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The amygdala mediates the impairing effect of the selective κ-opioid receptor agonist U-50,488 on memory in CD1 mice
259
Behavioural Brain Research, 30 (1988) 259-263 Elsevier BBR00834
The amygdala mediates the impairing effect of the selective c-opioid receptor agonist U-50,488 on memory in CD 1 mice C l a u d i o C a s t e l l a n o , V i n c e n z o Libri a n d M a r t i n e A m m a s s a r i - T e u l e Istituto di Psicobiologia e Psicofarmacologia del CNR, Roma (Italy) (Received 8 December 1987) (Revised version received 29 February 1980) (Accepted 29 February 1988)
Key words: U-50,488; Amygdaloid lesion; Passive avoidance; CD1 mouse
The effect of the selective r-opioid receptor agonist U-50,488 on passive avoidance behaviour was studied in CD 1 mice beating lesions of the amygdaloid complex. The results have shown that post-trial injections of U-50,488 in unoperated mice as well as lesions of the amygdaloid complex in untreated mice decreased retention performances. No further impairment was observed in lesioned mice treated with U-50,488, indicating that amygdala is involved in the mediation of the effects of r-opioid receptor agonists on memory. The possibility that r-opioid receptors could modulate the memory retention of CD1 mice by influencing their emotional state is discussed.
Increasing evidence has been collected in the recent years concerning the role of the amygdala in the modulation of memory processes 5'7'~°. Impairments of acquisition and retention in animals bearing lesions of this limbic structure have been demonstrated in a number of aversively motivated t a s k s 9'13"16. Since such lesions have been found to produce a clear reduction of fear-like behaviours in rats ~z, these effects have been interpreted in terms of decreased emotionality6. The fact that the amygdala is rich in opiate peptides and receptors ~° has contributed to focussing on the mechanisms through which the opioid receptors within this structure influence memory perfolanances. It has recently been shown that peripheral (intraperitoneal) ~,4 or central (amygdaloid)6 administration of #-opioid receptor agonists impair memory in rodents ~,6. The amygdala experiments have in particular led to the hypothesis that #-agonists might act through
an interference with pain-induced establishment of fear, by attenuating the emotional state of the animal6. This hypothesis was confirmed later on by experiments showing that morphine was less effective in impairing retention performance of mice familiarized with the testing apparatus 4. Since previous investigations have shown that post-training intraperitoneal administration of x-opioid receptor agonists also impair memory consolidation of mice tested in the passive avoidance situation 2,3,8,~1 and that this effect was also less evident in subjects familiarized with the testing apparatus as compared with non-familiarized subjects 2,11, it has been suggested that this opioid might impair retention by attenuating emotionality, i.e. by acting at the amygdala level through a mechanism similar to that demonstrated for #-agonists. If this were the case, the impairing effect exerted by the x-agonists on memory processes would have to be less evident
Correspondence: C. Castellano, Istituto di Psicobiologia e Psicofarmacologia, via Reno 1, 00198 Roma, Italy. 0166-4328/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
26{} in amygdala-lesioned mice. In order to test this hypothesis we have thus decided to investigate the effects of the ~:-opioid receptor agonist U-50, 488 (ref. 15) administered post-trial in amygdalalesioned mice tested in a passive avoidance situation. Male CD1 mice (Charles River laboratory), 11-12 weeks old and weighing 22-25 g at the beginning of the experiments, served as subjects. They were housed in transparent plastic cages (27 x 21 x 13.5 cm) with 4 animals per cage. The mice were fed with standard diet and had water ad libitum. The animals were maintained on a 12-h light/12-h dark cycle (07.00-19.00 h). For the lesion experiments, mice were anaesthetized with chloral hydrate (400 mg/kg) and placed in a Narishige stereotaxic apparatus with mouse adaptor. A stainless steel electrode (0.2 mm diameter), insulated except at the tip, was inserted bilaterally in the amygdaloid complex at the following coordinates based upon the Slotnick and Leonard' atlas~4: A, - 1 . 