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Epinephrine-induced memory facilitation: attenuation by adrenoceptor antagonists
European Journal of Pharmacology, 129 (1986) 189-193
189
Elsevier
EJP 439SC
Short communication
Epinephrine-induced memory facilitation: attenuation by adrenoceptor antagonists D e b r a B. Sternberg, D o n n a Korol, G a r y D. N o v a c k , and James L. M c G a u g h * Center for the Neurobiology of Learning and Memory and Department of Psychobiology, University of California, Irvine, CA 92 717, U.S.A. Received 11 July 1986, accepted 5 August 1986
The present study examined the relative importance of a- and fl-adrenoceptors in the memory modulatory effects of epinephrine. Posttraining epinephrine administration enhanced retention performance of a one-trial inhibitory avoidance response. Further pretraining injections of a variety of adrenoceptor antagonists, including selective al-, a2-, ill- and/or flz-adrenoceptor antagonists, attenuated the retention enhancing effects of posttraining epinephrine. These results suggest that a- and fl-adrenoceptors of both subtypes are involved in the memory-modulating effects of epinephrine. Memory facilitation; Epinephrine; Adrenoceptor antagonists; Inhibitory avoidance; (Rat) 1. Introduction
Evidence from a number of laboratories indicates that posttraining administration of epinephrine influences subsequent retention performance in rats and mice trained in a variety of aversively and appetitively motivated tasks (Borrell et al., 1983; McGaugh et al., 1984; Introini-Collison and McGaugh, 1986; Sternberg et al., 1985a,b). Retention is generally enhanced by low doses of epinephrine and impaired with higher doses. However, the nature (enhancement or impairment) and the degree of the effects of epinephrine on memory are influenced by a variety of factors including the doses used, the training conditions, and the temporal relationship between training and treatment (Gold and McGaugh, 1978; McGaugh et al., 1984). These findings support the view that endogenous epinephrine released by training experiences may be involved in regulating memory storage
* To whom all correspondence should be addressed. 0014-2999/86/$03.50 © 1986 Elsevier Science Publishers B.V.
processes (Gold and McGaugh, 1978). Other recent findings provide additional support for this view. Several studies have shown, for example, that training experiences increase plasma epinephrine levels (cf. Gold et al., 1982). Further, retention is impaired in adrenal demedullated rats and the impairment is attenuated by posttraining administration of epinephrine (Borrell et al., 1983; Liang et al., 1985). Other findings suggest that endogenously released epinephrine may also play a role in the effects of several treatments known to affect memory. For example, systemic administration of any of several a- or fl-adrenoceptor antagonists prior to training attenuates the enhancing and amnestic effectiveness of many treatments (cf. Gold et al., 1982; cf. McGaugh et al., 1984; Sternberg et al., 1985a,b). The finding that intracerebroventricular administration of several adrenoceptor antagonists does not block the amnestic effect of frontal cortex stimulation (Sternberg and Gold, 1981) suggests that epinephrine may influence memory through effects initiated at peripheral receptors. Several studies have reported that the effects of
190
posttraining epinephrine on memory are blocked in animals given adrenoceptor antagonists prior to training (cf. McGaugh et al., 1984; Sternberg et al., 1985a). As epinephrine is an agonist at a variety of adrenoceptors, we undertook the present study to determine the relative importance of a- and fl-adrenoceptors in the memory modulatory effects of epinephrine on retention of an inhibitory avoidance response.
