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Nifedipine blocks retention of a visual discrimination task in chicks
BEHAVIORAL AND NEURAL BIOLOGY 57,
260-262 (1992)
BRIEF REPORT Nifedipine Blocks Retention of a Visual Discrimination Task in Chicks RICHARD A. DEYO, DOROTHY A. NIX, AND T. W. PARKER 1
Department of Psychology, Winona State University, Winona, Minnesota 55987
nel antagonist (nimodipine) has been shown to improve learning and memory in neurologically intact subjects (Deyo, Panksepp, & Conner, 1990; Isaacson, Johnston, & Vargas, 1988). If an influx of Ca 2+ is required for learning and memory, one would predict that drugs which inhibit neuronal Ca 2+ entry (such as nimodipine) should impair learning and memory. Only one study has reported any amnesic effects following nimodipine treatment, and the dose required to impair memory was five times higher than the dose required to facilitate visual discrimination learning in chicks (Deyo et al., 1990). Although it is possible that indirect effects (e.g., enhancement of cerebral blood flow) could account for the nootropic effects, it has been widely assumed that nimodipine-induced behavioral improvements are the result of antagonism of neuronal L-type calcium channels (for review see Scriabine, Schuurman, & Traber, 1989). Given the paradox between the nimodipine studies and current theoretical models of the role of calcium in memory, it would be useful to determine whether any of the other dihydropyridines improve learning and memory. Unfortunately, relatively little is known about the behavioral effects of the other dihydropyridine calcium channel antagonists. Thus, the purpose of the present study was to evaluate the nootropic effects of nifedipine in chicks. The "pebble floor" visual discrimination task was selected on the basis of an earlier study in which we reported that acquisition and retention can be altered by nimodipine treatment (Deyo et al., 1990). Ninety-two Cornish Rock Broiler cockerels (Poultry Place Hatchery, Homer, MN) were received in the colony on the hatch day (designated as Day 1 posthatch), weighed and tagged for identification. Chicks were maintained in groups of 20-25 in 86.5 × 55.5 cm pens and allowed to adapt to the
Reports that the dihydropyridine Ca2÷ channel antagonists may facilitate memory led to the present study of the behavioral effects of nifedipine. Ninety-two 4-day-old male chicks received 0, 100 nM, 100 tLM, or 10 mM nifedipine. Drugs were administered in volumes of 2 Izl into the fourth cerebral ventricle 5 min before training on a visual discrimination task. Nifedipine did not produce any detectable changes in behavior during acquisition trials. Retention, however, was impaired 24 h after training in the 100 nM and 100 t~M nifedipine-treated chicks, which made significantly more errors than controls. Nifedipine did not affect the amount of time required to complete the task. No effects on body weight gain were detected, suggesting that the memory impairment was not due to a change in feeding behavior. These data are discussed in terms of the role of calcium-dependent processes in memory. ©1992 Academic Press, Inc. Although controversial differences distinguish current psychobiological theories of memory, one important component of many models involves the influx of Ca 2÷ and subsequent activation of second messenger systems (e.g., Edmonds, Klein, Dale, & Kandel, 1990; Lynch & Baudry, 1984; Malenka, Kauer, Zucker, & Nicoll, 1988). This view of memory is supported by studies demonstrating impaired neuronal plasticity and slowed learning and memory following the administration of drugs that are believed to disrupt Ca2+-dependent enzyme activity (Davis & Pico, 1987; Deyo, Connor, & Panskepp, 1987; Staubli, Baudry, & Lynch, 1984) and drugs which block Ca2+-dependent currents (Edmonds et al., 1990; Malenka et al., 1988). Interestingly, a dihydropyridine class Ca 2÷ chan' Please address correspondence and reprint requests to Dr. R. A. Deyo, Department of Psychology, Minne Hall, Winona State University, Winona, MN 55987. The authors thank Dr. A. J. Krutsch for invaluable comments and suggestions during the preparation of the manuscript. 260 0163-1047/92 $5.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
261
NIFEDIPINE AND MEMORY IN THE CHICK
12
T
o lO
-I"6 --r, ~,,,~ ,~ ,,~
: i =~: i
0
,
':.'!.'t
,
; i= ,,,
100nM
100pM
10mM
0
100nM
100pM
10mM
0
100nM
100pM
Dose of Nifedipine
Dose of Nffedipine
Dose of Nifedipine
First Block of Acquisition Trials
Last Block of Acquisition Trials
Rention Test
10 mM
FIG. l. Summary of the effects of selected dosages of nifedipine on the acquisition and retention of a visual discrimination task. Bars represent SEM. Asterisks denote significant comparisons using Dunnett's test for contrasts involving a control mean (p < .05).