8 to bregma; L, + 3.1 lateral to sagittal sinus; H, 4.3 ventral from the dura. A 5-mA anodal direct current was passed for 5 s through the electrode, the circuit being completed by clamping the cathode to the tail. Sham operations were performed by inserting the electrode at the coordinates used for lesioning the amygdaloid complex but without making electrocoagulation. Following surgery all the subjects were then left in their home cage for a recovery period of one week. Passive avoidance performances were estimated in an apparatus similar to that described by Castellano et al. 3. It consisted of a 20 x 20 x 20 cm lucite box with black walls and a grid floor. The front wall was placed at the edge of a table. A 12-cm long platform protruded from the front wall over this edge. The platform was 7.5 cm wide and lit by a 40 W lamp positioned 50 cm above it. The box was kept in darkness. During training, each mouse was placed on the platform. The time elapsed before the mouse had entered the box with all 4 feet (step-through latency) was recorded. The access to the platform was then blocked by a hand-operated sliding door and the mouse received a 50 Hz scrambled footshock of 0.7 mA through the grid floor for 1 s. The
mouse was successively removed from the apparatus to its home cage to await testing. On the retention test, 24 h later, mice were placed on the lighted platform as on the training session and their step-through latencies (maximum of 180 s) were recorded. The experiment was conducted in two steps. Firstly, 4 groups of 8 naive unoperated mice were injected intraperitoneally (i.p.) with 1, 2 or 4 mg/kg of U-50,488 (The Upjohn Company, Kalamazoo) and with saline (0.9~o NaC1) respectively, immediately after training in the passive avoidance apparatus. The doses of U-50,488 were chosen on the basis of previous experiments 3. Secondly, the highest dose (4 mg/kg) of U-50,488 was injected i.p. immediately after training in two groups of 8 amygdala-lesioned and 8 sham-operated mice submitted to the same test, and their performances were compared with the group of 8 amygdala-lesioned or sham salineinjected mice. All experiments were performed between 09.00 and 12.00h. The results were evaluated by non-parametric statistical tests. Median step-through latencies and interquartile ranges (Q1-Q3) were calculated for each experimental group, and significance of the differences between groups was calculated by means of the Kruskal-WaUis one-way ANOVA followed by the Mann-Whitney U-test. At the completion of the experiments lesioned and sham-operated mice were sacrificed, the brains were fixed in a Formalin solution (10 ~o), sectioned coronally at 50 #m and stained with Toluidine blue according to the Nissl method. Examination of the tissue revealed large lesions of the amygdaloid central nucleus extended in some cases to the basolateral nucleus (Fig. 1). Concerning the first group of experiments, in which the effect of U-50,488 was assessed in unoperated mice (Table I), a Kruskal-Wallis ANOVA showed significant between-group differences (H = 14.72, P < 0.002). Subsequent pair comparisons carried out with Mann-Whitney U-tests showed significant differences (P = 0.004) only between the performances of mice injected with the highest dose of U-50,488 (4 mg/kg) and those of the saline-injected mice. For the second group of experiments (Fig. 2), a
261
Fig. 1. Typical example showing site and extent of the amygdala lesion.
Kruskal-Wallis ANOVA, carried out for unoperated, sham- and amygdala-lesioned groups injected with saline or U-50,488 (4 mg/kg), showed significant between-group differences (H = 121.6, P < 0.001). Subsequent Mann-Whitney U-tests showed significant differences between the retention performances of: (1)
C_,
TABLE I
,7, ~ 200
Effect of posttraining administration of U-50,488 on latencies to step-through during the retention test
Step-through latencies (medians and interquartile ranges) on the test day of different groups of 8 CD1 mice tested in the passive avoidance apparatus 24 h after training. Treatment
saline and U-50,488-injected sham-lesioned mice (P = 0.002); (2) amygdala- and sham-lesioned mice injected with saline (P = 0.002). In addition, a significant difference was evident, in the amygdala-lesioned group, between the stepthrough latencies recorded on the training and on the test day (median latencies [interquartile
t-r
~1oo
Retention latencies (s) Median
Interquartile range
140.5 128.0 82.5 44.0
85.5-170.0 104.5-168.5 68.0-109.0 39.0- 65.0*
~,~ Saline U-50,488 1 mg/kg U-50,488 2 mg/kg U-50,488 4 mg/kg
I'--I SFILI NE 17--A U - 5 0 . 488
-r
*P = 0.004 (Mann-Whitney U test, one-tailed).
o CONT.
SHAM
AMTG.
_1
Fig. 2. Effects of post-trial administration of U-50,488 (4 mg/kg) on passive avoidance behaviour in CD1 mice. Cont., unoperated control mice; Sham, sham-lesioned mice; Amyg., amygdala-lesioned mice.
