BEHAVIORALAND NEURALBIOLOGY58, 58--63 (1992)
BRIEF REPORT Strain-Dependent Effects of Post-training Dopamine Receptor Agonists and Antagonists on Memory Storage in Mice VINCENZO CESTARI, CLAUDIO CASTELLANO, SIMONA CABIB, AND STEFANO PUGLISI-ALLEGRA1
Istituto di Psicobiologia e Psicofarmacologia, C.N.R., via Reno 1, 00198-1 Roma, Italy
strains through endogenous opioid and dopamine (DA) systems (Castellano & Puglisi-Allegra, 1983 a,b). Major strain-dependent differences have been observed in the behavioral effects of dopaminergic agonists, suggesting genotype-dependent modulation of central dopaminergic functioning. Moreover, genotypic variations and regional selectivity in the brain have been shown with regard to the concentration and turnover of DA as well as the specific activities of its synthesizing or degradative enzymes and receptor density (Cabib, Puglisi-Allegra, & Oliverio, 1985 for a review). The present study was designed in order to assess possible strain-dependent differences in the effects of selective D1 or D2 agonists and antagonists in a one-trial passive avoidance test. To this end, in a first set of experiments the effects of post-trial administration of SKF 38393 (D1 agonist), LY171555 (D2 agonist), SCH 23390 (D1 antagonist), and ( - ) sulpiride (D2 antagonist) were assessed in DBA/2 mice tested for one-trial inhibitory avoidance. In a second set of experiments, the effects of a single dose of aforementioned compounds in DBA/2 mice have been compared with those produced in C57BL/6 mice and their B6D2F1 hybrids. Male DBA/2 (DBA), C57BL/6 (C57) mice, and their F1 (B6D2F1) hybrids aged 8 weeks and weighing 20-23 g (Charles River Lab., Como, Italy) were used in this experiment. Upon arrival mice were housed in groups of eight in standard breeding cages (27 × 21 x 12 cm) and kept in a 12-h light/12-h dark cycle (lights were on from 0700 to 1900 h) at a constant temperature (22 _+ I°C), given food and water ad lib, and tested during the second half of the light period (between 1400 and 1700 h) in a sound-insulated room. Mice were trained on a step-through inhibitory
Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and ( - )-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance. ©1992AcadelnicPress,Inc. We have recently shown that post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently facilitates retention of an inhibitory avoidance response in mice of the C57BL/6 strain. By contrast, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride produce an impairment of retention (Castellano, Cestari, Cabib, & Puglisi-Allegra, 1991). These results are consistent with previous ones showing improvement of memory processes in animals receiving post-trial psychostimulants or memory impairment following DA depletion or haloperidol (Castellano et al., 1991 for a review). Previous studies have pointed to strain differences in the effects of drug treatment on memory consolidation. In particular opiates have been reported to improve retention in C57BL/6 mice while they impair in the mice of the DBA/2 strain (Castellano & Puglisi-Allegra, 1983b, for a review). Post-training stress produces similar effects on retention in these 1 The authors thank Ravizza for supplying (-)-sulpiride. Correspondence and reprint requests should be addressed to V. Cestari. 58 0163-1047/92 $5.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved
EFFECTS OF DOPAMINE ON MEMORY avoidance apparatus as previously described (McGaugh & Landfield, 1970). On the training day each mouse was placed in the lighted compartment, facing away from the dark compartment. When the mouse turned around, the door leading to the dark compartment was opened. When the mouse stepped with four paws into the dark side the door was closed, a footshock (0.2 mA, 50 Hz, 1 s) was delivered and the latency to step-through was recorded. The mouse was then removed from the apparatus and injected. Retention was tested 24 h later following a similar procedure, except that no shock was administered. SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro3-methyl-5-phenyl- 1H-3-benzazepine-7-ol maleate; Schering Corporation, USA) was dissolved in distilled water (H20) and administered at the doses of 0.025, 0.05, or 0.1 mg/kg. (-)-Sulpiride (Ravizza, Italy) was dissolved in HC1, diluted in H20, the pH was adjusted to 7.4 with NaOH, and administered a~ the doses of 6, 12, or 25 mg/kg. SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3benzazepine-7,8-diol-hydrochloride; Smith, Kline, & French Laboratories) and LY 171555 (trans-(-)-