2. Materials and methods
Male Sprague-Dawley rats (Charles River Laboratories; 70-90 days old) weighing 280-360 g were used in these experiments. The animals were individually housed upon arrival and were maintained on a 12 h light-dark cycle ( 7 : 0 0 a.m. o n - 7 : 0 0 p.m. off). During the first 7-10 days after arrival, the animals received ad libitum access to food and water. One week prior to training, the animals were placed on a water deprivation schedule that reduced their body weights to 85-90% of initial body weights. Each animal received a daily aliquot of water sufficient to maintain this weight level. All training and testing procedures were performed between 1 : 0 0 and 4 : 0 0 p.m. The animals were trained in a one-trial inhibitory (passive) avoidance task. The apparatus consisted of a trough-shaped alley divided by a sliding door into a well lit white start compartment and a dimly lit shock compartment. The walls and floor of the shock compartment consisted of stainless steel plates through which the footshock (350/xA, 0.7 s, constant current) was delivered. Each animal received a total of 5 pretraining sessions over a 3 day period. On each trial, the animal was placed in the start compartment. Ten seconds later, the door was opened and the animal was permitted access to a water spout that protruded from the far end of the shock compartment. The animal was allowed to drink for a 30 s period following the first lick. After 5 trials, all animals approached the spout within 20 s and drank for at least 25 s of the 30 s period. Thirty minutes prior to the training trial, each animal received an intraperitoneal injection of either saline, tylose (Hoechst), or one of the fol-
lowing a- or fl-antagonists: prazosin (0.5 m g / k g ; Pfizer Inc.), an al-adrenoceptor antagonist: yohimbine HC1 (1 m g / k g ; Sigma), an a2-adrenoce ptor antagonist; phentolamine HC1 (5 m g / k g ; Ciba-Geigy Co.), an al,2-adrenoceptor antagonist; atenolol (5 m g / k g ; Stuart Pharmaceuticals), a B1adrenoceptor antagonist; zinterol HC1 (1.0 m g / k g ; Bristol Myers Co.), a fl2-adrenoceptor antagonist; dl-propranolol (0.5 m g / k g ; Sigma), a /~l,2adrenoceptor antagonist; or medraxolol HC1 (1.0 m g / k g ; Merrell-Dow Pharmaceuticals), an al. 2, fl~.2-adrenoceptor antagonist. The drugs were dissolved in isotonic saline or suspended in tylose, and were injected at 1.0 ml/kg. Doses used for antagonists in this study are known to block adrenoceptors; and preliminary studies indicated that in these doses the antagonists do not affect retention performance, and do not affect flinch or j u m p thresholds (unpublished findings). The procedures used on the training trial were comparable to those on the pretraining trials except each animal received a footshock (350 ~A for 0.7 s) during the 10th s of drinking, and was then removed from the apparatus and given a subcutaneous injection of saline or epinephrine (0.01 m g / k g ; a dose which was previously shown to produce enhancement of retention in this task as well as other tasks). Eighteen groups of rats were trained (N = 8-22 for pre- and postdrug injected groups, N = 62 and 63, respectively, for saline + saline, and saline + epinephrine controls). On the 5th day, each rat was placed in the start compartment as before and retention performance was measured as the time required for each animal to drink from the water spout (i.e. latency to first lick). Retention scores were analyzed using analysis of variance, with Duncan's multiple-range test for between-group comparisons. In all analyses, the limit of statistical significance was 0.05. 3. Results
First, it should be noted that the drug treatments administered prior to training did not significantly affect training performance. There were no significant differences between any of the groups in entrance latencies on the training trial (means = 6-16 s).
191
The retention performance for all groups is shown in fig. 1. In all groups the retention latencies were higher than latencies on the last day of pretraining (paired t-tests, P < 0.05 for each comparison). Posttraining administration of epinephrine facilitated retention performance in those groups pretreated with saline and tylose. Pretreatment with any of the adrenoceptor antagonists antagonized the facilitatory effect of epinephrine on retention. A two-way analysis of variance revealed a significant interaction among the treatments (F(17,346) = 27.56, P < 0.001). In view of the significant interaction term, one-way analyses were performed for each pretraining drug treatment. Posttraining drug was a significant factor for only saline and tylose groups, (for these 2 groups, respectively, F(1,123)= 184.2, P < 0 . 0 0 1 and F(1,26) = 59.79, P < 0.001). No significant effect of posttraining epinephrine was observed in any of the groups given pretreatment injections of
an adrenoceptor antagonist. The only groups exhibiting a significant enhancement with posttrial epinephrine were those given pretrial saline and tylose. Retention latencies for groups given saline posttraining were similar, with the exception of the propranolol and atenolol groups. Separate one-way analyses with both saline and epinephrine as the posttraining drug revealed a significant effect for the pretraining drug (F(8,175)= 4.76, P < 0.001 and F(8,171) = 31.42, P < 0.001, respectively, for the 2 analyses). A Duncan's multiplerange test indicated that the retention latencies of the groups given pretraining injections of propranolol and atenolol were significantly higher than those of the saline controls (P < 0.05). In order to examine the possibility that these two antagonists affect approach behavior by themselves, propranolol- and atenolol-injected rats were trained without footshock (N = 8 per group). No
Legend
350
SAL
EPI 300
•~
250
Z O :'--
200
Z
150.
