating behavioral responses to stress. Alcohol in a dose of 0.75 g/kg reversed the suppressive effects of 0.5 #g CRF injected intracerebroventricularly on punished responding but augmented the suppression of unpunished responding by CRF. Results suggest that one mechanism for the tension reducing properties of acute alcohol intoxication may involve a suppression of brain CRF systems. corticotropin-releasing factor; alcohol; conflict
Introduction Two behavioral effects of alcohol thought to reflect its acute intoxicating actions are motor ataxia and tension reduction. While ataxia is a relatively common measure of the intoxicating effects of alcohol in animals and man [1], its tension-reducing properties have been more difficult to quantify [2]. Early work showed that these tension-reducing properties of alcohol were weak or Please address correspondence to: Dr. George F. Koob, Department of Basic and Clinical Research (BCR1), Scripps Clinic and Research Foundation, 10666 N. Torrey Pines Road, La Jolla, CA 92037, U.S.A. Telephone: (619) 455-9100 ext. 9736. 016%01 ! 5/86/$03.50 © 1986 Elsevier Science Publishers B.V. (Biomedical Division)
316 nonexistent when studied in operant conflict paradigms [2]. However, a modification of the Geller-Seifter procedure [3] using incremental shock [4] has proved particularly sensitive to alcohol effects [5-7]. Low doses of alcohol (0.5-1.0 g/kg intraperitoneally) produce a dose-dependent release of punished responding as reflected by an increase in lever pressing in the incremental shock conflict period [5,6]. The same doses of alcohol produce a dose-dependent decrease in responding during the unpunished component which presumably reflects the acute motor debilitating effects of alcohol [5,6]. The purpose of this study was to examine the effects of alcohol on the proconflict actions of centrally administered corticotropin-releasing factor (CRF), a peptide hypothesized to be important in mediating behavioral responses to stress [8]. The present study found that alcohol reverses the proconflict effects of CRF, but alcohol actually potentiates the disruptive effects of CRF on unpunished responding. These results suggest that brain CRF systems might be one possible site of action for alcohol's acute intoxicating effects.
Materials and Methods
Subjects The subjects were male albino Wistar rats weighing 250 g at the beginning of the experiment. All rats were housed in groups of three in a temperature-, humidity- and light-controlled environment.
Conflict training For conflict testing, rats were deprived of food for 24 h and then maintained on 10-15 g of food per day (gradually increasing during the first few weeks of training and then leveling off at 15 g/day). Rats were first trained to lever press for 45 mg Noyes food pellets on a continuous reinforcement schedule in sound-proof chambers (Coulbourn Instruments, Inc.). Continuous reinforcement training was followed subsequently by training on a random interval 30-s schedule. Finally, the rats were trained on a multiple schedule consisting of two cycles of three components: an unpunished component (5 min), a time out component (2 min) and a punished component (2 min). Responses made during the unpunished component were reinforced on a random interval, 30-s schedule in a darkened chamber. During the time out, the chamber was illuminated and responses were not reinforced. The conflict component was signaled by three flashing lights located above the lever (one per second), and responses were both reinforced with food and punished with foot shocks through stainless steel bars on the floor on a continuous reinforcement schedule. Footshock consisted of a scrambled constant current, biphasic square wave produced by a SGS-003 stimulator (BRS/LVE Div. Tech. Serv., Inc.). With each lever press during the conflict period the shock was incremented by 0.15 mA steps to a maximum of 3.3 mA (22 steps).
317
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Fig. 1. The interaction of alcohol (0.75 g]kg) IP and CRF (0.5 #g) ICV on responding during the conflict (top) and unpunished components (bottom) of an operant conflict test. Number of rats in each group is indicated at bottom of each column. Results are expressed as responses/rain (Mean 4- S.E.M.). * Significantly different from ICV saline (main CRF effect, ANOVA). t Significantly different from IP saline (main alcohol effect, ANOVA).
