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Tyr-D-Arg-Phe-β-Ala-NH2, a novel dermorphin analog, impairs memory consolidation in mice
European Journal of Pharmacology, 239 (1993) 237-240
237
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 21286
Short communication
Tyr-D-Arg-Phe-13-Ala-NH 2, a novel dermorphin analog, impairs memory consolidation in mice M a k o t o Ukai a, Kaori M o r i a S e t s u k o H a s h i m o t o a, T e t s u y a K o b a y a s h i a, Y u s u k e Sasaki b and Tsutomu Kameyama a a Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan, and b Department of Biochemistry, Tohoku College of Pharmacy, 4-1, Komatsushima 4-chome, Aoba-ku, Sendai 981, Japan Received 20 April 1993, revised MS received 19 May 1993, accepted 1 June 1993
Tyr-D-Arg-Phe-fl-Ala-NH 2 (TAPA), a novel dermorphin analog with high selectivity and affinity for/x-opioid receptors, was administered intracerebroventricularly to mice before or immediately after training in a one-trial step-down type passive avoidance task. The pre- and post-training administration of TAPA (0.3 and/or 3 ng) impaired retention performance 24 h after training. In particular, the post-training administration of TAPA was much more effective because a lower dose (0.3 ng) of TAPA exclusively inhibited retention performance. The amnesic effects of TAPA were reversed by the /z-selective opioid antagonist fl-funaltrexamine (5/zg, i.c.v.). In addition, TAPA (0.3 and 3 ng) had no effects on nociceptive responses in a tail-flick test or on behavioral responses to electric shock during training. These results suggest that activation of/z-opioid receptors impairs passive avoidance learning, resulting in a dysfunction of memory consolidation, without affecting other behavioral responses. [D-Arg2]Dermorphin analogue;/z-Opioid receptors; Memory;/3-Funaltrexamine; Passive avoidance response
1. Introduction
Opioids such as morphine, /3-endorphin and enkephalins reportedly impair memory processes, while naloxone facilitates them (Rigter et al., 1979; lzquierdo, 1980; Castellano and Pavone, 1985; Izquierdo and Netto, 1985; Izquierdo et al., 1985). It has recently been demonstrated that the 8-selective opioid agonist [D-Pen 2, D-Pen 5]enkephalin impairs memory (Schulteis et al., 1988; Martinez et al., 1992). However, although there is evidence, obtained by using selective agonists, that each of the main classes of receptors are involved in memory formation (Schulteis et al., 1988; Martinez et al., 1992), the specific role of opioid receptors in memory processes seems to be inconclusive (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo, 1989). Furthermore, the effects of opioids on memory are dependent upon the animal strain, injection schedule and behavioral task used (Castellano and Pavone, 1985; Schulteis et al., 1988).
Tyr-D-Arg-Phe-/3-Ala-NH 2 (TAPA), a recently introduced novel dermorphin analog, has a much higher selectivity and affinity for/z-opioid receptors than [DAla2,N-Me-Phe4,Gly-ol]enkephalin, which is often used as a selective ligand for/z-opioid receptors (Sasaki et al., 1991). The present study was designed to examine the involvement of /z-opioid receptors in memory processes by using the /z-selective opioid agonist TAPA, although the preferential involvement of tz-opioid receptors in post-training memory modulation has been suggested earlier (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo, 1989). In addition, the effects of TAPA on nociception in a tail-flick test and on behavioral responses such as flinch, jump, and vocalization during training were determined in an attempt to clarify the relationship between memory dysfunction and other responses induced by TAPA.
2. Materials and methods
2.1. Animals Correspondence to: Makoto Ukai, Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan. Tel. 81-52-832-1781 ext. 344, fax 81-52-834-8780.
Male ddY mice (Nihon SLC Co., Japan) weighing between 30 and 35 g were used. The animals were
238 housed in standard plastic cages in a temperature-controlled room (23 + I°C). Food and water were freely available and a 12-h l i g h t / d a r k cycle was set. The experiments were carried out between 10:00 and 17:00 h in a sound-attenuated room.