100"
50
SAL
TYL
MED
PHEN
PRAZ YOH TREATMENTS
PROP
ATEN
ZIN
Fig. 1. Retention performance of rats trained in a one-trial inhibitory avoidance task. Retention is expressed as latency to drink from the water spout 24 h following training. Significant facilitation was evident in animals receiving pretraining saline (SAL) or tylose (TYL) injections and posttraining epinephrine (EPI) administration. Pretraining injections of any of a host of adrenoceptor antagonists, representing selective al-, a2- , a 1- a n d / o r fl2-adrenoceptor antagonists, attenuated this facilitation. The adrenoceptor antagonists used were medraxolol (MED; al.2, fll,2, N = 9 and 8 for SAL and EPI respectively), phentolamine (PHENT; al. 2, N = 22 and 22 for SAL and EPI respectively), prazosin (PRAZ; al, N = 24 and 24), yohimbine (YOH; t~2, N = 20 and 18), propranolol (PROP; fll.2, N = 9 and 10), atenolol (ATEN; ill, N = 10 and 8), and zinterol (ZIN; f12, N = 13 and 14).
192 effect on retention performance was noted in these groups of rats (means = 3.4 and 5.2, respectively).
4. Discussion The objective of this study was to determine the receptors responsible for the facilitatory effects of epinephrine on memory. As epinephrine is a multiple agonist, acting at a 1, a 2, j31, 132 sites, we attempted to discern the responsible receptor by using relatively selective antagonists. Consistent with findings of other studies (cf. McG a u g h et al., 1984; Introini-Collison and McGaugh, 1986; Sternberg et al., 1985a,b), we found that posttrial administration of epinephrine enhances retention performance in rats. We also observed that pretraining injections of all adrenergic blocking agents that we examined attenuated the retention-enhancing effect of posttraining epinephrine. These results which are comparable to those obtained with an appetitive task (Sternberg et al., 1985a) indicate that a variety of adrenoceptor antagonists, representing selective a 1, a 2, /31 a n d / o r ]32 , attenuate the enhancing effects of posttraining epinephrine. The facilitatory effects of exogenous epinephrine m a y be due to a direct agonistic action of epinephrine at all of these receptor types, either in the periphery or, assuming some leakage of the blood-brain barrier perhaps, the central nervous system as well. Second, epinephrine might interact with only one of the various receptor types, but there may be indirect involvement of the other receptor types. For example the a-blockers may abolish the effects of epinephrine in an indirect manner (e.g. a constant a-activation m a y be necessary for /3-action). Thus while it is unclear whether epinephrine acts directly at all adrenoceptor subtypes, it appears clear that all adrenoceptor types are involved in the m e m o r y m o d u l a t o r y effects of epinephrine. O u r data strongly indicate that the antagonists' effects on performance are not due either to impairment of learning or effects on activity. We found no memory-impairing effects in groups given pretrial antagonists and posttrial saline. Of course, the facilitatory effect of propranolol and atenolol
are somewhat paradoxical. It is possible that this effect may be due specifically to petraining /3ladrenoceptor blockade. However, further work is needed to elucidate these findings. In a previous study (Novack et al., 1984) we found that, in mice, posttrial systemic injections of a- and /~-antagonists did not impair retention performance in an inhibitory-avoidance task. Together these findings indicate that antagonists of epinephrine do not interfere with retention performance in the control groups. To our knowledge, there have been no reports of learning impairment produced by systemic administration of adrenoceptor antagonists to intact animals. However, it has been shown that posttraining intra-amygdala injections of propranolol impair later retention performance and that the impairment is blocked by simultaneous intraamygdala injections of phentolamine (Gallagher and Kapp, 1981). Thus, the contrast in m e m o r y m o d u l a t o r y effectiveness of peripherally and centrally administered antagonist could be due to site of action. Clearly, additional experiments are needed to answer this important question.
Acknowledgements This research was supported by USPHS Research Grant MH12526 and Research Contract N-00014-82-K-0391 from the Office of Naval Research.