Experimental procedure After establishing stable responding ( + 10% o f average for three successive days), 46 rats were anesthetized with pentobarbital and implanted with lateral ventricular cannulae. A 7 m m 23-gauge stainless steel guide cannula was lowered to within 1 m m o f the lateral ventricle and secured with two stainless steel screws and dental cement. The stereotaxic coordinates, with the t o o t h b a r 5 m m above interaural zero, were: - 0 . 6 m m posterior to bregma, 4-2.0 m m lateral, and - 3 . 2 m m below the skull surface at the point o f entry. Cannulae were equally distributed between the left and right ventricles. After a m i n i m u m o f five days recovery f r o m surgery the rats were divided r a n d o m l y into four g r o u p s in a 2 x 2 factorial design. One g r o u p (n = 10) received saline injected infraventricularly (ICV) and saline intraperitoneally (IP). A second g r o u p (n = 11) received 0.5 #g C R F injected I C V and saline IP. A third g r o u p (n = 13)
318
received saline ICV and alcohol 0.75 g/kg IP. A fourth group (n = 12) received 0.5 /~g CRF ICV and alcohol 0.75 g/kg 1P. Rat CRF was synthesized by Jean Rivier (Clayton Foundation Laboratories for Peptide Biology, The Salk Institute) and dissolved in 0.9% saline in a concentration of 0.25 /~g/#l. Two ~tl of CRF were injected 30 min prior to the test by gravity. Alcohol was dissolved in saline in a concentration of 10% (w/v) and injected 15 min prior to the test in a volume according to body weight sufficient to produce a dose of 0.75 g/kg.
Data analysis Response rates were computed for each rat in each condition by obtaining the mean rate across replications within a given session. 'lhe drug effects were analyzed with a two-factor (Alcohol x CRF) analysis of variance (ANOVA). This analysis procedure permitted the assessment of the main effects for each drug treatment as well as any statistical interaction between the drug/saline combinations.
Experimental Results The effects of alcohol alone and in combination with CRF are illustrated in the top portion of Figure 1 for the conflict condition and in the bottom portion of Figure 1 for the unpunished condition. During the conflict component, response rates were increased when alcohol was administered for both the saline and CRF treatment conditions to produce a significant main effect for the presence of alcohol .(F = 9.31, df = 1,42, P < 0.01). However, response rates were decreased when CRF was administered for both the saline and alcohol treatment conditions to produce a significant main effect for the presence of CRF (F 13.92, df = 1,42, P < 0.01). No interaction between these factors was obtained (F < 1). During the unpunished component, response rates were decreased when alcohol was administered for both the saline and CRF treatment conditions to produce a significant main effect for the presence of alcohol (F = 5.80, df = 1,42, P < 0.01). Response rates were decreased in the unpunished component as well by CRF for both the saline and alcohol treatment conditions to produce a significant main effect for the presence o f C R F (F = 18.09, df = 1,42, P < 0.01). No interaction between these factors was obtained (F > 1).
Discussion Alcohol produced a release of punished responding in an operant test of conflict as previously demonstrated [5-7], while CRF produced a suppression of both punished and unpunished responding as previously reported [10]. However, alcohol reversed the suppression of punished responding produced by CRF but failed to reverse the suppression of unpunished responding produced by CRF. Indeed, alcohol actually augmented this suppression of unpunished responding. The differential effects
319 of alcohol on the different schedule components are not likely due to the reinforcement scheduling per se, since similar effects were observed with other schedules. For example, if the unpunished component consists of a signalled fixed internal schedule, alcohol reduces the rate of responding but fails to alter the number of reinforcers earned. Alcohol, however, still causes a release of punished responding in the conflict component (reinforcement density was equal in both components) (Koob and Thatcher-Britton, unpublished results). The suppression of unpunished responding produced by CRF is consistent with previous investigations showing that CRF produces behavioral responses in aversive situations suggestive of increased 'stress' [8,11,12]. In addition, systemically administered benzodiazepine (chlordiazepoxide) attenuated the response suppressing effects of CRF [10]. Taken together, these results suggest that exogenous administration of CRF can produce behavioral results consistent with an increase in the aversiveness of the punishing stimulus. Of particular interest is the observation that the alcohol/CRF drug effects in the conflict component reflect the addition of a treatment that releases punished responding (alcohol) and suppresses punished responding (CRF). At the same time, however, these effects also demonstrate the addition of two treatments that suppress unpunished responding. Thus, it seems that the effects of CRF on unpunished responding do not necessarily indicate a generalization of its proconflict effect, since alcohol, if this was the case, should reverse the rate-decreasing effects of CRF on both components. However, as was observed with other alcohol/stimulant effects [5], CRF actually potentiated the disruptive influence of alcohol on operant responding. The reversal of the proconflict effects of CRF on punished responding suggests that at some neuronal level CRF and alcohol may be interacting to produce changes in conflict behavior. This is not a true classic antagonist action in that alcohol and CRF both have effects that are additive in the conflict component which cancel each other out. However, such a clearcut antagonist action is difficult to establish in any system where the antagonist or agonist interacts with an endogenous substrate. For example, both naloxone - the opiate antagonist and FG 7142 - a benzodiazepine ligand can reverse agonist actions but also have actions on their own. Thus, while alcohol's reversal of the proconflict effect of CRF by no means proves a central nervous system interaction, a failure to observe such a reversal would effectively rule out such a possibility. While the cellular and molecular mechanisms [7,15] underlying the biological effects of alcohol are largely unknown, there is evidence to support the hypothesis that alcohol modulates the benzodiazepine GABA receptor ionophore complex via the picrotoxin site [13]. Both biochemically and pharmacologically, alcohol can facilitate GABA function in the central nervous system [14]; the GABA antagonist, picrotoxin, also reverses the anti-conflict effects of alcohol. Whether brain CRF systems might be a particularly sensitive substrate for these neuronal actions of alcohol in producing its acute intoxicating effects remains to be determined.