lab environment for 3 days prior to behavioral testing. Food and water were freely available, b u t food was removed during the dark cycle immediately preceding behavioral testing. On Day 4 posthatch, chicks were randomly assigned to one of four treatment groups (n = 23 chicks each) defined on the basis of the dose administered: 0, 100 nM, 100 tLM, or 10 m M nifedipine. Nifedipine was dissolved in absolute ETOH and diluted to the appropriate concentration using polyethylene glycol (PEG) (MW 300). The control treatment (0 M nifedipine) consisted of the same concentration of ETOH in P E G that was used in nifedipine solutions (8.67 x 10 7% ETOH). Drugs were prepared and stored in a dark room at 4°C. Drugs were allowed to warm to room temperature immediately prior to injections. In all phases of the experiment, procedures were followed that minimized nifedipine exposure to light. All injections were in volumes of 2 t~l into the fourth ventricle as previously described (Panksepp, Vilberg, Bean, Coy, & Kastin, 1978). Injections occurred 5 min prior to testing. Visual discrimination learning was assessed on an apparatus used previously to evaluate visual learning in chicks (Deyo et al., 1987). A 25 x 25cm board was divided into 100 2.5-cm 2 grids. Each grid contained three food pellets and nine pebbles selected on the basis of size and color to resemble a food pellet (Purina Feeds Chick Starter). Chicks were required to learn to discriminate between the smooth texture of the pebbles and the rough texture of the food targets. The pebbles were fixed to the board with a clear glue. The apparatus was centered in a chamber consisting of three sides made of mirrors and one side of clear plastic. Each chick was individually placed on the visual discrimination board. Each peck was scored for ac-
curacy and constituted one trial. Scorers were unaware of treatment assignments. Sixty acquisition trials were given. Chicks received 20 additional trials 24 h later. The total number of errors and the amount of time required to complete the task were recorded. Body weight was recorded after the retention test session and compared to the body weight recorded on Day 1 posthatch. Data were analyzed using a one-way analysis of variance followed by Dunnett's test for contrasts involving a control mean. A s u m m a r y of the mean number of errors committed during acquisition trials 1-20 and 41-60, and the 20 retention trials are presented in Fig. 1. Initially (during trials 1-20) chicks in all groups responded with a large number of errors. A significant training effect (F(2, 176) = 13.5, p < .01) indicated that performance improved by trials 4 1 60, but no statistically significant differences were detected between groups on the number of errors (F(3, 88) = 1.1, p > .05). In addition, the trial by drug interaction effect was not significant (F(6, 176) = 1.2, p > .05). Analysis of the amount of time required to complete the visual discrimination task also failed to detect any significant differences between groups during acquisition training (F(3, 88) = 0.5, p > .05). Analyses of the number of errors made during the retention trials indicated a significant group effect (F(3, 88) = 3.30, p < .025). Calculation of Dunnett's test for contrasts involving a control mean indicated that chicks receiving 100 n M and 100 t~M dosages of nifedipine made significantly more errors when compared to vehicle-treated controls (Fig. 1). There were no statistically significant group differences detected in the amount of time required to complete the retention test (F(3, 88) = 1.1, p > .05). In order to determine whether the retention def-
262
DEYO, NIX, AND PARKER
icits were due to an effect on feeding, an analysis of the growth rate was completed for each group. A difference score was calculated for each subject by subtracting the body weight recorded on Day 1 from t h a t recorded on Day 5. Chicks in all groups gained weight during the experiment. The change in body weight recorded for chicks in each t r e a t m e n t condition was not statistically different (F(3, 88) = 2.6, p > .05). Nifedipine impaired retention of the pebble floor visual discrimination task in chicks without altering acquisition or the amount of time required to complete the task. The fact t h a t no significant changes in body weight gain were detected suggests t h a t the data reflect a memory impairment r a t h e r t h a n a nonspecific effect on feeding behavior. These