262
range]: saline = 5.5 (4.5-8.5) s, amygdala = 45 (36.5-53.5) s, P = 0.001). No significant difference was evident between the performances of: (1) sham and unoperated saline- or (U-50,488injected mice, (2) saline- and U-50,488-injected amygdala-lesioned mice. The present results firstly show that post-trial administration of the selective x-opioid receptor agonist U-50,488 in unoperated CD1 mice impaired memory consolidation similarly to what has previously been observed in the DBA/2 strain 3. Concerning this point, it must be noted that U-50,488 can also exert memory-improving effects, such as in C57BL/6 mice3, which differ from DBA/2 mice in the responses to the administration of/~- and b-opioid receptor agonists and in some emotional behaviors, such as reactivity to stress 1. As pointed out previously 1"3, genetic differences in levels and turnovers of neurotransmitters and in number and/or distribution of opioid receptors in the brain might account for these strain-dependent effects. From the second group of experiments, when operated mice are considered, it is evident that the performance of amygdala-lesioned animals (A) was lower than that of sham-operated animals and (B) was not modified by post-trial injections of U-50,488, while such injections strongly impaired the performance of sham-operated mice. It seems in particular important to note that the lack of effect following U-50,488 treatment in the amygdalalesioned mice cannot be ascribed to a floor effect. In fact the significant elevation in the retention latencies relative to the initial training day, evident in the amygdala-lesioned animals injected with saline, demonstrates that sufficient residual memory existed to show an effect of U-50,488. The disrupting effect of amygdala lesions on memory observed in the present work extends to the mouse observations made previously in other animal species 6'9 and confirms the involvement of this limbic structure in the storage of memories. Moreover, the fact that no further impairment of performance was evident in lesioned animals after U-50,488 administration indicates that the amygdala is involved in mediating the effect of rc-opioid receptor agonists on memory processes similarly to what has already been demonstrated
for/~-receptors agonist in another experimental context 6. From a functional point of view, we previously outlined that post-training administrations of #-agonists within amygdala have been assumed to impair retention by attenuating emotionality6. This hypothesis has been successively confn'med and extended to ~-agonists by a number of reports indicating that both #-(morphine) and tc-(tifluadom, bremazocine) agonists are less effective in disrupting memory in mice familiarized with the testing apparatus than in nonfamiliarized mice2"4a~. In the light of these observations, the present results strongly suggest a role of amygdaloid x-receptors in modulating memory performance of CD1 mice through a regulation of their emotional state. We thank Dr. P.F. Von Voigtlander (The Upjohn Company) for the gift of U-50,488. Vincenzo Libri is a postdoctoral fellow from the Institute of Pharmacology, Faculty of Medicine, University of Reggio Calabria, Catanzaro (Italy). Partial support to V.L. from Fidia Research Laboratories is gratefully acknowledged. REFERENCES 1 Castellano, C., A pharmacogenetic approach to learning and memory. In J.L. McGaugh (Ed.), Contemporary Psychology: Biological Processes and Theoretical Issue, Elsevier, Amsterdam, 1985, pp. 45-67. 2 Castellano, C. and Pavone, F., Effects ofbremazocine on passive avoidance behaviour in mice, Arch. lnt. Pharmacodyn., 283 (1986) 199-208. 3 Castellano, C. and Pavone, F., Effects of the selective K-opioid receptor agonist U-50,488 on locomotor activity and passive avoidance behaviour in DBA/2 and C57BL/6 mice, Arch. Int. Pharmacodyn., 288 (1987) 270-280. 4 Castellano, C., Pavone, F. and Puglisi Allegra, S., Morphine and memory in DBA/2 mice: effects of stress and of prior experience, Behav. Brain Res., 11 (1984) 3-1 t. 5 Ellis, M. and Kesner, R. P., The noradrenergic system of the amygdala and aversive memory processing, Behav. Neurosci., 55 (1983) 399-415. 6 Gallagher, M. and Kapp, B.S., Influence of amygdalaopiate-sensitive mechanisms, fear-motivated responses, and memory processes for aversive experiences. In J.L Martinez, R.A. Jensen, R.B. Messing, H. Rigter and J.L. McGaugh (Eds.), Endogenous Peptides and Learning and Memory Processes, Academic, New York, 1981, pp. 445-461. 7 Gallagher, M. Kapp, B.S., Pascoe, J.P. and Rapp, P.R., A neuropharmacology of the amygdaloid system which
263
8
9
10
11
contributes to learning and memory. In Y. Ben-Aft (Ed.), The Amygdaloid Complex, Elsevier, Amsterdam, 1981, pp. 343-354. Introini-Collison, I., Cahill, L., Baratti, C.M. and McGaugh, J.L., Dynorphin induces task-specific impairment of memory, Psychobiology, 15 (1987) 171-174. Liang, K.C., McGaugh, J.L., Martinez, J.L., Jensen, R.A., Vasquez, B.J. and Messing, R.B., Post-training amygdaloid lesions impair retention of an inhibitory avoidance response, Behav. Brain Res., 4 (1982) 237-249. Miskin, M., Malamut, B. and Bachevalier, J., Memories and habits: two neural systems. In G. Lynch, J.L. McGaugh and N.M. Weinberger (Eds.), Neurobiology of Learning and Memory, Guilford, New York, 1984. Pavone, F. and Castellano, C., Effects of tifluadom on passive avoidance behaviour in DBA/2 mice, Behav. Brain Res., 15 (1985) 177-181.