4aR,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH(or
2H)-
pyrazolo (3,4,-g)quinoline monohydrochloride; Eli Lilly & Co.) were dissolved in distilled water. SKF 38393 was administered at the doses of 5, 10, or 20 mg/kg. LY 171555 was administered at the doses of 0.25, 0.5 and 1 mg/kg. The highest doses of the four compounds were administered to C57 and B6D2F1 mice. The drug solutions were injected at a volume of 10 ml/kg. In all experiments the highest dose of each drug was administered to an additional group of mice 120 min after training, as well as immediately after training to other groups of mice which did not receive footshock. Drug-injected animals were compared with vehicle-injected animals. All drugs were injected intraperitoneally. Groups of eight animals were used in all experiments. Additional experiments were carried out, using separate groups of animals (n = 8) in order to evaluate shock sensitivity. Pain reactivity was measured using a modification of the flinch-jump test (Puglisi-Allegra, Cab|b, Ebel, Kempf, & Castellano, 1986). Individual animals were placed in the test chamber where they received six series of six shocks (1-s duration) delivered at a 20-s interval through the metal floor. Shock series were administered in alternating ascending and descending order, the first series being an ascending one. Shock threshold was defined as the lowest shock intensity (t~A) at
59
which an animal's hind foot left the metal floor. For each mouse the m e a n value of shock thresholds recorded in each series was calculated. The results were evaluated by either one- or twoway ANOVA, factors being strain (3 levels = DBA, C57, B6D2F1) and t r e a t m e n t (2 levels = vehicle and drug), in which the m e a n step-through latencies on the test day were compared. Individual betweengroup comparisons, where appropriate, were carried out by post hoc test (Duncan multiple range test). Student's t test (two-tailed) was also used. Both SKF 38393 and LY 171555 administered immediately post-training produced a dose-related impairment in retention performance of DBA mice, while immediate post-training administration of SCH 23390 and (-)-sulpiride improved retention performance dose dependently (Fig. 1). By contrast, the two DA receptor agonists produced a clear-cut improvement in retention in both C57 and B6D2F1 mice, while the two antagonists impaired retention performance. No significant differences between C57 and B6D2F1 mice were evident for each treatment (Fig. 2). For the three strains, the retention performance of animals injected with SKF 38393 (20 mg/kg), LY 171555 (1.0 mg/kg), SCH 23390 (0.1 mg/kg), and ( - )-sulpiride (25 mg/kg) 120 min after training did not differ from that of their controls. Moreover, no difference was observed between the performance of drug-injected animals that did not receive footshock on the training day, and the performance of their controls (Table 1). Drug-free animals of the three strains did not show significant differences in sensitivity to shock (as shown by shock thresholds (tLA): C57 = 81.2 _+11.9; DBA = 87.5 -+ 7.2; B6D2F1 = 84.3 _+ 6.5; F(2, 23) = 0.1; n.s.) or to light (as shown by m e a n step-through latencies on the training day: C57 = 7.6 + 0.9; DBA -- 6.7 + 0.7; B6D2F1 = 7.1 -+0.6; F(2, 23) = 0.3; n.s.), and more interesting in memory consolidation (as shown by mean stepthrough latencies on the testing trial: C57 = 70.0 -+ 2.0; DBA = 67.3 + 2.5; B6D2F1 = 67.5 -+ 2.3; F(2, 23) = 0.4; n.s.). The present results show that post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impair retention of an inhibitory avoidance response in DBA mice. By contrast, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those previously reported (Castellano et al., 1991) in mice of the C57 strain treated with the same doses of DA receptor agonists or antagonists used in the present study.
