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Naltrexone blocks the response-latency increasing effects but not the discriminative effects of diazepam in rats
European Journal of Pharrnacology, 88 (1983) 121-124 Elsevier Biomedical Press
121
Short communication
NALTREXONE BLOCKS THE RESPONSE-LATENCY INCREASING EFFECTS BUT NOT THE D I S C R I M I N A T I V E E F F E C T S OF D I A Z E P A M IN RATS SEYMORE HERLING *
National Institute on Drug Abuse, Division of Research, Addiction Research Center, P.O. Box 12390, Lexington, Kentucky 40583, U.S.A. Received 12 January 1983, accepted 17 January 1983
S. H E R L I N G , Naltrexone blocks the response-latency increasing effects but not the discriminative effects of diazepam in rats, E u r o p e a n J. Pharmacol. 88 (1983) 121-124. Interactions between d i a z e p a m a n d naltrexone were evaluated in male F344 rats that were trained to discriminate between saline a n d 3.0 m g / k g of diazepam in a two-choice discrete-trial avoidance task. Naltrexone, up to 100 m g / k g s.c., had n o effect on the discriminative effects of d i a z e p a m (0.1-10.0 m g / k g s.c.), but produced a dose-related a t t e n u a t i o n of the increase in response latency produced by 3.0 and 10.0 m g / k g of diazepam. These results suggest that the effects of d i a z e p a m on response latency, but not the drug's discriminative effects, are mediated by a nahrexone-sensitive mechanism.
Naltrexone
Diazepam
Discriminative stimulus effects
1. Introduction
2. Materials and methods
A number of recent reports have indicated that narcotic antagonists (e.g., naloxone, naltrexone) block certain of the behavioral effects of sedativehypnotics. For example, naloxone blocks the increase in punished responding produced by diazepam, meprobamate, alcohol and chlordiazepoxide (Koob et al., 1980; Duka et al., 1981) and it has been suggested that the anxiolytic actions of these compounds are the result of activation of endogenous opioid systems. On the other hand, Shearman et al. (1983) have recently shown that naloxone, up to 80 m g / k g , fails to modify the discriminative stimulus effects produced by diazepam. The purpose of the present experiment was to extend this latter finding and determine whether the discriminative effects of diazepam or the effects of diazepam on response latency, might be antagonized by the more potent narcotic antagonist naltrexone.
Male, Fischer-derived F344 rats were trained to discriminate between saline and 3.0 m g / k g diazepam in a two-choice, discrete-trial avoidance task similar to that described in detail elsewhere (Shannon, 1981). Experimental sessions were conducted in standard rat chambers that were modified as described previously (Shannon, 1981). Diazepam or saline was administered s.c. 30 min prior to daily training sessions which consisted of 20 trials. During each trial, the subject was required to press a starting response lever, then to move to the opposite side of the chamber and press one of two choice levers in order to avoid or escape a 1.0 mA electric shock that was delivered to the grid floor of the chamber. The appropriate choice lever to be pressed was determined by the presession injection (e.g., left lever after diazepam, right lever after saline). The rats were trained until they reliably completed at least 90% of the trials during each training session on the appropriate choice lever. When acquisition of the discrimination was completed, test sessions were interposed among training sessions. During training sessions,
* Present address; Addiction Research Foundation, 33 Russell Street, Toronto, Ontario, Canada M5S 2S1.
122
only a response on the appropriate choice lever terminated a trial; during test sessions, a response on either choice lever terminated a trial. In all other respects, test sessions were identical to training sessions. During tests sessions, diazepam (0.1-10.0 m g / k g s.c.) was administered alone or concomitantly with either saline or naltrexone (3.0-100 m g / k g s.c.), 30 min before the session. The data for the discriminative control of responding exerted by diazepam alone or in combination with naltrexone are presented as the percentage of trials, out of 20, completed on the diazepam-appropriate lever. In addition, the latency to respond on the starting response lever was recorded cumulatively throughout the session. Since the response latency data were not normally distributed, a square root transformation was made on all the latency data obtained (Edwards, 1967). Subsequent statistical analyses on the response latency data, including analysis of variance, orthogonal comparisons and Student's t-test for group observations, were performed on the transformed data.