12 Rodgers, R.J., Influence of intra-amygdaloid opiate injections on shock thresholds, tail flick latencies and open field behavior in rats, Brain Res., 153 (1978) 211-216. 13 Sarter, M. and Markowitsch, H.J., Involvement of the amygdala in learning and memory: a critical review with emphasis on anatomical relations, Behav. Neurosci., 99 (1985) 342-380. 14 Slotnick, B.M. and Leonard, C.M., A Stereotaxic Atlas of the Albino Mouse Brain, U.S. Dept. of Health Education and Welfare, publication N. 74-100, Rockville, D, 1975. 15 Von Voigtlander, P.P. and Lewis, R.A., U-50,488, a selective kappa-agonist: comparison to other reputed kappaagonists, Prog. Neuropsychopharmacol. Biol. Psychiat., 6 (1982) 467-470. 16 Werka, T., Skar, J. and Ursin, I.I., Exploration and avoidance in rats with lesions in amygdala and piriform cortex, J. Comp. Physiol. Psychol., 92 (1978) 672-681.
Behavioural Brain Research, 30 (1988) 259-263 Elsevier BBR00834
The amygdala mediates the impairing effect of the selective c-opioid receptor agonist U-50,488 on memory in CD 1 mice C l a u d i o C a s t e l l a n o , V i n c e n z o Libri a n d M a r t i n e A m m a s s a r i - T e u l e Istituto di Psicobiologia e Psicofarmacologia del CNR, Roma (Italy) (Received 8 December 1987) (Revised version received 29 February 1980) (Accepted 29 February 1988)
Key words: U-50,488; Amygdaloid lesion; Passive avoidance; CD1 mouse
The effect of the selective r-opioid receptor agonist U-50,488 on passive avoidance behaviour was studied in CD 1 mice beating lesions of the amygdaloid complex. The results have shown that post-trial injections of U-50,488 in unoperated mice as well as lesions of the amygdaloid complex in untreated mice decreased retention performances. No further impairment was observed in lesioned mice treated with U-50,488, indicating that amygdala is involved in the mediation of the effects of r-opioid receptor agonists on memory. The possibility that r-opioid receptors could modulate the memory retention of CD1 mice by influencing their emotional state is discussed.