data are consistent with studies showing impaired memory following the administration of drugs which disrupt Ca2+-dependent processes in chicks (Davis & Pico, 1987; Deyo et al., 1987), and support the hypothesis t h a t Ca2÷-dependent processes play an important role in memory. The effects of nifedipine described here are opposite to the memory enhancement reported in chicks using nimodipine (Deyo et al., 1990). Evaluation of the differences between these two dihydropyridines should lead to a better understanding of which biophysical properties underlie nootropic effects. The dihydropyridines vary in a number of important biophysical properties, and we propose t h a t those properties related to increases in cerebral blood flow contribute to the observed enhancement of memory with nimodipine. Nimodipine is typically administered peripherally in behavioral studies. Thus, it is not known whether nimodipine's effects are due to changes at the neuronal level, changes in cerebral blood flow, or some as yet unidentified effect on peripheral physiology. In the present experiment, we administered nifedipine directly into the cerebrospinal fluid. Although we cannot completely rule out the possibility t h a t nifedipine acted on vascular Ca 2 ~ channels, this procedure should have minimized such effects. Hence, these results suggest t h a t inhibition of neuronal calcium channels alone is insufficient to facilitate learning and memory in neurologically intact chicks. Since it seems clear t h a t the nifedipine-induced memory deficits reported here are not due to vascular effects, it is important to identify possible alternative Ca 2+~dependent mechanisms by which nifedipine might act to disrupt memory. At least two
nifedipine-sensitive mechanisms could contribute either individually or in combination to impair memory. The Ca2+-dependent modulation of neurotransmitter release represents an important component of plasticity in A p l y s i a sensory neurons. Nifedipine disrupts this form of plasticity in A p l y s i a (Edmonds et al., 1990). Nifedipine also affects the activity of the Ca2+-dependent enzyme calpain in chicken brain (E1-Fawal, Correll, Gay, & Ehrich, 1990). Since calpain inhibitors have been reported to produce learning and memory deficits in chicks (Davis & Pico, 1987; Deyo et al., 1987), it is possible t h a t nifedipine's amnesic effects are due to changes in calpain activity. Currently, however, the mechanism underlying nifedipine-induced memory deficits is unknown. F u r t h e r study of the amnesic effects of nifedipine is indicated. REFERENCES Davis, J. L., & Pico, R. M. (1987). A tripeptide protease inhibitor attenuates conditionedavoidancebehavior. Brain Research, 406, 10-16. Deyo, R. A., Conner, R. L., & Panksepp, J. (1987). Perinatal leupeptin retards subsequent acquisition of a visual discrimination task in chicks. Behavioral and Neural Biology, 47, 219-224. Deyo, R. A., Panksepp, J., & Conner, R. L. (1990). Nimodipine alters acquisition of a visual discriminationtask in chicks. Behavioral and Neural Biology, 53, 149-152. Edmonds, B., Klein, M., Dale, N., & Kandel, E. R. (1990). Contributions of two types of calcium channels to synaptictransmission and plasticity. Science, 250, 1142-1147. E1-Fawal, H. A. N., Correll, L., Gay, L., & Ehrich, M. (1990). Protease activity in brain, nerve, and muscle of hens given neuropathy-inducingogranophosphatesand a calcium channel blocker. Toxicology and Applied Pharmacology, 163, 133142. Isaacson, R. L., Johnston, J. E., & Vargas, D. M. (1988). The effect of a calcium antagonist on the retention of simple associational learning. Physmlogy and Behavior, 42, 447452. Lynch, G., & Baudry, M. (1984). The biochemistry of memory: a new and specifichypothesis. Science, 224, 1057-1063. Malenka, R. C., Kauer, J. A., Zucker,R. S., & Nicoll,R. A. (1988). Postsynaptic calcium is sufficientfor potentiation of hippocampal synaptic transmission. Science, 242, 81-87. Panksepp, J., Vilberg, T., Bean, N. J., Coy, D. H., & Kastin, A. (1978). Reductionof distress vocalizationin chicksby opiatelike peptides. Brain Research Bulletin, 3, 663-667. Scriabine, A,, Schuurman, T., & Traber, J. (1989). Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB Journal, 3, 1799-1806. Staubli, U., Baudry, M., & Lynch, G. (1984). Leupeptin, a thiol proteinase inhibitor, causes a selectiveimpairmentof spatial maze performance in rats. Behavioral and Neural Biology, 40, 58-69.