References Borrell, J., E.R. De Kloet and B. Bohus, 1983, Corticosterone decreases the efficacy of adrenaline to affect passive avoidance retention of adrenalectomized rats, Life Sci. 34, 99. Gallagher, M. and B.S. Kapp, 1981, Effect of phentolamine administration into the amygdala complex of rats on timedependent memory processes, Behav. Neurol. Biol. 39, 277. Gold, P.E., R. McCarty and D.B. Sternberg, 1982, Peripheral catecholamines and memory modulation, in: Neuronal Plasticity and Memory Formation, eds. C.A. Marsan and H. Manhies (Raven, New York) p. 327. Gold, P.E. and J.L. McGaugh, 1978, Endogenous modulators of memory storage processes, in: Clinical Psychoneuroendocrinology in Reproduction, eds. L. Carenza, P. Pancheri and L. Zichella (Academic, London) p. 25. Introini-Collison, I.B. and J.L. McGaugh, 1986, Epinephrine
193 modulates long-term retention of an aversively-motivated discrimination task, Behav. Neurol. Biol. 45, 358. Liang, K.C., C. Bennett and J.L. McGaugh, 1985, Peripheral epinephrine modulates the effects of post-training amygdala stimulation on memory, Behav. Brain Res. 15, 93. McGaugh, J.L., K.C. Liang, C. Bennett and D.B. Sternberg, 1984, Adrenergic influences on memory storage: Interaction of peripheral and central system, in: Neurobiology of Learning and Memory, eds. G. Lynch, J.L. McGaugh and N.M. Weinberger (The Guilford Press, New York) p. 313. Novack, G., D.B. Sternberg and J.L. McGaugh, 1984, Role of a- and fl-adrenergic receptors in learning and memory in mice, Neurosci. Abstr. 10, 254.
Sternberg, D.B. and P.E. Gold, 1981, Intraventricular adrenergic antagonists: Failure to attenuate retrograde amnesia, Physiol. Behav. 27, 551. Sternberg, D.B., K. Issacs, P.E. Gold and J.L. McGaugh, 1985a, Epinephrine facilitation of appetitive learning: Attenuation with adrenergic receptor antagonists, Behav. Neurol. Biol. 44, 447. Sternberg, D.B., J. Martinez, P.E. Gold and J.L. McGaugh, 1985b, Age-related memory deficit in rats and mice: Enhancement with peripheral injections of epinephrine, Behav. Neurol. Biol. 44, 213.
189
Elsevier
EJP 439SC
Short communication
Epinephrine-induced memory facilitation: attenuation by adrenoceptor antagonists D e b r a B. Sternberg, D o n n a Korol, G a r y D. N o v a c k , and James L. M c G a u g h * Center for the Neurobiology of Learning and Memory and Department of Psychobiology, University of California, Irvine, CA 92 717, U.S.A. Received 11 July 1986, accepted 5 August 1986
The present study examined the relative importance of a- and fl-adrenoceptors in the memory modulatory effects of epinephrine. Posttraining epinephrine administration enhanced retention performance of a one-trial inhibitory avoidance response. Further pretraining injections of a variety of adrenoceptor antagonists, including selective al-, a2-, ill- and/or flz-adrenoceptor antagonists, attenuated the retention enhancing effects of posttraining epinephrine. These results suggest that a- and fl-adrenoceptors of both subtypes are involved in the memory-modulating effects of epinephrine. Memory facilitation; Epinephrine; Adrenoceptor antagonists; Inhibitory avoidance; (Rat) 1. Introduction
Evidence from a number of laboratories indicates that posttraining administration of epinephrine influences subsequent retention performance in rats and mice trained in a variety of aversively and appetitively motivated tasks (Borrell et al., 1983; McGaugh et al., 1984; Introini-Collison and McGaugh, 1986; Sternberg et al., 1985a,b). Retention is generally enhanced by low doses of epinephrine and impaired with higher doses. However, the nature (enhancement or impairment) and the degree of the effects of epinephrine on memory are influenced by a variety of factors including the doses used, the training conditions, and the temporal relationship between training and treatment (Gold and McGaugh, 1978; McGaugh et al., 1984). These findings support the view that endogenous epinephrine released by training experiences may be involved in regulating memory storage
* To whom all correspondence should be addressed. 0014-2999/86/$03.50 © 1986 Elsevier Science Publishers B.V.
