calcium channel antagonists enhance retention of passive avoidance and maze learning in mice

Neurobiology of Learning and Memory 75, 77–90 (2001)

doi:10.1006/nlme.1999.3958, available online at http://www.idealibrary.com on

Calcium Channel Antagonists EnhanceRetention of Passive Avoidance and

Maze Learning in Mice

David Quartermain, Victoria Garcia deSoria, and Alice Kwan

Department of Neurology, New York University School of Medicine,New York, New York 10016

Although a number of studies have shown that treatment with calcium channelantagonists (CCAs) can ameliorate impairments in learning and memory in agedanimals, evidence for a general nootropic effect of CCAs in neurologically normalyoung adult animals is ambiguous. This study attempts to resolve some of thisambiguity by comparing the effects of several CCAs on retention of passive avoid-ance learning and acquisition and retention of appetitively motivated spatial discrim-ination learning in young adult mice. Animals were trained in a step through passiveavoidance apparatus and, immediately after training, injected subcutaneously withdifferent doses of nimodipine, nifedipine, amlodipine, flunarazine, diltiazem, orverapamil. Retention was tested 24 h after training. In the maze-learning task micewere treated with the same doses of the aforementioned CCAs immediately aftera brief training session in a linear maze and retention was tested 24 h after training.The most effective dose of each agent in the maze-retention experiment was adminis-tered to additional groups of animals 1 h prior to training to determine the effectsof CCAs on acquisition processes. The effects of central administration of CCAswere examined by intracerebroventricular injection of different doses of amlodipineimmediately after passive avoidance training. Results showed (1) all peripherallyadministered drugs except verapamil facilitated retention of passive avoidancetraining in a dose-dependent manner, (2) all drugs dose dependently facilitatedretention of linear maze learning, (3) all doses of the drugs (except verapamil)which facilitated maze retention also facilitated maze learning, and (4) centraladministration of the dihydropyridine amlodipine produced a dose-dependent facili-tation of the retention of passive avoidance learning. These data indicate that drugswhich block calcium channels can enhance retention of two different types oflearning in mice. q 2001 Academic Press

Key Words: calcium channel antagonists; memory enhancement; passive avoid-ance; maze learning; intracerbroventricular administration; mice.

Address correspondence and reprint requests to David Quartermain, Laboratory of Behavioral Neurology,Department of Neurology, NYU School of Medicine, 550 1st Avenue, New York, NY 10016. Fax: 212-263-2880. E-mail: [email protected].

77 1074-7427/01 $35.00Copyright q 2001 by Academic Press

All rights of reproduction in any form reserved.

78 QUARTERMAIN, GARCIA DESORIA, AND KWAN

INTRODUCTION

Calcium channel antagonists (CCAs) are a heterogeneous group of drugs which havebeen subdivided into three classes based on chemical structure, pharmacokinetic profile,and therapeutic use: the dihydropyridines (e.g., nimodipine), the benzothiazapines (e.g.,diltiazem), and the phenylalkylamines (e.g., verapamil). Drugs in all three classes blockcalcium entry at specific L-type channels in vascular and cardiac smooth muscle and onneuronal cell bodies and cerebral vasculature (Golden, McBurney, & Turner, 1996; Bean,1989; Miller, 1987). All of the CCAs are potent vasodilators, a functional effect whichprovides the rationale for their use in the treatment of various cardiovascular and neurologi-cal conditions such as angina, hypertension, cerebrovascular disease, and migraine (VanZwieten & Pfaffendorf, 1993; Spedding & Lepagnol, 1995; Golden, McBurney, & Turner,1996). Dihydropyridine CCAs such as nimodipine have also been investigated as possibletreatments for age-associated impairments in motor and cognitive behavior. For example,nimodipine has been shown to improve passive avoidance retention in senescence-acceler-ated prone mice (Yamamoto, Suzuki, Ozawa, Uchida, Yamada, & Kimura, 1995), water-maze learning and sensorimotor function in aged rats (Schuurman & Traber, 1989), traceeye-blink conditioning in old rabbits (Deyo, Straube, & Disterhoft, 1989), and delayedmatching to sample in senescent monkeys (Sandin, Jasmin, & LeVere, 1990).