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3. Results
Fig. 1. Failure of nahrexone (NTX), 10 or 100 m g / k g s.c., to modify the discriminative effects of diazepam. Upper panel ordinates: % diazepam-lever responses. Lower panel ordinates: cumulative starting response-lever latency (s). Abscissae: dose of diazepam ( m g / k g s.c.). Dashed lines in the lower panel indicate the range of response latencies following the administration of saline. Each point is the average of a single observation in each of 5 rats.
When administered alone, diazepam (0.1-3.0 m g / k g ) produced a dose-related increase in the percentage of responses emitted on the diazepamappropriate lever, with 3.0 m g / k g producing nearly 100% diazepam-choice lever responses (fig. 1, upper panel; closed circles). Doses of diazepam up to and including 1.0 m g / k g had no effect on the latency to respond on the starting lever (fig. 1, lower panel; closed circles). However, the highest diazepam dose, 3.0 m g / k g , produced approximately a two-fold increase in the cumulative starting response latency (t(8) = 2.96, P < 0.05, vs. saline). Naltrexone (10.0 or 100 m g / k g ) had little or no effect on diazepam-appropriate responding produced by increasing doses of diazepam (fig. 1, upper panel). In contrast, the increased response latency produced by 3.0 m g / k g of diazepam was antagonized by both 10.0 and 100 m g / k g of nahrexone (fig. 1, lower panel). To investigate further the apparent antagonism of the effects of diazepam on response latency, a
second group of five rats was administered diazepam, 3.0 or 10.0 m g / k g , with saline or increasing doses of naltrexone (3.0-100 mg/kg). Diazepam, when administered with saline, produced a dose-related increase in response latency (fig. 2, lower panel: points above 'S'). Analysis of variance yielded significant effects of diazepam dose (F(2,52)= 6.00, P < 0.005). These doses of diazepam resulted in more than 99% diazepam-lever responses (fig. 2, upper panel: points above 'S'). Increasing doses of naltrexone, although having no effect on the percentage of diazepam-lever responses produced by either 3.0 or 10.0 m g / k g of diazepam (fig. 2, upper panel), produced a dose-related attenuation of the response-latency increasing effects of both doses of diazepam (fig. 2, lower panel). The dose-effect curves for naltrexone's blockade of diazepam's effect on response latency were significantly linear over the dose range of 3.0 to 30.0 m g / k g (F(2,28)= 5.87, P < 0.02). Naltre-
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NALTREXONE ( mg/kg, s.c.) Fig. 2. Nahrexone blocks the response-latency increasing effects of diazepam (lower panel) but not the discriminative effects of diazepam (upper panel). Ordinates: as in fig. 1. Abscissae: dose of naltrexone ( m g / k g s.c.). Points above 'S' indicate the effects of saline either alone (triangle) or in combination with 3.0 m g / k g (open circles) or 10.0 m g / k g (closed circles) of diazepam. Other details as in fig. 1.
xone (30.0 and 100 mg/kg), administered alone, had no effect on response latency and produced only saline-appropriate responding (fig. 2; open triangles).
4. Discussion Diazepam produced dose-related increases in responses made on the diazepam-appropriate lever (i.e., discriminative effects) and dose-related increases in response latency. While the effects of a drug on latency to respond may be a function of several different actions of the drug, it has been suggested that latency to respond, in the context of the present procedure, is a quantitative measure of behavioral stimulation or depression during the