processes (Gold and McGaugh, 1978). Other recent findings provide additional support for this view. Several studies have shown, for example, that training experiences increase plasma epinephrine levels (cf. Gold et al., 1982). Further, retention is impaired in adrenal demedullated rats and the impairment is attenuated by posttraining administration of epinephrine (Borrell et al., 1983; Liang et al., 1985). Other findings suggest that endogenously released epinephrine may also play a role in the effects of several treatments known to affect memory. For example, systemic administration of any of several a- or fl-adrenoceptor antagonists prior to training attenuates the enhancing and amnestic effectiveness of many treatments (cf. Gold et al., 1982; cf. McGaugh et al., 1984; Sternberg et al., 1985a,b). The finding that intracerebroventricular administration of several adrenoceptor antagonists does not block the amnestic effect of frontal cortex stimulation (Sternberg and Gold, 1981) suggests that epinephrine may influence memory through effects initiated at peripheral receptors. Several studies have reported that the effects of
190
posttraining epinephrine on memory are blocked in animals given adrenoceptor antagonists prior to training (cf. McGaugh et al., 1984; Sternberg et al., 1985a). As epinephrine is an agonist at a variety of adrenoceptors, we undertook the present study to determine the relative importance of a- and fl-adrenoceptors in the memory modulatory effects of epinephrine on retention of an inhibitory avoidance response.
2. Materials and methods
Male Sprague-Dawley rats (Charles River Laboratories; 70-90 days old) weighing 280-360 g were used in these experiments. The animals were individually housed upon arrival and were maintained on a 12 h light-dark cycle ( 7 : 0 0 a.m. o n - 7 : 0 0 p.m. off). During the first 7-10 days after arrival, the animals received ad libitum access to food and water. One week prior to training, the animals were placed on a water deprivation schedule that reduced their body weights to 85-90% of initial body weights. Each animal received a daily aliquot of water sufficient to maintain this weight level. All training and testing procedures were performed between 1 : 0 0 and 4 : 0 0 p.m. The animals were trained in a one-trial inhibitory (passive) avoidance task. The apparatus consisted of a trough-shaped alley divided by a sliding door into a well lit white start compartment and a dimly lit shock compartment. The walls and floor of the shock compartment consisted of stainless steel plates through which the footshock (350/xA, 0.7 s, constant current) was delivered. Each animal received a total of 5 pretraining sessions over a 3 day period. On each trial, the animal was placed in the start compartment. Ten seconds later, the door was opened and the animal was permitted access to a water spout that protruded from the far end of the shock compartment. The animal was allowed to drink for a 30 s period following the first lick. After 5 trials, all animals approached the spout within 20 s and drank for at least 25 s of the 30 s period. Thirty minutes prior to the training trial, each animal received an intraperitoneal injection of either saline, tylose (Hoechst), or one of the fol-
lowing a- or fl-antagonists: prazosin (0.5 m g / k g ; Pfizer Inc.), an al-adrenoceptor antagonist: yohimbine HC1 (1 m g / k g ; Sigma), an a2-adrenoce ptor antagonist; phentolamine HC1 (5 m g / k g ; Ciba-Geigy Co.), an al,2-adrenoceptor antagonist; atenolol (5 m g / k g ; Stuart Pharmaceuticals), a B1adrenoceptor antagonist; zinterol HC1 (1.0 m g / k g ; Bristol Myers Co.), a fl2-adrenoceptor antagonist; dl-propranolol (0.5 m g / k g ; Sigma), a /~l,2adrenoceptor antagonist; or medraxolol HC1 (1.0 m g / k g ; Merrell-Dow Pharmaceuticals), an al. 2, fl~.2-adrenoceptor antagonist. The drugs were dissolved in isotonic saline or suspended in tylose, and were injected at 1.0 ml/kg. Doses used for antagonists in this study are known to block adrenoceptors; and preliminary studies indicated that in these doses the antagonists do not affect retention performance, and do not affect flinch or j u m p thresholds (unpublished findings). The procedures used on the training trial were comparable to those on the pretraining trials except each animal received a footshock (350 ~A for 0.7 s) during the 10th s of drinking, and was then removed from the apparatus and given a subcutaneous injection of saline or epinephrine (0.01 m g / k g ; a dose which was previously shown to produce enhancement of retention in this task as well as other tasks). Eighteen groups of rats were trained (N = 8-22 for pre- and postdrug injected groups, N = 62 and 63, respectively, for saline + saline, and saline + epinephrine controls). On the 5th day, each rat was placed in the start compartment as before and retention performance was measured as the time required for each animal to drink from the water spout (i.e. latency to first lick). Retention scores were analyzed using analysis of variance, with Duncan's multiple-range test for between-group comparisons. In all analyses, the limit of statistical significance was 0.05. 3. Results
First, it should be noted that the drug treatments administered prior to training did not significantly affect training performance. There were no significant differences between any of the groups in entrance latencies on the training trial (means = 6-16 s).