2.2. Drugs T A P A , which was synthesized by a solid-phase method (Sasaki et al., 1991), and /3-funaltrexamine (Research Biochemicals, USA) were used. T A P A was dissolved in sterile isotonic saline in polypropylene containers. The injection was made with a 4-mm-long needle (30 gauge) attached to a 50-/~1 Hamilton microsyringe according to the method of Haley and McCormick (1957).
TABLE 1 Effects of Tyr-D-Arg-Phe-/3-Ala-NH 2 (TAPA) and/or /3funaltrexamine (5 /zg) on the step-down latency in a passive avoidance task with mice. TAPA was given to mice 15 min before (A) and immediately after (B) training, while the peptide and /3-funaltrexamine were given immediately after and 24 h before training, respectively (C). n: the number of mice used. Each value represents the median and interquartile ranges. Treatments (~ Vehicle TAPA
2. 4. Behavioral responses Behavioral responses, such as flinch, vocalization, and jump, to electric shock were observed during training. The following scoring system was used, 0: no behavioral response, 1: startle and tremor, 2: flinch, jump (once or twice) and slight vocalization, 3: jump (more than 2 times), hypermotility and frequent vocalization.
2.5. Antinociceptive effects Antinociceptive activity was determined with a tailflick test. Mice were gently held with their tail positioned in an apparatus for radiant heat stimulation of the dorsal surface of the tail. The intensity of heat stimulus was adjusted so that the mouse flicked its tail between 1.5 and 5 s after heat stimulation. Tail-flick responses were measured 4 times at 15-min intervals immediately after T A P A injection. An u p p e r cut-off time was set at 15 s.
n
Step-downlatency (s)
0.3 3
20 16 15
270 (48-300) 164 (17-157) 121 (9- 91) b
0.03 0.3 3 30 300
25 14 14 23 20 20
251 (162-300) 182 (67-259) 79 (50-114) b 117 (39-156) b 134 (67-185) 218 (101-300)
3
13 13 13
300 (218-300) 291 (143-300) 106 (24-190) a
3
14
300 (208-300) c
(B)
Vehicle TAPA
2.3. Passive avoidance response The step-down type passive avoidance task used has been described in detail ( K a m e y a m a et al., 1986). In a training period, each mouse was placed gently onto a wooden platform. W h e n the mouse stepped down from the platform and placed all its paws on a grid floor, an intermittent electric shock (1 Hz, 0.5 s, 60 V DC) was delivered. The retention test was done 24 h after training, with each mouse again being placed onto the platform, and the step-down latency was measured. An u p p e r cut-off time was set at 300 s. T A P A was administered 15 min before or immediately after training, while /3-funaltrexamine was administered 24 h before training.
Dose (ng)
(C) Vehicle /3-Funaltrexamine TAPA TAPA +/3-Funaltrexamine
a p < 0.05, b p < 0.01 vs. vehicle-treated groups, c p < 0.01 vs. TAPA-treated group.
2.6. Statistical analysis D a t a are expressed as the median and interquartile ranges (passive avoidance response) or the means + S.E. (behavioral responses to electric shock and tailflick responses). A Kruskal-Wallis nonparametric oneway analysis of variance was first applied, and further statistical analyses for individual groups were done with a two-tailed Bonferroni's test.