60
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BRIEF REPORT Strain-Dependent Effects of Post-training Dopamine Receptor Agonists and Antagonists on Memory Storage in Mice VINCENZO CESTARI, CLAUDIO CASTELLANO, SIMONA CABIB, AND STEFANO PUGLISI-ALLEGRA1
Istituto di Psicobiologia e Psicofarmacologia, C.N.R., via Reno 1, 00198-1 Roma, Italy
strains through endogenous opioid and dopamine (DA) systems (Castellano & Puglisi-Allegra, 1983 a,b). Major strain-dependent differences have been observed in the behavioral effects of dopaminergic agonists, suggesting genotype-dependent modulation of central dopaminergic functioning. Moreover, genotypic variations and regional selectivity in the brain have been shown with regard to the concentration and turnover of DA as well as the specific activities of its synthesizing or degradative enzymes and receptor density (Cabib, Puglisi-Allegra, & Oliverio, 1985 for a review). The present study was designed in order to assess possible strain-dependent differences in the effects of selective D1 or D2 agonists and antagonists in a one-trial passive avoidance test. To this end, in a first set of experiments the effects of post-trial administration of SKF 38393 (D1 agonist), LY171555 (D2 agonist), SCH 23390 (D1 antagonist), and ( - ) sulpiride (D2 antagonist) were assessed in DBA/2 mice tested for one-trial inhibitory avoidance. In a second set of experiments, the effects of a single dose of aforementioned compounds in DBA/2 mice have been compared with those produced in C57BL/6 mice and their B6D2F1 hybrids. Male DBA/2 (DBA), C57BL/6 (C57) mice, and their F1 (B6D2F1) hybrids aged 8 weeks and weighing 20-23 g (Charles River Lab., Como, Italy) were used in this experiment. Upon arrival mice were housed in groups of eight in standard breeding cages (27 × 21 x 12 cm) and kept in a 12-h light/12-h dark cycle (lights were on from 0700 to 1900 h) at a constant temperature (22 _+ I°C), given food and water ad lib, and tested during the second half of the light period (between 1400 and 1700 h) in a sound-insulated room. Mice were trained on a step-through inhibitory
Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and ( - )-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance. ©1992AcadelnicPress,Inc. We have recently shown that post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently facilitates retention of an inhibitory avoidance response in mice of the C57BL/6 strain. By contrast, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride produce an impairment of retention (Castellano, Cestari, Cabib, & Puglisi-Allegra, 1991). These results are consistent with previous ones showing improvement of memory processes in animals receiving post-trial psychostimulants or memory impairment following DA depletion or haloperidol (Castellano et al., 1991 for a review). Previous studies have pointed to strain differences in the effects of drug treatment on memory consolidation. In particular opiates have been reported to improve retention in C57BL/6 mice while they impair in the mice of the DBA/2 strain (Castellano & Puglisi-Allegra, 1983b, for a review). Post-training stress produces similar effects on retention in these 1 The authors thank Ravizza for supplying (-)-sulpiride. Correspondence and reprint requests should be addressed to V. Cestari. 58 0163-1047/92 $5.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved
EFFECTS OF DOPAMINE ON MEMORY avoidance apparatus as previously described (McGaugh & Landfield, 1970). On the training day each mouse was placed in the lighted compartment, facing away from the dark compartment. When the mouse turned around, the door leading to the dark compartment was opened. When the mouse stepped with four paws into the dark side the door was closed, a footshock (0.2 mA, 50 Hz, 1 s) was delivered and the latency to step-through was recorded. The mouse was then removed from the apparatus and injected. Retention was tested 24 h later following a similar procedure, except that no shock was administered. SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro3-methyl-5-phenyl- 1H-3-benzazepine-7-ol maleate; Schering Corporation, USA) was dissolved in distilled water (H20) and administered at the doses of 0.025, 0.05, or 0.1 mg/kg. (-)-Sulpiride (Ravizza, Italy) was dissolved in HC1, diluted in H20, the pH was adjusted to 7.4 with NaOH, and administered a~ the doses of 6, 12, or 25 mg/kg. SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3benzazepine-7,8-diol-hydrochloride; Smith, Kline, & French Laboratories) and LY 171555 (trans-(-)-