191
The retention performance for all groups is shown in fig. 1. In all groups the retention latencies were higher than latencies on the last day of pretraining (paired t-tests, P < 0.05 for each comparison). Posttraining administration of epinephrine facilitated retention performance in those groups pretreated with saline and tylose. Pretreatment with any of the adrenoceptor antagonists antagonized the facilitatory effect of epinephrine on retention. A two-way analysis of variance revealed a significant interaction among the treatments (F(17,346) = 27.56, P < 0.001). In view of the significant interaction term, one-way analyses were performed for each pretraining drug treatment. Posttraining drug was a significant factor for only saline and tylose groups, (for these 2 groups, respectively, F(1,123)= 184.2, P < 0 . 0 0 1 and F(1,26) = 59.79, P < 0.001). No significant effect of posttraining epinephrine was observed in any of the groups given pretreatment injections of
an adrenoceptor antagonist. The only groups exhibiting a significant enhancement with posttrial epinephrine were those given pretrial saline and tylose. Retention latencies for groups given saline posttraining were similar, with the exception of the propranolol and atenolol groups. Separate one-way analyses with both saline and epinephrine as the posttraining drug revealed a significant effect for the pretraining drug (F(8,175)= 4.76, P < 0.001 and F(8,171) = 31.42, P < 0.001, respectively, for the 2 analyses). A Duncan's multiplerange test indicated that the retention latencies of the groups given pretraining injections of propranolol and atenolol were significantly higher than those of the saline controls (P < 0.05). In order to examine the possibility that these two antagonists affect approach behavior by themselves, propranolol- and atenolol-injected rats were trained without footshock (N = 8 per group). No
Legend
350
SAL
EPI 300
•~
250
Z O :'--
200
Z
150.
100"
50
SAL
TYL
MED
PHEN
PRAZ YOH TREATMENTS
PROP
ATEN
ZIN
Fig. 1. Retention performance of rats trained in a one-trial inhibitory avoidance task. Retention is expressed as latency to drink from the water spout 24 h following training. Significant facilitation was evident in animals receiving pretraining saline (SAL) or tylose (TYL) injections and posttraining epinephrine (EPI) administration. Pretraining injections of any of a host of adrenoceptor antagonists, representing selective al-, a2- , a 1- a n d / o r fl2-adrenoceptor antagonists, attenuated this facilitation. The adrenoceptor antagonists used were medraxolol (MED; al.2, fll,2, N = 9 and 8 for SAL and EPI respectively), phentolamine (PHENT; al. 2, N = 22 and 22 for SAL and EPI respectively), prazosin (PRAZ; al, N = 24 and 24), yohimbine (YOH; t~2, N = 20 and 18), propranolol (PROP; fll.2, N = 9 and 10), atenolol (ATEN; ill, N = 10 and 8), and zinterol (ZIN; f12, N = 13 and 14).
192 effect on retention performance was noted in these groups of rats (means = 3.4 and 5.2, respectively).