3. Results
3.1. Effects of TAPA on step-down latency in passive avoidance task The pre-training administration of T A P A (0.3 and 3 ng) had a significant effect on the step-down latency in the retention test (Kruskal-Wallis analysis: H = 10.85, P < 0.01). T A P A (3 ng) significantly shortened the step-down latency in the retention test (table 1A), demonstrating an impairment of passive avoidance learning. Moreover, the immediate post-training administration of T A P A (0.03, 0.3, 3, 30 and 300 ng) had a significant effect on the step-down latency in the retention test (Kruskal-Wallis analysis: H - 23.98, P < 0.01). T A P A (0.3 and 3 ng) given immediately after training impaired passive avoidance learning in the
239 15
~¢o ~6¢0v >'1239 *~** 0
Timafter e administr(rai ation)
Fig. 1. Effects of Tyr-D-Arg-Phe-fl-Ala-NH 2 (TAPA) on nociceptive (tail-flick) responses in mice. Values above time 0 in the abscissa were obtained immediately before the i.c.v, injection of isotonic saline or TAPA. (©) Control; (o) TAPA 0.3 rig; ( [] ) TAPA 3 ng; ( • ) TAPA 30 ng. Values represent the means_+ S.E. for six or seven mice. * P < 0.05, * * P < 0.01 vs. control.
retention test (table 1B), whereas fl-funaltrexamine (5 /zg) significantly reversed the effects of TAPA (3 ng) (table 1C). 3.2. Effects of TAPA on behavioral responses TAPA (0.3 and 3 ng) had no significant effects on the step-down latency or the behavioral responses to electric shock during training. Step-down latency values during training were 7.2 + 1.3 (control), 5.8 _+ 0.8 (TAPA 0.3 ng) and 5.3 _ 0.8 (TAPA 3 ng), while those of behavioral scores during training were 1.0 + 0.3 (control), 1.6 _+ 0.2 (TAPA 0.3 ng) and 0.9 _ 0.3 (TAPA 3 ng). 3.3. Effects of TAPA on tail-flick response TAPA (0.3, 3 and 30 ng) had a significant effect on the tail-flick latency at 15, 30, 45 and 60 min after injection (Kruskal-Wallis analysis: H = 14.82, P < 0.01; H = 12.41, P < 0.01; H = 16.44, P < 0.01; H = 13.35, P < 0.01, respectively). Although TAPA (30 rig) significantly prolonged the tail-flick latency over 60 min after injection, the amnesic doses (0.3 and 3 rig) of TAPA failed to affect the tail-flick latency markedly (fig. 1).
4. Discussion It has been reported that a variety of opioids cause retrograde amnesia (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo et al., 1985; Izquierdo, 1989). In this study, the extremely /z-selective opioid receptor agonist TAPA impaired passive avoidance learning after both pre-training and immediate post-training administration. In particular, the post-training administration of TAPA was much more effective in producing
amnesia because a lower dose (0.3 ng) of TAPA exclusively inhibited the passive avoidance response. Moreover, the effects of TAPA were antagonized by the g-selective opioid antagonist fl-funaltrexamine (Portoghese et al., 1980), suggesting that the impairing effects of TAPA on memory are mediated via/.~-opioid receptors. In contrast, TAPA at doses (0.3 and 3 ng) which impaired passive avoidance learning failed to affect nociceptive responses or behavioral responses to electric shock during training, although only a higher dose (30 ng) of TAPA produced antinociception. Additionally, TAPA (0.3 and 3 ng) did not alter locomotor activity in mice (unpublished data). These results strongly imply that the activation of /.,-opioid systems impairs memory consolidation without influencing other behavioral responses.
Acknowledgements This investigation was supported in part by The Mochida Memorial Foundation for Medical and Pharmaceutical Research. The authors appreciate Mr. N. Shinkai for his secretarial help.