Other studies have suggested that the CCAs may be useful as general cognitive enhancerson the basis of their ability to improve learning and memory in neurologically normalyoung adult animals. For instance, peripherally administered CCAs have been shown toreverse experimentally induced amnesias (e.g., Genkova-Papazova, Petokova, Bakor-ova, & Stoytcheva, 1997; Zupan, Vitezic, Mrsic, Matesic, & Simonic, 1996; Zupan,Mrsic, & Simonic, 1993), ameliorate the effects of brain lesions on learning (e.g., Popovic,Popovic, Jovanova-Nesic, Bokonjic, Dobric, Kostic, & Rosic, 1997; Finger, Green, Tarnoff,Mortman, & Anderson, 1990), facilitate retention of instrumental and Pavlovian condition-ing (e.g., Isaacson, Johnston, & Vargas, 1988; Quartermain, Hawxhurst, Ermita, & Puente,1993; Vetulani, Battalgia, & Sansone, 1997), improve spatial working memory (Levy,Kong, Stillman, Shukitt-Hale, Kadar, Rauch, & Lieberman, 1991) and reversal learning(McMonagle-Strucko & Fanelli, 1993), and enhance acquisition of visual discriminationlearning in chicks (Deyo, Panksepp, & Connor, 1990). However, the interpretation ofthese studies is complicated by the results of other experiments which have either failedto find any effects of CCAs on learning or retention (e.g., Clements, Rose, & Tiunova,1995; Isaacson, Maier, & Mandel, 1989; Vetulani, Battaglia, Castellano, & Sansome,1993) or have demonstrated impaired performance following administration of CCAs(e.g., Maurice, Bale, & Privat, 1995; Nikolaev & Kaczmarek, 1994; Deyo, Nix, & Parker,1992). The absence of consistency in these studies suggests that CCA-induced retentionenhancement in young animals may not be a robust phenomenon. Indeed the notion thatblockade of calcium channels can improve learning and retention appears paradoxicalsince it is widely accepted that calcium influx into neurons is a major triggering eventfor the cascade of biochemical reactions which precedes memory storage (Lynch & Baudry,1984; Goelet, Castellucci, Schacher, & Kandel, 1986; Nicoll & Malenka, 1995; Izquierdo &Medina, 1997). The enhancement of learning and memory seen in senescent animals afteradministration of CCAs has been attributed to a reversal of age-associated disturbances

CALCIUM CHANNEL ANTAGONISTS ENHANCE RETENTION IN MICE 79

in calcium metabolism (Thompson, Meyer, Black, & Disterhoft, 1992;), but this explana-tion could not account for enhanced performance in young animals.

Before investigating the mechanisms mediating possible enhancement effects in younganimals it will be necessary to resolve the question of the reliability of the phenomenon.This undertaking would be aided by experiments comparing the effects of several CCAsin different learning tasks to determine the reproducibility of the effect over a range ofstimulus and response conditions. Most of the previous studies have investigated a singleCCA (most frequently nimodipine) and there has been little attempt to design studies whererepresentatives of the different classes of CCAs are compared directly using behavioralprocedures which permit separation of drug effects on memory from those on otherprocesses such as attention, motivation, or emotion (McGaugh, 1989).

The purpose of the present study was to attempt to determine the effectiveness ofseveral CCAs representing different drug classes as memory enhancers in both a multitrialappetitively motivated spatial discrimination task and single-trial inhibitory avoidance.An additional aim was to determine if CCAs would facilitate acquisition in young animalsas they have been reported to do in senescent subjects (e.g., Thompson, Deyo, & Disterhoft,1990). Since it has been suggested that CCAs may facilitate retention when they areadministered peripherally but not when injected directly into the brain (Deyo & Hittner,1995), the present study also examined the effects of central (intracerebroventricular)administration of one of the CCAs (amlodipine) which has previously been shown tofacilitate retention of passive avoidance learning when administered subcutaneously imme-diately posttraining (Quartermain et al., 1993).

METHODS

Subjects

Subjects for this study were male Swiss Webster mice 6 to 8 weeks old weighingbetween 20 and 30 g and housed five per cage.

Apparatus

Passive avoidance. Apparatus consisted of a shock compartment 13 cm long, 9 cmwide, and 13 cm high to which was attached an entry platform 15 cm long and 2.75 cmwide. The compartment was made from black Plexiglas with a floor constructed fromstainless steel rods. The platform, which was made from unpainted plywood, was separatedfrom the chamber by a guillotine door. The apparatus was situated on the end of a tablein such a position that the platform was suspended 1 m above floor level. Foot shockwas delivered to the rods from a Colbourn constant-current shock source.

Linear maze. This is a semiautomated two-choice spatial discrimination apparatuswhich has been previously described (Quartermain, Mower, Rafferty, Herting, & Lanthorn,1994) in which animals are trained to shuttle between the goal boxes to obtain sucrosereward. Mice are not handled during either training or testing. The maze was constructedfrom wood and measured 75 cm long, 11.5 cm wide, and 10 cm high. Each segment was24 cm in length and contained a 15-cm-long dividing wall equipped with end walls whichprevented mice from seeing the barriers from the choice points. Alleys were 5 cm wide.


Removable barriers could be positioned on either side of the center of each wall. Goalboxes were 12 cm long with a 3.5-cm entranceway and a hinged end wall to allow foreasy removal of the animal from the apparatus. Mice could be retained in each goal boxby a sliding door. Each goal box contained a fluid cup which was attached to the endwall. The entire apparatus was covered with a clear Plexiglas lid. Reinforcement (0.05ml of a 4% sucrose solution) was dispensed from a fluid delivery system controlled byconventional programming equipment.