4. Discussion The objective of this study was to determine the receptors responsible for the facilitatory effects of epinephrine on memory. As epinephrine is a multiple agonist, acting at a 1, a 2, j31, 132 sites, we attempted to discern the responsible receptor by using relatively selective antagonists. Consistent with findings of other studies (cf. McG a u g h et al., 1984; Introini-Collison and McGaugh, 1986; Sternberg et al., 1985a,b), we found that posttrial administration of epinephrine enhances retention performance in rats. We also observed that pretraining injections of all adrenergic blocking agents that we examined attenuated the retention-enhancing effect of posttraining epinephrine. These results which are comparable to those obtained with an appetitive task (Sternberg et al., 1985a) indicate that a variety of adrenoceptor antagonists, representing selective a 1, a 2, /31 a n d / o r ]32 , attenuate the enhancing effects of posttraining epinephrine. The facilitatory effects of exogenous epinephrine m a y be due to a direct agonistic action of epinephrine at all of these receptor types, either in the periphery or, assuming some leakage of the blood-brain barrier perhaps, the central nervous system as well. Second, epinephrine might interact with only one of the various receptor types, but there may be indirect involvement of the other receptor types. For example the a-blockers may abolish the effects of epinephrine in an indirect manner (e.g. a constant a-activation m a y be necessary for /3-action). Thus while it is unclear whether epinephrine acts directly at all adrenoceptor subtypes, it appears clear that all adrenoceptor types are involved in the m e m o r y m o d u l a t o r y effects of epinephrine. O u r data strongly indicate that the antagonists' effects on performance are not due either to impairment of learning or effects on activity. We found no memory-impairing effects in groups given pretrial antagonists and posttrial saline. Of course, the facilitatory effect of propranolol and atenolol
are somewhat paradoxical. It is possible that this effect may be due specifically to petraining /3ladrenoceptor blockade. However, further work is needed to elucidate these findings. In a previous study (Novack et al., 1984) we found that, in mice, posttrial systemic injections of a- and /~-antagonists did not impair retention performance in an inhibitory-avoidance task. Together these findings indicate that antagonists of epinephrine do not interfere with retention performance in the control groups. To our knowledge, there have been no reports of learning impairment produced by systemic administration of adrenoceptor antagonists to intact animals. However, it has been shown that posttraining intra-amygdala injections of propranolol impair later retention performance and that the impairment is blocked by simultaneous intraamygdala injections of phentolamine (Gallagher and Kapp, 1981). Thus, the contrast in m e m o r y m o d u l a t o r y effectiveness of peripherally and centrally administered antagonist could be due to site of action. Clearly, additional experiments are needed to answer this important question.
Acknowledgements This research was supported by USPHS Research Grant MH12526 and Research Contract N-00014-82-K-0391 from the Office of Naval Research.
References Borrell, J., E.R. De Kloet and B. Bohus, 1983, Corticosterone decreases the efficacy of adrenaline to affect passive avoidance retention of adrenalectomized rats, Life Sci. 34, 99. Gallagher, M. and B.S. Kapp, 1981, Effect of phentolamine administration into the amygdala complex of rats on timedependent memory processes, Behav. Neurol. Biol. 39, 277. Gold, P.E., R. McCarty and D.B. Sternberg, 1982, Peripheral catecholamines and memory modulation, in: Neuronal Plasticity and Memory Formation, eds. C.A. Marsan and H. Manhies (Raven, New York) p. 327. Gold, P.E. and J.L. McGaugh, 1978, Endogenous modulators of memory storage processes, in: Clinical Psychoneuroendocrinology in Reproduction, eds. L. Carenza, P. Pancheri and L. Zichella (Academic, London) p. 25. Introini-Collison, I.B. and J.L. McGaugh, 1986, Epinephrine
193 modulates long-term retention of an aversively-motivated discrimination task, Behav. Neurol. Biol. 45, 358. Liang, K.C., C. Bennett and J.L. McGaugh, 1985, Peripheral epinephrine modulates the effects of post-training amygdala stimulation on memory, Behav. Brain Res. 15, 93. McGaugh, J.L., K.C. Liang, C. Bennett and D.B. Sternberg, 1984, Adrenergic influences on memory storage: Interaction of peripheral and central system, in: Neurobiology of Learning and Memory, eds. G. Lynch, J.L. McGaugh and N.M. Weinberger (The Guilford Press, New York) p. 313. Novack, G., D.B. Sternberg and J.L. McGaugh, 1984, Role of a- and fl-adrenergic receptors in learning and memory in mice, Neurosci. Abstr. 10, 254.
Sternberg, D.B. and P.E. Gold, 1981, Intraventricular adrenergic antagonists: Failure to attenuate retrograde amnesia, Physiol. Behav. 27, 551. Sternberg, D.B., K. Issacs, P.E. Gold and J.L. McGaugh, 1985a, Epinephrine facilitation of appetitive learning: Attenuation with adrenergic receptor antagonists, Behav. Neurol. Biol. 44, 447. Sternberg, D.B., J. Martinez, P.E. Gold and J.L. McGaugh, 1985b, Age-related memory deficit in rats and mice: Enhancement with peripheral injections of epinephrine, Behav. Neurol. Biol. 44, 213.