References Castellano, C. and F. Pavone, 1985, Dose- and strain-dependent effects of dermorphin and [D-AlaE-D-LeuS]enkephalin on passive avoidance behavior in mice, Behav. Neurosci. 99, 1120. Gallagher, M., 1982, Naloxone enhancement of memory processes: effects of other opiate antagonists, Behav. Neural Biol. 35, 375. Haley, T.J. and W.G. McCormick, 1957, Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse, Br. J. Pharmacol. 12, 12. Izquierdo, I., 1980, Effects of fl-endorphin and naloxone on acquisition, memory, and retrieval of shuttle avoidance and habituation learning in rats, Psychopharmacology 69, 111. Izquierdo, I., 1989, Different forms of post-training memory processing, Behav. Neural Biol. 51, 171. Izquierdo, I. and C.A. Netto, 1985, Role of fl-endorphin in behavioral regulation, Ann. NY Acad. Sci. 444, 162. Izquierdo, I., M.A.M.R. De Almeida and V.R. Emiliano, 1985, Unlike /3-endorphin, dynorphin 1-13 does not cause retrograde amnesia for shuttle avoidance or inhibitory avoidance learning in rats, Psychopharmacology 87, 216. Kameyama, T., T. Nabeshima and Y. Noda, 1986, Cholinergic modulation of memory for step-down type passive avoidance task in mice, Res. Commun. Psychol. Psychiat. Behav. 11, 193. Martinez, Jr., J.L., R.V. Hernandez and S.W. Weinberger, 1992, D-Pen2-[D-PenS]enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats, Peptides 13, 885. Portoghese, P.S., D.L. Larson, L.M. Sayre and D.S. Fries, 1980, A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities, J. Med. Chem. 23, 233. Rigter, H., T.J. Hannan, R.B. Messing, J.L. Martinez, Jr., B.J. Vasquez, R.A. Jensen, J. Veliquette and J.L. McGaugh, 1979, Enkephalins interfere with acquisition of an active avoidance response, Life Sci. 26, 337.
240 Sasaki, Y., A. Ambo and K. Suzuki, 1991, Studies on analgesic oligopeptides. VII. Solid phase synthesis and biological properties of Tyr-D-Arg-Phe-/3-Aia-NH 2 and its fluorinated aromatic acid derivatives, Chem. Pharm. Bull. 39, 2316.
Schulteis, G., J.L. Martinez, Jr., E.L. Bennet, M.R. Rosenzweig and V.L. Hruby, 1988, Stimulation and antagonism of opioid delta receptors produce opposite effects on active avoidance conditioning in mice, Behav. Neurosci. 102, 678.
237
© 1993 Elsevier Science Publishers B.V. All rights reserved 0014-2999/93/$06.00
EJP 21286
Short communication
Tyr-D-Arg-Phe-13-Ala-NH 2, a novel dermorphin analog, impairs memory consolidation in mice M a k o t o Ukai a, Kaori M o r i a S e t s u k o H a s h i m o t o a, T e t s u y a K o b a y a s h i a, Y u s u k e Sasaki b and Tsutomu Kameyama a a Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan, and b Department of Biochemistry, Tohoku College of Pharmacy, 4-1, Komatsushima 4-chome, Aoba-ku, Sendai 981, Japan Received 20 April 1993, revised MS received 19 May 1993, accepted 1 June 1993
Tyr-D-Arg-Phe-fl-Ala-NH 2 (TAPA), a novel dermorphin analog with high selectivity and affinity for/x-opioid receptors, was administered intracerebroventricularly to mice before or immediately after training in a one-trial step-down type passive avoidance task. The pre- and post-training administration of TAPA (0.3 and/or 3 ng) impaired retention performance 24 h after training. In particular, the post-training administration of TAPA was much more effective because a lower dose (0.3 ng) of TAPA exclusively inhibited retention performance. The amnesic effects of TAPA were reversed by the /z-selective opioid antagonist fl-funaltrexamine (5/zg, i.c.v.). In addition, TAPA (0.3 and 3 ng) had no effects on nociceptive responses in a tail-flick test or on behavioral responses to electric shock during training. These results suggest that activation of/z-opioid receptors impairs passive avoidance learning, resulting in a dysfunction of memory consolidation, without affecting other behavioral responses. [D-Arg2]Dermorphin analogue;/z-Opioid receptors; Memory;/3-Funaltrexamine; Passive avoidance response
1. Introduction
Opioids such as morphine, /3-endorphin and enkephalins reportedly impair memory processes, while naloxone facilitates them (Rigter et al., 1979; lzquierdo, 1980; Castellano and Pavone, 1985; Izquierdo and Netto, 1985; Izquierdo et al., 1985). It has recently been demonstrated that the 8-selective opioid agonist [D-Pen 2, D-Pen 5]enkephalin impairs memory (Schulteis et al., 1988; Martinez et al., 1992). However, although there is evidence, obtained by using selective agonists, that each of the main classes of receptors are involved in memory formation (Schulteis et al., 1988; Martinez et al., 1992), the specific role of opioid receptors in memory processes seems to be inconclusive (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo, 1989). Furthermore, the effects of opioids on memory are dependent upon the animal strain, injection schedule and behavioral task used (Castellano and Pavone, 1985; Schulteis et al., 1988).