Increasing evidence has been collected in the recent years concerning the role of the amygdala in the modulation of memory processes 5'7'~°. Impairments of acquisition and retention in animals bearing lesions of this limbic structure have been demonstrated in a number of aversively motivated t a s k s 9'13"16. Since such lesions have been found to produce a clear reduction of fear-like behaviours in rats ~z, these effects have been interpreted in terms of decreased emotionality6. The fact that the amygdala is rich in opiate peptides and receptors ~° has contributed to focussing on the mechanisms through which the opioid receptors within this structure influence memory perfolanances. It has recently been shown that peripheral (intraperitoneal) ~,4 or central (amygdaloid)6 administration of #-opioid receptor agonists impair memory in rodents ~,6. The amygdala experiments have in particular led to the hypothesis that #-agonists might act through
an interference with pain-induced establishment of fear, by attenuating the emotional state of the animal6. This hypothesis was confirmed later on by experiments showing that morphine was less effective in impairing retention performance of mice familiarized with the testing apparatus 4. Since previous investigations have shown that post-training intraperitoneal administration of x-opioid receptor agonists also impair memory consolidation of mice tested in the passive avoidance situation 2,3,8,~1 and that this effect was also less evident in subjects familiarized with the testing apparatus as compared with non-familiarized subjects 2,11, it has been suggested that this opioid might impair retention by attenuating emotionality, i.e. by acting at the amygdala level through a mechanism similar to that demonstrated for #-agonists. If this were the case, the impairing effect exerted by the x-agonists on memory processes would have to be less evident
Correspondence: C. Castellano, Istituto di Psicobiologia e Psicofarmacologia, via Reno 1, 00198 Roma, Italy. 0166-4328/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
26{} in amygdala-lesioned mice. In order to test this hypothesis we have thus decided to investigate the effects of the ~:-opioid receptor agonist U-50, 488 (ref. 15) administered post-trial in amygdalalesioned mice tested in a passive avoidance situation. Male CD1 mice (Charles River laboratory), 11-12 weeks old and weighing 22-25 g at the beginning of the experiments, served as subjects. They were housed in transparent plastic cages (27 x 21 x 13.5 cm) with 4 animals per cage. The mice were fed with standard diet and had water ad libitum. The animals were maintained on a 12-h light/12-h dark cycle (07.00-19.00 h). For the lesion experiments, mice were anaesthetized with chloral hydrate (400 mg/kg) and placed in a Narishige stereotaxic apparatus with mouse adaptor. A stainless steel electrode (0.2 mm diameter), insulated except at the tip, was inserted bilaterally in the amygdaloid complex at the following coordinates based upon the Slotnick and Leonard' atlas~4: A, - 1 . 8 to bregma; L, + 3.1 lateral to sagittal sinus; H, 4.3 ventral from the dura. A 5-mA anodal direct current was passed for 5 s through the electrode, the circuit being completed by clamping the cathode to the tail. Sham operations were performed by inserting the electrode at the coordinates used for lesioning the amygdaloid complex but without making electrocoagulation. Following surgery all the subjects were then left in their home cage for a recovery period of one week. Passive avoidance performances were estimated in an apparatus similar to that described by Castellano et al. 3. It consisted of a 20 x 20 x 20 cm lucite box with black walls and a grid floor. The front wall was placed at the edge of a table. A 12-cm long platform protruded from the front wall over this edge. The platform was 7.5 cm wide and lit by a 40 W lamp positioned 50 cm above it. The box was kept in darkness. During training, each mouse was placed on the platform. The time elapsed before the mouse had entered the box with all 4 feet (step-through latency) was recorded. The access to the platform was then blocked by a hand-operated sliding door and the mouse received a 50 Hz scrambled footshock of 0.7 mA through the grid floor for 1 s. The
mouse was successively removed from the apparatus to its home cage to await testing. On the retention test, 24 h later, mice were placed on the lighted platform as on the training session and their step-through latencies (maximum of 180 s) were recorded. The experiment was conducted in two steps. Firstly, 4 groups of 8 naive unoperated mice were injected intraperitoneally (i.p.) with 1, 2 or 4 mg/kg of U-50,488 (The Upjohn Company, Kalamazoo) and with saline (0.9~o NaC1) respectively, immediately after training in the passive avoidance apparatus. The doses of U-50,488 were chosen on the basis of previous experiments 3. Secondly, the highest dose (4 mg/kg) of U-50,488 was injected i.p. immediately after training in two groups of 8 amygdala-lesioned and 8 sham-operated mice submitted to the same test, and their performances were compared with the group of 8 amygdala-lesioned or sham salineinjected mice. All experiments were performed between 09.00 and 12.00h. The results were evaluated by non-parametric statistical tests. Median step-through latencies and interquartile ranges (Q1-Q3) were calculated for each experimental group, and significance of the differences between groups was calculated by means of the Kruskal-WaUis one-way ANOVA followed by the Mann-Whitney U-test. At the completion of the experiments lesioned and sham-operated mice were sacrificed, the brains were fixed in a Formalin solution (10 ~o), sectioned coronally at 50 #m and stained with Toluidine blue according to the Nissl method. Examination of the tissue revealed large lesions of the amygdaloid central nucleus extended in some cases to the basolateral nucleus (Fig. 1). Concerning the first group of experiments, in which the effect of U-50,488 was assessed in unoperated mice (Table I), a Kruskal-Wallis ANOVA showed significant between-group differences (H = 14.72, P < 0.002). Subsequent pair comparisons carried out with Mann-Whitney U-tests showed significant differences (P = 0.004) only between the performances of mice injected with the highest dose of U-50,488 (4 mg/kg) and those of the saline-injected mice. For the second group of experiments (Fig. 2), a
261
Fig. 1. Typical example showing site and extent of the amygdala lesion.