320
Acknowledgements This work was supported in part by a Merit Review Grant from the Veterans Administration, La Jolla, CA, Alochol Research Center Grant AA06420 and NIH Grant P01 AM26741. We thank Ms. Gin Lee for excellent technical assistance, Dr. Jean Rivier (The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute) for providing the corticotropin-releasing factor, and Dr. John Polich for statistical advice and help on the manuscript. We thank the Basic and Clinical Research Word Processing Center for manuscript preparation. This is publication number 4433BCR from the Research Institute of Scripps Clinic, La Jolla, CA, U.S.A.
References 1 Wallgren, H. and Barry, H., Ili (Eds.), Actions of Alcohol, Elsevier, Amsterdam, 1970. 2 Barry, H., Alcohol. In S.N. Pradhan and S.M. Dutta (Eds.), Drug Abuse: Clinical and Basic Aspects, Mosby, St. Louis, MO, 1977. 3 Geller, I. and Seifter, J., The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in rat, Psychopharmacologia, 1 (1960) 482-492. 4 Pollard, G.T. and Howard, J.L., The Geller-Seifter conflict paradigm with incremental shock, Psychopharmacology, 62 (1979) 117-121. 5 Aston-Jones, S., Aston-Jones, G. and Koob, G.F., Cocaine antagonizes anxiolytic effects of alcohol, Psychopharmacology, 84 (1984) 28-31. 6 Koob, G.F., Thatcher-Britton, K., Britton, D., Roberts, D.C.S. and Bloom, F.E., Destruction of the locus coeruleus or dorsal noradrenergic bundle does not alter release of punished responding by ethanol and chlordiazepoxide, Physiol. Behav., 33 (1984) 479-485. 7 Koob, G.F., Braestrup, C. and Thatcher-Britton, K., The effects of FG7142 and RO15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol, Psychopharmacology, 90 (1986) 173-178. 8 Koob, G.F. and Bloom, F.E., Corticotropin releasing factor and behavior. Fed. Proc., 44 (1985) 259-263. 9 Winer, B.J., Statistical Principles in Experimental Design, McGraw-Hill, New York, 1971. 10 Thatcher-Britton, K., Morgan, J., Rivier, J., Vale, W. and Koob, G.F., Chlordiazepoxide attenuates CRF-induced response suppression in the conflict test, Psychopharmacology, 86 (1985) 170-174. 11 Britton, D.R., Koob, G.F., Rivier, J. and Vale, W., Intraventricular corticotropin releasing factor enhances behavioral effects of novelty, Life Sci., 31 (1982) 363-367. 12 Sutton, R.E., Koob, G.F., LeMoal, M., Rivier, J. and Vale, W., Corticotropin releasing factor produces behavioral activation in rats, Nature, 297 (1982) 331-333. 13 Ticku, M.K., Burch, T.P. and Davis, W.C., The interactions of ethanol with the benzodiazepine GABA receptor ionophore complex, Pharmacol. Biochem. Behav., 18 (1983) Suppl 15-18. 14 Ticku, M.K. and Burch, T., Alterations in GABA receptor sensitivity following acute and chronic ethanol treatment, J. Neurochem. 34 (1980) 417-423. 15 Liljequist, S. and Engel, J.A., Effects of GABAergic agonists and antagonists on various ethanolinduced behavioral changes, Psychopharmacology, 78 (1982) 71-75.