260-262 (1992)
BRIEF REPORT Nifedipine Blocks Retention of a Visual Discrimination Task in Chicks RICHARD A. DEYO, DOROTHY A. NIX, AND T. W. PARKER 1
Department of Psychology, Winona State University, Winona, Minnesota 55987
nel antagonist (nimodipine) has been shown to improve learning and memory in neurologically intact subjects (Deyo, Panksepp, & Conner, 1990; Isaacson, Johnston, & Vargas, 1988). If an influx of Ca 2+ is required for learning and memory, one would predict that drugs which inhibit neuronal Ca 2+ entry (such as nimodipine) should impair learning and memory. Only one study has reported any amnesic effects following nimodipine treatment, and the dose required to impair memory was five times higher than the dose required to facilitate visual discrimination learning in chicks (Deyo et al., 1990). Although it is possible that indirect effects (e.g., enhancement of cerebral blood flow) could account for the nootropic effects, it has been widely assumed that nimodipine-induced behavioral improvements are the result of antagonism of neuronal L-type calcium channels (for review see Scriabine, Schuurman, & Traber, 1989). Given the paradox between the nimodipine studies and current theoretical models of the role of calcium in memory, it would be useful to determine whether any of the other dihydropyridines improve learning and memory. Unfortunately, relatively little is known about the behavioral effects of the other dihydropyridine calcium channel antagonists. Thus, the purpose of the present study was to evaluate the nootropic effects of nifedipine in chicks. The "pebble floor" visual discrimination task was selected on the basis of an earlier study in which we reported that acquisition and retention can be altered by nimodipine treatment (Deyo et al., 1990). Ninety-two Cornish Rock Broiler cockerels (Poultry Place Hatchery, Homer, MN) were received in the colony on the hatch day (designated as Day 1 posthatch), weighed and tagged for identification. Chicks were maintained in groups of 20-25 in 86.5 × 55.5 cm pens and allowed to adapt to the
Reports that the dihydropyridine Ca2÷ channel antagonists may facilitate memory led to the present study of the behavioral effects of nifedipine. Ninety-two 4-day-old male chicks received 0, 100 nM, 100 tLM, or 10 mM nifedipine. Drugs were administered in volumes of 2 Izl into the fourth cerebral ventricle 5 min before training on a visual discrimination task. Nifedipine did not produce any detectable changes in behavior during acquisition trials. Retention, however, was impaired 24 h after training in the 100 nM and 100 t~M nifedipine-treated chicks, which made significantly more errors than controls. Nifedipine did not affect the amount of time required to complete the task. No effects on body weight gain were detected, suggesting that the memory impairment was not due to a change in feeding behavior. These data are discussed in terms of the role of calcium-dependent processes in memory. ©1992 Academic Press, Inc. Although controversial differences distinguish current psychobiological theories of memory, one important component of many models involves the influx of Ca 2÷ and subsequent activation of second messenger systems (e.g., Edmonds, Klein, Dale, & Kandel, 1990; Lynch & Baudry, 1984; Malenka, Kauer, Zucker, & Nicoll, 1988). This view of memory is supported by studies demonstrating impaired neuronal plasticity and slowed learning and memory following the administration of drugs that are believed to disrupt Ca2+-dependent enzyme activity (Davis & Pico, 1987; Deyo, Connor, & Panskepp, 1987; Staubli, Baudry, & Lynch, 1984) and drugs which block Ca2+-dependent currents (Edmonds et al., 1990; Malenka et al., 1988). Interestingly, a dihydropyridine class Ca 2÷ chan' Please address correspondence and reprint requests to Dr. R. A. Deyo, Department of Psychology, Minne Hall, Winona State University, Winona, MN 55987. The authors thank Dr. A. J. Krutsch for invaluable comments and suggestions during the preparation of the manuscript. 260 0163-1047/92 $5.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved.