Tyr-D-Arg-Phe-/3-Ala-NH 2 (TAPA), a recently introduced novel dermorphin analog, has a much higher selectivity and affinity for/z-opioid receptors than [DAla2,N-Me-Phe4,Gly-ol]enkephalin, which is often used as a selective ligand for/z-opioid receptors (Sasaki et al., 1991). The present study was designed to examine the involvement of /z-opioid receptors in memory processes by using the /z-selective opioid agonist TAPA, although the preferential involvement of tz-opioid receptors in post-training memory modulation has been suggested earlier (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo, 1989). In addition, the effects of TAPA on nociception in a tail-flick test and on behavioral responses such as flinch, jump, and vocalization during training were determined in an attempt to clarify the relationship between memory dysfunction and other responses induced by TAPA.
2. Materials and methods
2.1. Animals Correspondence to: Makoto Ukai, Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Nagoya 468, Japan. Tel. 81-52-832-1781 ext. 344, fax 81-52-834-8780.
Male ddY mice (Nihon SLC Co., Japan) weighing between 30 and 35 g were used. The animals were
238 housed in standard plastic cages in a temperature-controlled room (23 + I°C). Food and water were freely available and a 12-h l i g h t / d a r k cycle was set. The experiments were carried out between 10:00 and 17:00 h in a sound-attenuated room.
2.2. Drugs T A P A , which was synthesized by a solid-phase method (Sasaki et al., 1991), and /3-funaltrexamine (Research Biochemicals, USA) were used. T A P A was dissolved in sterile isotonic saline in polypropylene containers. The injection was made with a 4-mm-long needle (30 gauge) attached to a 50-/~1 Hamilton microsyringe according to the method of Haley and McCormick (1957).
TABLE 1 Effects of Tyr-D-Arg-Phe-/3-Ala-NH 2 (TAPA) and/or /3funaltrexamine (5 /zg) on the step-down latency in a passive avoidance task with mice. TAPA was given to mice 15 min before (A) and immediately after (B) training, while the peptide and /3-funaltrexamine were given immediately after and 24 h before training, respectively (C). n: the number of mice used. Each value represents the median and interquartile ranges. Treatments (~ Vehicle TAPA
2. 4. Behavioral responses Behavioral responses, such as flinch, vocalization, and jump, to electric shock were observed during training. The following scoring system was used, 0: no behavioral response, 1: startle and tremor, 2: flinch, jump (once or twice) and slight vocalization, 3: jump (more than 2 times), hypermotility and frequent vocalization.
2.5. Antinociceptive effects Antinociceptive activity was determined with a tailflick test. Mice were gently held with their tail positioned in an apparatus for radiant heat stimulation of the dorsal surface of the tail. The intensity of heat stimulus was adjusted so that the mouse flicked its tail between 1.5 and 5 s after heat stimulation. Tail-flick responses were measured 4 times at 15-min intervals immediately after T A P A injection. An u p p e r cut-off time was set at 15 s.