performance of the discrimination (Shannon and Holtzman, 1976). Rats receiving high doses of diazepam (3.0-10.0 mg/kg) in the present experiment were observed to be moderately to markedly sedated, in that the motor activity of the rats, both before and after the experimental session, was reduced. Thus, the ability of diazepam to increase response latency in the present experiment may be related to the drug's sedative effects. Naltrexone had no effect on the discriminative effects of diazepam, but it did produce a dose-related attenuation of the effects of diazepam on response latency. These results suggest that the discriminative effects of diazepam and the effects of diazepam on response latency are mediated differently. The inability of naltrexone to modify the discriminative effects of diazepam is in direct contrast to results obtained with either Ro 15-1788 or CGS 8216, potent antagonists at the benzodiazepine receptor in the CNS (e.g., Czernik et al., 1982). These latter compounds have been shown to antagonize both the discriminative and responselatency increasing effects of diazepam (Herling and Shannon, 1982 and unpublished observations), indicating that both effects of diazepam are mediated in part by central benzodiazepine receptors. That naltrexone, a potent opioid antagonist, did not block the discriminative effects of diazepam suggests that endogenous opioid systems are not involved in the discriminative effects of diazepam, and extends recent finclings by Shearman et al. (1983) on the inability of naloxone to antagonize the discriminative effects of diazepam. As noted in the introduction, however, certain other effects of diazepam (e.g., its ability to increase punished responding) do appear to be blocked by narcotic antagonists and may involve opioid systems (e.g., Duka et al., 1981). Naltrexone did reverse, although incompletely, the increase in response latency produced by large doses of diazepam. While this effect may be related to naltrexone's ability to block diazepaminduced activation of endogenous opioid systems, another possibility, considering the large doses of naltrexone needed, is that naltrexone blocks the effects of diazepam on response latency through GABAergic mechanisms. A primary effect of ben-
124 z o d i a z e p i n e s is to e n h a n c e G A B A e r g i c n e u r o t r a n s m i s s i o n ( H a e f e l y et al., 1975) a n d n a l o x o n e , at h i g h doses, acts as a G A B A a n t a g o n i s t ( D i n g l e d i n e et al., 1978). W h e t h e r n a l t r e x o n e d o e s as well, has yet to b e d e t e r m i n e d , a l t h o u g h at least o n e b e h a v i o r a l effect s h a r e d b y h i g h d o s e s of n a l o x o n e a n d n a l t r e x o n e , c o n v u l s i o n s , c a n be b l o c k e d b y d i a z e p a m ( B l u m b e r g et al., 1977; D i n g l e d i n e et al., 1978), a n d n a l o x o n e - i n d u c e d c o n v u l s i o n s are t h o u g h t to be t h e result o f G A B A r e c e p t o r block a d e ( D i n g l e d i n e et al., 1978). P e r h a p s d i a z e p a m and other benzodiazepines interact with central b e n z o d i a z e p i n e r e c e p t o r s that are a s s o c i a t e d w i t h G A B A r e c e p t o r s to p r o d u c e effects o n r e s p o n s e l a t e n c y ( p e r h a p s s e d a t i v e effects), a n d n a l t r e x o n e , at h i g h doses, acts as a G A B A a n t a g o n i s t to b l o c k t h e s e effects. T h e d i s c r i m i n a t i v e effects of dia z e p a m , o n the o t h e r h a n d , m a y be m e d i a t e d by b e n z o d i a z e p i n e sites t h a t d o n o t i n t e r a c t w i t h G A B A e r g i c s y s t e m s since the d i s c r i m i n a t i v e effects of d i a z e p a m are n o t a n t a g o n i z e d b y the G A B A s y n a p t i c a n t a g o n i s t p i c r o t o x i n (S. H e r l i n g a n d G. W i n g e r , u n p u b l i s h e d o b s e r v a t i o n s ) n o r w e r e these effects a n t a g o n i z e d b y n a l t r e x o n e in the p r e s e n t e x p e r i m e n t . In s u m m a r y , the p r e s e n t results suggest t h a t c e r t a i n effects of d i a z e p a m (perh a p s s e d a t i v e effects) are b l o c k e d by n a l t r e x o n e , w h e r e a s c e r t a i n o t h e r effects (e.g., d i s c r i m i n a t i v e e f f e c t s ) are not.
Acknowledgements I thank Harlan Shannon and Charles Gorodetzky for helpful suggestions that improved the manuscript, Bruce Vaupel for statistical advice, and Wanda Roberts for help in preparing the text.