261
NIFEDIPINE AND MEMORY IN THE CHICK
12
T
o lO
-I"6 --r, ~,,,~ ,~ ,,~
: i =~: i
0
,
':.'!.'t
,
; i= ,,,
100nM
100pM
10mM
0
100nM
100pM
10mM
0
100nM
100pM
Dose of Nifedipine
Dose of Nffedipine
Dose of Nifedipine
First Block of Acquisition Trials
Last Block of Acquisition Trials
Rention Test
10 mM
FIG. l. Summary of the effects of selected dosages of nifedipine on the acquisition and retention of a visual discrimination task. Bars represent SEM. Asterisks denote significant comparisons using Dunnett's test for contrasts involving a control mean (p < .05).
lab environment for 3 days prior to behavioral testing. Food and water were freely available, b u t food was removed during the dark cycle immediately preceding behavioral testing. On Day 4 posthatch, chicks were randomly assigned to one of four treatment groups (n = 23 chicks each) defined on the basis of the dose administered: 0, 100 nM, 100 tLM, or 10 m M nifedipine. Nifedipine was dissolved in absolute ETOH and diluted to the appropriate concentration using polyethylene glycol (PEG) (MW 300). The control treatment (0 M nifedipine) consisted of the same concentration of ETOH in P E G that was used in nifedipine solutions (8.67 x 10 7% ETOH). Drugs were prepared and stored in a dark room at 4°C. Drugs were allowed to warm to room temperature immediately prior to injections. In all phases of the experiment, procedures were followed that minimized nifedipine exposure to light. All injections were in volumes of 2 t~l into the fourth ventricle as previously described (Panksepp, Vilberg, Bean, Coy, & Kastin, 1978). Injections occurred 5 min prior to testing. Visual discrimination learning was assessed on an apparatus used previously to evaluate visual learning in chicks (Deyo et al., 1987). A 25 x 25cm board was divided into 100 2.5-cm 2 grids. Each grid contained three food pellets and nine pebbles selected on the basis of size and color to resemble a food pellet (Purina Feeds Chick Starter). Chicks were required to learn to discriminate between the smooth texture of the pebbles and the rough texture of the food targets. The pebbles were fixed to the board with a clear glue. The apparatus was centered in a chamber consisting of three sides made of mirrors and one side of clear plastic. Each chick was individually placed on the visual discrimination board. Each peck was scored for ac-
curacy and constituted one trial. Scorers were unaware of treatment assignments. Sixty acquisition trials were given. Chicks received 20 additional trials 24 h later. The total number of errors and the amount of time required to complete the task were recorded. Body weight was recorded after the retention test session and compared to the body weight recorded on Day 1 posthatch. Data were analyzed using a one-way analysis of variance followed by Dunnett's test for contrasts involving a control mean. A s u m m a r y of the mean number of errors committed during acquisition trials 1-20 and 41-60, and the 20 retention trials are presented in Fig. 1. Initially (during trials 1-20) chicks in all groups responded with a large number of errors. A significant training effect (F(2, 176) = 13.5, p < .01) indicated that performance improved by trials 4 1 60, but no statistically significant differences were detected between groups on the number of errors (F(3, 88) = 1.1, p > .05). In addition, the trial by drug interaction effect was not significant (F(6, 176) = 1.2, p > .05). Analysis of the amount of time required to complete the visual discrimination task also failed to detect any significant differences between groups during acquisition training (F(3, 88) = 0.5, p > .05). Analyses of the number of errors made during the retention trials indicated a significant group effect (F(3, 88) = 3.30, p < .025). Calculation of Dunnett's test for contrasts involving a control mean indicated that chicks receiving 100 n M and 100 t~M dosages of nifedipine made significantly more errors when compared to vehicle-treated controls (Fig. 1). There were no statistically significant group differences detected in the amount of time required to complete the retention test (F(3, 88) = 1.1, p > .05). In order to determine whether the retention def-
262
DEYO, NIX, AND PARKER