Kruskal-Wallis ANOVA, carried out for unoperated, sham- and amygdala-lesioned groups injected with saline or U-50,488 (4 mg/kg), showed significant between-group differences (H = 121.6, P < 0.001). Subsequent Mann-Whitney U-tests showed significant differences between the retention performances of: (1)
C_,
TABLE I
,7, ~ 200
Effect of posttraining administration of U-50,488 on latencies to step-through during the retention test
Step-through latencies (medians and interquartile ranges) on the test day of different groups of 8 CD1 mice tested in the passive avoidance apparatus 24 h after training. Treatment
saline and U-50,488-injected sham-lesioned mice (P = 0.002); (2) amygdala- and sham-lesioned mice injected with saline (P = 0.002). In addition, a significant difference was evident, in the amygdala-lesioned group, between the stepthrough latencies recorded on the training and on the test day (median latencies [interquartile
t-r
~1oo
Retention latencies (s) Median
Interquartile range
140.5 128.0 82.5 44.0
85.5-170.0 104.5-168.5 68.0-109.0 39.0- 65.0*
~,~ Saline U-50,488 1 mg/kg U-50,488 2 mg/kg U-50,488 4 mg/kg
I'--I SFILI NE 17--A U - 5 0 . 488
-r
*P = 0.004 (Mann-Whitney U test, one-tailed).
o CONT.
SHAM
AMTG.
_1
Fig. 2. Effects of post-trial administration of U-50,488 (4 mg/kg) on passive avoidance behaviour in CD1 mice. Cont., unoperated control mice; Sham, sham-lesioned mice; Amyg., amygdala-lesioned mice.
262
range]: saline = 5.5 (4.5-8.5) s, amygdala = 45 (36.5-53.5) s, P = 0.001). No significant difference was evident between the performances of: (1) sham and unoperated saline- or (U-50,488injected mice, (2) saline- and U-50,488-injected amygdala-lesioned mice. The present results firstly show that post-trial administration of the selective x-opioid receptor agonist U-50,488 in unoperated CD1 mice impaired memory consolidation similarly to what has previously been observed in the DBA/2 strain 3. Concerning this point, it must be noted that U-50,488 can also exert memory-improving effects, such as in C57BL/6 mice3, which differ from DBA/2 mice in the responses to the administration of/~- and b-opioid receptor agonists and in some emotional behaviors, such as reactivity to stress 1. As pointed out previously 1"3, genetic differences in levels and turnovers of neurotransmitters and in number and/or distribution of opioid receptors in the brain might account for these strain-dependent effects. From the second group of experiments, when operated mice are considered, it is evident that the performance of amygdala-lesioned animals (A) was lower than that of sham-operated animals and (B) was not modified by post-trial injections of U-50,488, while such injections strongly impaired the performance of sham-operated mice. It seems in particular important to note that the lack of effect following U-50,488 treatment in the amygdalalesioned mice cannot be ascribed to a floor effect. In fact the significant elevation in the retention latencies relative to the initial training day, evident in the amygdala-lesioned animals injected with saline, demonstrates that sufficient residual memory existed to show an effect of U-50,488. The disrupting effect of amygdala lesions on memory observed in the present work extends to the mouse observations made previously in other animal species 6'9 and confirms the involvement of this limbic structure in the storage of memories. Moreover, the fact that no further impairment of performance was evident in lesioned animals after U-50,488 administration indicates that the amygdala is involved in mediating the effect of rc-opioid receptor agonists on memory processes similarly to what has already been demonstrated