References Blumberg, H., L.L. Di Palma and C. Ikeda, 1977, Counteraction of tremors and convulsions produced by large doses of the narcotic antagonist naltrexone in mice, Fed. Proc. 36, 1025. Czernik, A.J., B. Petrack, H.J. Kalinsky, S. Psychoyos, W.D. Cash, C. Tsai, R.K. Rinehart, F.R. Granat, R.A. Lovelk D.E. Brundish and R. Wade, 1982, CGS 8216: Receptor binding characteristics of a potent benzodiazepine antagonist, Life Sci. 30, 363. Dingledine, R., L.L. Iversen and E. Breuker, 1978, Naloxone as a GABA antagonist: evidence from iontophoretic, receptor binding and convulsant studies, European J. Pharmacol. 47, 19. Duka, T., R. Cumin, W. Haefely and A. Herz, 1981, Naloxone blocks the effect of diazepam and meprobamate on conflict behaviour in rats, Pharmacol. Biochem. Behav. 15, 115. Edwards, A.L., 1967, Statistical Methods, 2nd ed. (Holt, Rinehart and Winston, New York). Haefely, W., A. Kulcsar, H. Mohler, L. Pieri. P. Polc and R. Schaffner, 1975, Possible involvement of GABA in the central actions of benzodiazepines, in: Mechanisms of Action of Benzodiazepines, eds. E. Costa and P. Greengard (Raven Press, New York) p. 131. Herling, S. and H.E. Shannon, 1982, Ro 15-1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital, Life Sci. 31, 2105. Koob, G.F., R.E. Strecker and F.E. Bloom, 1980, Effects of naloxone on the anticonflict properties of alcohol and chlordiazepoxide, Subst. Alc. Actions/Misuse 1,447. Shannon, H.E., 1981, Evaluation of phencyclidine analogs on the basis of their discriminative stimulus properties in the rat, J. Pharmacol. Exp. Ther. 216. 543. Shannon, H.E. and S.G. Holtzman, 1976, Evaluation of the discriminative effects of morphine in the rat, J. Pharmacol. Exp. Ther. 198, 54. Shearman, G.T., M.J. Millan and A. Herz, 1983, Lack of evidence for a role of endorphinergic mechanisms in mediating a discriminative stimulus produced by diazepam in rats, Psychopharmacol. (in press).
121
Short communication
NALTREXONE BLOCKS THE RESPONSE-LATENCY INCREASING EFFECTS BUT NOT THE D I S C R I M I N A T I V E E F F E C T S OF D I A Z E P A M IN RATS SEYMORE HERLING *
National Institute on Drug Abuse, Division of Research, Addiction Research Center, P.O. Box 12390, Lexington, Kentucky 40583, U.S.A. Received 12 January 1983, accepted 17 January 1983
S. H E R L I N G , Naltrexone blocks the response-latency increasing effects but not the discriminative effects of diazepam in rats, E u r o p e a n J. Pharmacol. 88 (1983) 121-124. Interactions between d i a z e p a m a n d naltrexone were evaluated in male F344 rats that were trained to discriminate between saline a n d 3.0 m g / k g of diazepam in a two-choice discrete-trial avoidance task. Naltrexone, up to 100 m g / k g s.c., had n o effect on the discriminative effects of d i a z e p a m (0.1-10.0 m g / k g s.c.), but produced a dose-related a t t e n u a t i o n of the increase in response latency produced by 3.0 and 10.0 m g / k g of diazepam. These results suggest that the effects of d i a z e p a m on response latency, but not the drug's discriminative effects, are mediated by a nahrexone-sensitive mechanism.
Naltrexone
Diazepam
Discriminative stimulus effects
1. Introduction
2. Materials and methods
A number of recent reports have indicated that narcotic antagonists (e.g., naloxone, naltrexone) block certain of the behavioral effects of sedativehypnotics. For example, naloxone blocks the increase in punished responding produced by diazepam, meprobamate, alcohol and chlordiazepoxide (Koob et al., 1980; Duka et al., 1981) and it has been suggested that the anxiolytic actions of these compounds are the result of activation of endogenous opioid systems. On the other hand, Shearman et al. (1983) have recently shown that naloxone, up to 80 m g / k g , fails to modify the discriminative stimulus effects produced by diazepam. The purpose of the present experiment was to extend this latter finding and determine whether the discriminative effects of diazepam or the effects of diazepam on response latency, might be antagonized by the more potent narcotic antagonist naltrexone.
Male, Fischer-derived F344 rats were trained to discriminate between saline and 3.0 m g / k g diazepam in a two-choice, discrete-trial avoidance task similar to that described in detail elsewhere (Shannon, 1981). Experimental sessions were conducted in standard rat chambers that were modified as described previously (Shannon, 1981). Diazepam or saline was administered s.c. 30 min prior to daily training sessions which consisted of 20 trials. During each trial, the subject was required to press a starting response lever, then to move to the opposite side of the chamber and press one of two choice levers in order to avoid or escape a 1.0 mA electric shock that was delivered to the grid floor of the chamber. The appropriate choice lever to be pressed was determined by the presession injection (e.g., left lever after diazepam, right lever after saline). The rats were trained until they reliably completed at least 90% of the trials during each training session on the appropriate choice lever. When acquisition of the discrimination was completed, test sessions were interposed among training sessions. During training sessions,
* Present address; Addiction Research Foundation, 33 Russell Street, Toronto, Ontario, Canada M5S 2S1.