icits were due to an effect on feeding, an analysis of the growth rate was completed for each group. A difference score was calculated for each subject by subtracting the body weight recorded on Day 1 from t h a t recorded on Day 5. Chicks in all groups gained weight during the experiment. The change in body weight recorded for chicks in each t r e a t m e n t condition was not statistically different (F(3, 88) = 2.6, p > .05). Nifedipine impaired retention of the pebble floor visual discrimination task in chicks without altering acquisition or the amount of time required to complete the task. The fact t h a t no significant changes in body weight gain were detected suggests t h a t the data reflect a memory impairment r a t h e r t h a n a nonspecific effect on feeding behavior. These data are consistent with studies showing impaired memory following the administration of drugs which disrupt Ca2+-dependent processes in chicks (Davis & Pico, 1987; Deyo et al., 1987), and support the hypothesis t h a t Ca2÷-dependent processes play an important role in memory. The effects of nifedipine described here are opposite to the memory enhancement reported in chicks using nimodipine (Deyo et al., 1990). Evaluation of the differences between these two dihydropyridines should lead to a better understanding of which biophysical properties underlie nootropic effects. The dihydropyridines vary in a number of important biophysical properties, and we propose t h a t those properties related to increases in cerebral blood flow contribute to the observed enhancement of memory with nimodipine. Nimodipine is typically administered peripherally in behavioral studies. Thus, it is not known whether nimodipine's effects are due to changes at the neuronal level, changes in cerebral blood flow, or some as yet unidentified effect on peripheral physiology. In the present experiment, we administered nifedipine directly into the cerebrospinal fluid. Although we cannot completely rule out the possibility t h a t nifedipine acted on vascular Ca 2 ~ channels, this procedure should have minimized such effects. Hence, these results suggest t h a t inhibition of neuronal calcium channels alone is insufficient to facilitate learning and memory in neurologically intact chicks. Since it seems clear t h a t the nifedipine-induced memory deficits reported here are not due to vascular effects, it is important to identify possible alternative Ca 2+~dependent mechanisms by which nifedipine might act to disrupt memory. At least two
nifedipine-sensitive mechanisms could contribute either individually or in combination to impair memory. The Ca2+-dependent modulation of neurotransmitter release represents an important component of plasticity in A p l y s i a sensory neurons. Nifedipine disrupts this form of plasticity in A p l y s i a (Edmonds et al., 1990). Nifedipine also affects the activity of the Ca2+-dependent enzyme calpain in chicken brain (E1-Fawal, Correll, Gay, & Ehrich, 1990). Since calpain inhibitors have been reported to produce learning and memory deficits in chicks (Davis & Pico, 1987; Deyo et al., 1987), it is possible t h a t nifedipine's amnesic effects are due to changes in calpain activity. Currently, however, the mechanism underlying nifedipine-induced memory deficits is unknown. F u r t h e r study of the amnesic effects of nifedipine is indicated. REFERENCES Davis, J. L., & Pico, R. M. (1987). A tripeptide protease inhibitor attenuates conditionedavoidancebehavior. Brain Research, 406, 10-16. Deyo, R. A., Conner, R. L., & Panksepp, J. (1987). Perinatal leupeptin retards subsequent acquisition of a visual discrimination task in chicks. Behavioral and Neural Biology, 47, 219-224. Deyo, R. A., Panksepp, J., & Conner, R. L. (1990). Nimodipine alters acquisition of a visual discriminationtask in chicks. Behavioral and Neural Biology, 53, 149-152. Edmonds, B., Klein, M., Dale, N., & Kandel, E. R. (1990). Contributions of two types of calcium channels to synaptictransmission and plasticity. Science, 250, 1142-1147. E1-Fawal, H. A. N., Correll, L., Gay, L., & Ehrich, M. (1990). Protease activity in brain, nerve, and muscle of hens given neuropathy-inducingogranophosphatesand a calcium channel blocker. Toxicology and Applied Pharmacology, 163, 133142. Isaacson, R. L., Johnston, J. E., & Vargas, D. M. (1988). The effect of a calcium antagonist on the retention of simple associational learning. Physmlogy and Behavior, 42, 447452. Lynch, G., & Baudry, M. (1984). The biochemistry of memory: a new and specifichypothesis. Science, 224, 1057-1063. Malenka, R. C., Kauer, J. A., Zucker,R. S., & Nicoll,R. A. (1988). Postsynaptic calcium is sufficientfor potentiation of hippocampal synaptic transmission. Science, 242, 81-87. Panksepp, J., Vilberg, T., Bean, N. J., Coy, D. H., & Kastin, A. (1978). Reductionof distress vocalizationin chicksby opiatelike peptides. Brain Research Bulletin, 3, 663-667. Scriabine, A,, Schuurman, T., & Traber, J. (1989). Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB Journal, 3, 1799-1806. Staubli, U., Baudry, M., & Lynch, G. (1984). Leupeptin, a thiol proteinase inhibitor, causes a selectiveimpairmentof spatial maze performance in rats. Behavioral and Neural Biology, 40, 58-69.