4aR,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH(or
2H)-
pyrazolo (3,4,-g)quinoline monohydrochloride; Eli Lilly & Co.) were dissolved in distilled water. SKF 38393 was administered at the doses of 5, 10, or 20 mg/kg. LY 171555 was administered at the doses of 0.25, 0.5 and 1 mg/kg. The highest doses of the four compounds were administered to C57 and B6D2F1 mice. The drug solutions were injected at a volume of 10 ml/kg. In all experiments the highest dose of each drug was administered to an additional group of mice 120 min after training, as well as immediately after training to other groups of mice which did not receive footshock. Drug-injected animals were compared with vehicle-injected animals. All drugs were injected intraperitoneally. Groups of eight animals were used in all experiments. Additional experiments were carried out, using separate groups of animals (n = 8) in order to evaluate shock sensitivity. Pain reactivity was measured using a modification of the flinch-jump test (Puglisi-Allegra, Cab|b, Ebel, Kempf, & Castellano, 1986). Individual animals were placed in the test chamber where they received six series of six shocks (1-s duration) delivered at a 20-s interval through the metal floor. Shock series were administered in alternating ascending and descending order, the first series being an ascending one. Shock threshold was defined as the lowest shock intensity (t~A) at
59
which an animal's hind foot left the metal floor. For each mouse the m e a n value of shock thresholds recorded in each series was calculated. The results were evaluated by either one- or twoway ANOVA, factors being strain (3 levels = DBA, C57, B6D2F1) and t r e a t m e n t (2 levels = vehicle and drug), in which the m e a n step-through latencies on the test day were compared. Individual betweengroup comparisons, where appropriate, were carried out by post hoc test (Duncan multiple range test). Student's t test (two-tailed) was also used. Both SKF 38393 and LY 171555 administered immediately post-training produced a dose-related impairment in retention performance of DBA mice, while immediate post-training administration of SCH 23390 and (-)-sulpiride improved retention performance dose dependently (Fig. 1). By contrast, the two DA receptor agonists produced a clear-cut improvement in retention in both C57 and B6D2F1 mice, while the two antagonists impaired retention performance. No significant differences between C57 and B6D2F1 mice were evident for each treatment (Fig. 2). For the three strains, the retention performance of animals injected with SKF 38393 (20 mg/kg), LY 171555 (1.0 mg/kg), SCH 23390 (0.1 mg/kg), and ( - )-sulpiride (25 mg/kg) 120 min after training did not differ from that of their controls. Moreover, no difference was observed between the performance of drug-injected animals that did not receive footshock on the training day, and the performance of their controls (Table 1). Drug-free animals of the three strains did not show significant differences in sensitivity to shock (as shown by shock thresholds (tLA): C57 = 81.2 _+11.9; DBA = 87.5 -+ 7.2; B6D2F1 = 84.3 _+ 6.5; F(2, 23) = 0.1; n.s.) or to light (as shown by m e a n step-through latencies on the training day: C57 = 7.6 + 0.9; DBA -- 6.7 + 0.7; B6D2F1 = 7.1 -+0.6; F(2, 23) = 0.3; n.s.), and more interesting in memory consolidation (as shown by mean stepthrough latencies on the testing trial: C57 = 70.0 -+ 2.0; DBA = 67.3 + 2.5; B6D2F1 = 67.5 -+ 2.3; F(2, 23) = 0.4; n.s.). The present results show that post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impair retention of an inhibitory avoidance response in DBA mice. By contrast, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those previously reported (Castellano et al., 1991) in mice of the C57 strain treated with the same doses of DA receptor agonists or antagonists used in the present study.
60
CESTARI ET AL.
260]
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