122
only a response on the appropriate choice lever terminated a trial; during test sessions, a response on either choice lever terminated a trial. In all other respects, test sessions were identical to training sessions. During tests sessions, diazepam (0.1-10.0 m g / k g s.c.) was administered alone or concomitantly with either saline or naltrexone (3.0-100 m g / k g s.c.), 30 min before the session. The data for the discriminative control of responding exerted by diazepam alone or in combination with naltrexone are presented as the percentage of trials, out of 20, completed on the diazepam-appropriate lever. In addition, the latency to respond on the starting response lever was recorded cumulatively throughout the session. Since the response latency data were not normally distributed, a square root transformation was made on all the latency data obtained (Edwards, 1967). Subsequent statistical analyses on the response latency data, including analysis of variance, orthogonal comparisons and Student's t-test for group observations, were performed on the transformed data.
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DIAZEPAM (mg/kg, s.c.)
3. Results
Fig. 1. Failure of nahrexone (NTX), 10 or 100 m g / k g s.c., to modify the discriminative effects of diazepam. Upper panel ordinates: % diazepam-lever responses. Lower panel ordinates: cumulative starting response-lever latency (s). Abscissae: dose of diazepam ( m g / k g s.c.). Dashed lines in the lower panel indicate the range of response latencies following the administration of saline. Each point is the average of a single observation in each of 5 rats.
When administered alone, diazepam (0.1-3.0 m g / k g ) produced a dose-related increase in the percentage of responses emitted on the diazepamappropriate lever, with 3.0 m g / k g producing nearly 100% diazepam-choice lever responses (fig. 1, upper panel; closed circles). Doses of diazepam up to and including 1.0 m g / k g had no effect on the latency to respond on the starting lever (fig. 1, lower panel; closed circles). However, the highest diazepam dose, 3.0 m g / k g , produced approximately a two-fold increase in the cumulative starting response latency (t(8) = 2.96, P < 0.05, vs. saline). Naltrexone (10.0 or 100 m g / k g ) had little or no effect on diazepam-appropriate responding produced by increasing doses of diazepam (fig. 1, upper panel). In contrast, the increased response latency produced by 3.0 m g / k g of diazepam was antagonized by both 10.0 and 100 m g / k g of nahrexone (fig. 1, lower panel). To investigate further the apparent antagonism of the effects of diazepam on response latency, a
second group of five rats was administered diazepam, 3.0 or 10.0 m g / k g , with saline or increasing doses of naltrexone (3.0-100 mg/kg). Diazepam, when administered with saline, produced a dose-related increase in response latency (fig. 2, lower panel: points above 'S'). Analysis of variance yielded significant effects of diazepam dose (F(2,52)= 6.00, P < 0.005). These doses of diazepam resulted in more than 99% diazepam-lever responses (fig. 2, upper panel: points above 'S'). Increasing doses of naltrexone, although having no effect on the percentage of diazepam-lever responses produced by either 3.0 or 10.0 m g / k g of diazepam (fig. 2, upper panel), produced a dose-related attenuation of the response-latency increasing effects of both doses of diazepam (fig. 2, lower panel). The dose-effect curves for naltrexone's blockade of diazepam's effect on response latency were significantly linear over the dose range of 3.0 to 30.0 m g / k g (F(2,28)= 5.87, P < 0.02). Naltre-
123 I
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NALTREXONE ( mg/kg, s.c.) Fig. 2. Nahrexone blocks the response-latency increasing effects of diazepam (lower panel) but not the discriminative effects of diazepam (upper panel). Ordinates: as in fig. 1. Abscissae: dose of naltrexone ( m g / k g s.c.). Points above 'S' indicate the effects of saline either alone (triangle) or in combination with 3.0 m g / k g (open circles) or 10.0 m g / k g (closed circles) of diazepam. Other details as in fig. 1.
xone (30.0 and 100 mg/kg), administered alone, had no effect on response latency and produced only saline-appropriate responding (fig. 2; open triangles).