for/~-receptors agonist in another experimental context 6. From a functional point of view, we previously outlined that post-training administrations of #-agonists within amygdala have been assumed to impair retention by attenuating emotionality6. This hypothesis has been successively confn'med and extended to ~-agonists by a number of reports indicating that both #-(morphine) and tc-(tifluadom, bremazocine) agonists are less effective in disrupting memory in mice familiarized with the testing apparatus than in nonfamiliarized mice2"4a~. In the light of these observations, the present results strongly suggest a role of amygdaloid x-receptors in modulating memory performance of CD1 mice through a regulation of their emotional state. We thank Dr. P.F. Von Voigtlander (The Upjohn Company) for the gift of U-50,488. Vincenzo Libri is a postdoctoral fellow from the Institute of Pharmacology, Faculty of Medicine, University of Reggio Calabria, Catanzaro (Italy). Partial support to V.L. from Fidia Research Laboratories is gratefully acknowledged. REFERENCES 1 Castellano, C., A pharmacogenetic approach to learning and memory. In J.L. McGaugh (Ed.), Contemporary Psychology: Biological Processes and Theoretical Issue, Elsevier, Amsterdam, 1985, pp. 45-67. 2 Castellano, C. and Pavone, F., Effects ofbremazocine on passive avoidance behaviour in mice, Arch. lnt. Pharmacodyn., 283 (1986) 199-208. 3 Castellano, C. and Pavone, F., Effects of the selective K-opioid receptor agonist U-50,488 on locomotor activity and passive avoidance behaviour in DBA/2 and C57BL/6 mice, Arch. Int. Pharmacodyn., 288 (1987) 270-280. 4 Castellano, C., Pavone, F. and Puglisi Allegra, S., Morphine and memory in DBA/2 mice: effects of stress and of prior experience, Behav. Brain Res., 11 (1984) 3-1 t. 5 Ellis, M. and Kesner, R. P., The noradrenergic system of the amygdala and aversive memory processing, Behav. Neurosci., 55 (1983) 399-415. 6 Gallagher, M. and Kapp, B.S., Influence of amygdalaopiate-sensitive mechanisms, fear-motivated responses, and memory processes for aversive experiences. In J.L Martinez, R.A. Jensen, R.B. Messing, H. Rigter and J.L. McGaugh (Eds.), Endogenous Peptides and Learning and Memory Processes, Academic, New York, 1981, pp. 445-461. 7 Gallagher, M. Kapp, B.S., Pascoe, J.P. and Rapp, P.R., A neuropharmacology of the amygdaloid system which
263
8
9
10
11
contributes to learning and memory. In Y. Ben-Aft (Ed.), The Amygdaloid Complex, Elsevier, Amsterdam, 1981, pp. 343-354. Introini-Collison, I., Cahill, L., Baratti, C.M. and McGaugh, J.L., Dynorphin induces task-specific impairment of memory, Psychobiology, 15 (1987) 171-174. Liang, K.C., McGaugh, J.L., Martinez, J.L., Jensen, R.A., Vasquez, B.J. and Messing, R.B., Post-training amygdaloid lesions impair retention of an inhibitory avoidance response, Behav. Brain Res., 4 (1982) 237-249. Miskin, M., Malamut, B. and Bachevalier, J., Memories and habits: two neural systems. In G. Lynch, J.L. McGaugh and N.M. Weinberger (Eds.), Neurobiology of Learning and Memory, Guilford, New York, 1984. Pavone, F. and Castellano, C., Effects of tifluadom on passive avoidance behaviour in DBA/2 mice, Behav. Brain Res., 15 (1985) 177-181.
12 Rodgers, R.J., Influence of intra-amygdaloid opiate injections on shock thresholds, tail flick latencies and open field behavior in rats, Brain Res., 153 (1978) 211-216. 13 Sarter, M. and Markowitsch, H.J., Involvement of the amygdala in learning and memory: a critical review with emphasis on anatomical relations, Behav. Neurosci., 99 (1985) 342-380. 14 Slotnick, B.M. and Leonard, C.M., A Stereotaxic Atlas of the Albino Mouse Brain, U.S. Dept. of Health Education and Welfare, publication N. 74-100, Rockville, D, 1975. 15 Von Voigtlander, P.P. and Lewis, R.A., U-50,488, a selective kappa-agonist: comparison to other reputed kappaagonists, Prog. Neuropsychopharmacol. Biol. Psychiat., 6 (1982) 467-470. 16 Werka, T., Skar, J. and Ursin, I.I., Exploration and avoidance in rats with lesions in amygdala and piriform cortex, J. Comp. Physiol. Psychol., 92 (1978) 672-681.