n
Step-downlatency (s)
0.3 3
20 16 15
270 (48-300) 164 (17-157) 121 (9- 91) b
0.03 0.3 3 30 300
25 14 14 23 20 20
251 (162-300) 182 (67-259) 79 (50-114) b 117 (39-156) b 134 (67-185) 218 (101-300)
3
13 13 13
300 (218-300) 291 (143-300) 106 (24-190) a
3
14
300 (208-300) c
(B)
Vehicle TAPA
2.3. Passive avoidance response The step-down type passive avoidance task used has been described in detail ( K a m e y a m a et al., 1986). In a training period, each mouse was placed gently onto a wooden platform. W h e n the mouse stepped down from the platform and placed all its paws on a grid floor, an intermittent electric shock (1 Hz, 0.5 s, 60 V DC) was delivered. The retention test was done 24 h after training, with each mouse again being placed onto the platform, and the step-down latency was measured. An u p p e r cut-off time was set at 300 s. T A P A was administered 15 min before or immediately after training, while /3-funaltrexamine was administered 24 h before training.
Dose (ng)
(C) Vehicle /3-Funaltrexamine TAPA TAPA +/3-Funaltrexamine
a p < 0.05, b p < 0.01 vs. vehicle-treated groups, c p < 0.01 vs. TAPA-treated group.
2.6. Statistical analysis D a t a are expressed as the median and interquartile ranges (passive avoidance response) or the means + S.E. (behavioral responses to electric shock and tailflick responses). A Kruskal-Wallis nonparametric oneway analysis of variance was first applied, and further statistical analyses for individual groups were done with a two-tailed Bonferroni's test.
3. Results
3.1. Effects of TAPA on step-down latency in passive avoidance task The pre-training administration of T A P A (0.3 and 3 ng) had a significant effect on the step-down latency in the retention test (Kruskal-Wallis analysis: H = 10.85, P < 0.01). T A P A (3 ng) significantly shortened the step-down latency in the retention test (table 1A), demonstrating an impairment of passive avoidance learning. Moreover, the immediate post-training administration of T A P A (0.03, 0.3, 3, 30 and 300 ng) had a significant effect on the step-down latency in the retention test (Kruskal-Wallis analysis: H - 23.98, P < 0.01). T A P A (0.3 and 3 ng) given immediately after training impaired passive avoidance learning in the
239 15
~¢o ~6¢0v >'1239 *~** 0
Timafter e administr(rai ation)
Fig. 1. Effects of Tyr-D-Arg-Phe-fl-Ala-NH 2 (TAPA) on nociceptive (tail-flick) responses in mice. Values above time 0 in the abscissa were obtained immediately before the i.c.v, injection of isotonic saline or TAPA. (©) Control; (o) TAPA 0.3 rig; ( [] ) TAPA 3 ng; ( • ) TAPA 30 ng. Values represent the means_+ S.E. for six or seven mice. * P < 0.05, * * P < 0.01 vs. control.
retention test (table 1B), whereas fl-funaltrexamine (5 /zg) significantly reversed the effects of TAPA (3 ng) (table 1C). 3.2. Effects of TAPA on behavioral responses TAPA (0.3 and 3 ng) had no significant effects on the step-down latency or the behavioral responses to electric shock during training. Step-down latency values during training were 7.2 + 1.3 (control), 5.8 _+ 0.8 (TAPA 0.3 ng) and 5.3 _ 0.8 (TAPA 3 ng), while those of behavioral scores during training were 1.0 + 0.3 (control), 1.6 _+ 0.2 (TAPA 0.3 ng) and 0.9 _ 0.3 (TAPA 3 ng). 3.3. Effects of TAPA on tail-flick response TAPA (0.3, 3 and 30 ng) had a significant effect on the tail-flick latency at 15, 30, 45 and 60 min after injection (Kruskal-Wallis analysis: H = 14.82, P < 0.01; H = 12.41, P < 0.01; H = 16.44, P < 0.01; H = 13.35, P < 0.01, respectively). Although TAPA (30 rig) significantly prolonged the tail-flick latency over 60 min after injection, the amnesic doses (0.3 and 3 rig) of TAPA failed to affect the tail-flick latency markedly (fig. 1).