4. Discussion Diazepam produced dose-related increases in responses made on the diazepam-appropriate lever (i.e., discriminative effects) and dose-related increases in response latency. While the effects of a drug on latency to respond may be a function of several different actions of the drug, it has been suggested that latency to respond, in the context of the present procedure, is a quantitative measure of behavioral stimulation or depression during the
performance of the discrimination (Shannon and Holtzman, 1976). Rats receiving high doses of diazepam (3.0-10.0 mg/kg) in the present experiment were observed to be moderately to markedly sedated, in that the motor activity of the rats, both before and after the experimental session, was reduced. Thus, the ability of diazepam to increase response latency in the present experiment may be related to the drug's sedative effects. Naltrexone had no effect on the discriminative effects of diazepam, but it did produce a dose-related attenuation of the effects of diazepam on response latency. These results suggest that the discriminative effects of diazepam and the effects of diazepam on response latency are mediated differently. The inability of naltrexone to modify the discriminative effects of diazepam is in direct contrast to results obtained with either Ro 15-1788 or CGS 8216, potent antagonists at the benzodiazepine receptor in the CNS (e.g., Czernik et al., 1982). These latter compounds have been shown to antagonize both the discriminative and responselatency increasing effects of diazepam (Herling and Shannon, 1982 and unpublished observations), indicating that both effects of diazepam are mediated in part by central benzodiazepine receptors. That naltrexone, a potent opioid antagonist, did not block the discriminative effects of diazepam suggests that endogenous opioid systems are not involved in the discriminative effects of diazepam, and extends recent finclings by Shearman et al. (1983) on the inability of naloxone to antagonize the discriminative effects of diazepam. As noted in the introduction, however, certain other effects of diazepam (e.g., its ability to increase punished responding) do appear to be blocked by narcotic antagonists and may involve opioid systems (e.g., Duka et al., 1981). Naltrexone did reverse, although incompletely, the increase in response latency produced by large doses of diazepam. While this effect may be related to naltrexone's ability to block diazepaminduced activation of endogenous opioid systems, another possibility, considering the large doses of naltrexone needed, is that naltrexone blocks the effects of diazepam on response latency through GABAergic mechanisms. A primary effect of ben-
124 z o d i a z e p i n e s is to e n h a n c e G A B A e r g i c n e u r o t r a n s m i s s i o n ( H a e f e l y et al., 1975) a n d n a l o x o n e , at h i g h doses, acts as a G A B A a n t a g o n i s t ( D i n g l e d i n e et al., 1978). W h e t h e r n a l t r e x o n e d o e s as well, has yet to b e d e t e r m i n e d , a l t h o u g h at least o n e b e h a v i o r a l effect s h a r e d b y h i g h d o s e s of n a l o x o n e a n d n a l t r e x o n e , c o n v u l s i o n s , c a n be b l o c k e d b y d i a z e p a m ( B l u m b e r g et al., 1977; D i n g l e d i n e et al., 1978), a n d n a l o x o n e - i n d u c e d c o n v u l s i o n s are t h o u g h t to be t h e result o f G A B A r e c e p t o r block a d e ( D i n g l e d i n e et al., 1978). P e r h a p s d i a z e p a m and other benzodiazepines interact with central b e n z o d i a z e p i n e r e c e p t o r s that are a s s o c i a t e d w i t h G A B A r e c e p t o r s to p r o d u c e effects o n r e s p o n s e l a t e n c y ( p e r h a p s s e d a t i v e effects), a n d n a l t r e x o n e , at h i g h doses, acts as a G A B A a n t a g o n i s t to b l o c k t h e s e effects. T h e d i s c r i m i n a t i v e effects of dia z e p a m , o n the o t h e r h a n d , m a y be m e d i a t e d by b e n z o d i a z e p i n e sites t h a t d o n o t i n t e r a c t w i t h G A B A e r g i c s y s t e m s since the d i s c r i m i n a t i v e effects of d i a z e p a m are n o t a n t a g o n i z e d b y the G A B A s y n a p t i c a n t a g o n i s t p i c r o t o x i n (S. H e r l i n g a n d G. W i n g e r , u n p u b l i s h e d o b s e r v a t i o n s ) n o r w e r e these effects a n t a g o n i z e d b y n a l t r e x o n e in the p r e s e n t e x p e r i m e n t . In s u m m a r y , the p r e s e n t results suggest t h a t c e r t a i n effects of d i a z e p a m (perh a p s s e d a t i v e effects) are b l o c k e d by n a l t r e x o n e , w h e r e a s c e r t a i n o t h e r effects (e.g., d i s c r i m i n a t i v e e f f e c t s ) are not.
Acknowledgements I thank Harlan Shannon and Charles Gorodetzky for helpful suggestions that improved the manuscript, Bruce Vaupel for statistical advice, and Wanda Roberts for help in preparing the text.
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