4. Discussion It has been reported that a variety of opioids cause retrograde amnesia (Gallagher, 1982; Izquierdo and Netto, 1985; Izquierdo et al., 1985; Izquierdo, 1989). In this study, the extremely /z-selective opioid receptor agonist TAPA impaired passive avoidance learning after both pre-training and immediate post-training administration. In particular, the post-training administration of TAPA was much more effective in producing
amnesia because a lower dose (0.3 ng) of TAPA exclusively inhibited the passive avoidance response. Moreover, the effects of TAPA were antagonized by the g-selective opioid antagonist fl-funaltrexamine (Portoghese et al., 1980), suggesting that the impairing effects of TAPA on memory are mediated via/.~-opioid receptors. In contrast, TAPA at doses (0.3 and 3 ng) which impaired passive avoidance learning failed to affect nociceptive responses or behavioral responses to electric shock during training, although only a higher dose (30 ng) of TAPA produced antinociception. Additionally, TAPA (0.3 and 3 ng) did not alter locomotor activity in mice (unpublished data). These results strongly imply that the activation of /.,-opioid systems impairs memory consolidation without influencing other behavioral responses.
Acknowledgements This investigation was supported in part by The Mochida Memorial Foundation for Medical and Pharmaceutical Research. The authors appreciate Mr. N. Shinkai for his secretarial help.
References Castellano, C. and F. Pavone, 1985, Dose- and strain-dependent effects of dermorphin and [D-AlaE-D-LeuS]enkephalin on passive avoidance behavior in mice, Behav. Neurosci. 99, 1120. Gallagher, M., 1982, Naloxone enhancement of memory processes: effects of other opiate antagonists, Behav. Neural Biol. 35, 375. Haley, T.J. and W.G. McCormick, 1957, Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse, Br. J. Pharmacol. 12, 12. Izquierdo, I., 1980, Effects of fl-endorphin and naloxone on acquisition, memory, and retrieval of shuttle avoidance and habituation learning in rats, Psychopharmacology 69, 111. Izquierdo, I., 1989, Different forms of post-training memory processing, Behav. Neural Biol. 51, 171. Izquierdo, I. and C.A. Netto, 1985, Role of fl-endorphin in behavioral regulation, Ann. NY Acad. Sci. 444, 162. Izquierdo, I., M.A.M.R. De Almeida and V.R. Emiliano, 1985, Unlike /3-endorphin, dynorphin 1-13 does not cause retrograde amnesia for shuttle avoidance or inhibitory avoidance learning in rats, Psychopharmacology 87, 216. Kameyama, T., T. Nabeshima and Y. Noda, 1986, Cholinergic modulation of memory for step-down type passive avoidance task in mice, Res. Commun. Psychol. Psychiat. Behav. 11, 193. Martinez, Jr., J.L., R.V. Hernandez and S.W. Weinberger, 1992, D-Pen2-[D-PenS]enkephalin impairs acquisition and enhances retention of a one-way active avoidance response in rats, Peptides 13, 885. Portoghese, P.S., D.L. Larson, L.M. Sayre and D.S. Fries, 1980, A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities, J. Med. Chem. 23, 233. Rigter, H., T.J. Hannan, R.B. Messing, J.L. Martinez, Jr., B.J. Vasquez, R.A. Jensen, J. Veliquette and J.L. McGaugh, 1979, Enkephalins interfere with acquisition of an active avoidance response, Life Sci. 26, 337.
240 Sasaki, Y., A. Ambo and K. Suzuki, 1991, Studies on analgesic oligopeptides. VII. Solid phase synthesis and biological properties of Tyr-D-Arg-Phe-/3-Aia-NH 2 and its fluorinated aromatic acid derivatives, Chem. Pharm. Bull. 39, 2316.
Schulteis, G., J.L. Martinez, Jr., E.L. Bennet, M.R. Rosenzweig and V.L. Hruby, 1988, Stimulation and antagonism of opioid delta receptors produce opposite effects on active avoidance conditioning in mice, Behav. Neurosci. 102, 678.