Drugs

The following calcium channel antagonists were used: diltiazem (Marion; 0, 1, 5, 10,and 20 mg/kg), flunarazine (RBI; 0, 0.1, 1, 10, and 20 mg/kg), nifedipine (Pfizer; 0, 0.1,1, 10, and 20 mg/kg), amlodipine (Pfizer; 0, 0.1, 1, 5, 10, and 20 mg/kg), nimodipine(Miles; 0, 0.1, 1, 10, and 20 mg/kg), verapamil (Knoll; 0, 1, 2, 10, and 20 mg/kg).

Nimodipine, nifedipine, and amlodipine are dihydropyridines; diltiazem is a representa-tive of the benzothiazapine class; and verapamil is a phenylalkylamine CCA. Flunarazineis a difluorinated piparazine. The dihydropyridines are principally vasodilators, have nomajor influence on cardiac activity (Van Zwieten & Pfaffendorf, 1993), and penetrate theblood–brain barrier with varying degrees of success. Verapamil is also a vasodilator buthas additional effects on heart rate and cardiac contractibility (Antonios & MacGregor,1998). Diltiazem is considered to be intermediate between the dihydropyridines and thephenylalkylamines (van Zwieten & Pfaffendorf, 1993). Flunarazine readily crosses theblood–brain barrier and antagonizes a broad range of calcium channels (Golden et al.,1996) but has been reported not to directly effect neuronal activity when administeredintravenously (Thompson, Deyo, & Disterhoft, 1990). The dose ranges for each drug werebased on pilot studies using the passive avoidance task. Amlodipine, diltiazem, andverapamil were dissolved in distilled water. Flunarazine, nifedipine, and nimodipine weredissolved in 40% methanol/60% PEG 400 solution and brought to a volume of 10 ml byaddition of distilled water. Drugs were injected in a volume of 10 ml per kilogram body-weight.

Surgical Procedure

Mice were anesthetized with 0.04 ml of a 1:1 mixture of ketamine and xylazine andplaced in a stereotaxic instrument modified to accommodate small rodents. The head washeld in a horizontal position by the use of ear bars and by stabilizing the nose to theinstrument with adhesive tape. The skull was exposed and cleaned with isopropyl alcoholand bregma was identified. Coordinates relative to bregma were 0.6 mm posterior, 1.5mm lateral, and 2.5 mm in depth from skull surface. A 1-mm-diameter hole was drilledby hand into the skull using a miniature hand drill. The drug was administered in a volumeof 3 ml using a Hamilton microsyringe attached to the arm of the stereotaxic instrument.Following the injection the skin was sutured and animals were returned to the home cage.Previous research from this laboratory using the above coordinates has shown that injectionof 3 ml of Evans Blue dye penetrates the lateral and third ventricles in 95% of miceweighing between 20 and 30 g.


Behavioral Procedures

Passive avoidance. On the training trial mice were placed on the platform facingaway from the door. When the animal entered the compartment the door was loweredand a 1-s 0.1-mA shock was automatically delivered. Immediately after training, groupsof mice (n 5 11–13 per group) were injected subcutaneously with the drugs and doselevels described above. Retention was tested 24 h after training. Mice were placed on theplatform and the door was raised. Animals failing to enter the compartment in 400 s wereassigned that time as a test score.

Linear maze retention. Following 24 h of water deprivation mice were initially famil-iarized with the apparatus in a 5-min adaptation session in which they were permitted toexplore the maze without barriers present in the alleys and to drink in both goal boxes.Mice were allowed 30 min of free access to water in the home cage after adaptation.Twenty-four hours later one of the alleys was blocked by placing a barrier in each unitand mice were required to learn the correct path between the goal boxes. For half of theanimals the left alley was blocked and the right for the remaining half. An error wasrecorded if any part of the animal’s body entered a blocked alley or if the animal reverseddirection. Animals were permitted to run freely between the goal boxes and were nothandled during training. The training session was terminated after five trials; a trial beingdefined as a run in one direction followed by consumption of the reward. Previous work(Quartermain et al., 1993) had established that drug-induced enhancement of learningcould be readily detected 24 h later with this level of training. Groups of mice (n 5

11–13 per group) were injected s.c. with the same drugs and dose levels used in thepassive avoidance task immediately after the fifth trial. All animals were given 30 minof free access to water in the home cage after training. Performance was tested 24 h laterby determining the number of trials required to reach a criterion of four errorless runs ina block of five trials.

Linear maze acquisition. To determine the effects of calcium channel blockade onthe acquisition of spatial learning, the most effective dose of each drug based on the linearmaze retention data was administered to groups of mice (n 5 11–13 per group) 1 h priorto the training session. All mice were given the standard adaptation session followed by30 min of free access to water in the home cage. The following day animals were trainedusing the procedure described above. Training was terminated when mice reached acriterion of four errorless runs in a block of five trials.

Effects of intracerebroventricular administration of amlodipine. In order to determinewhether CCAs would facilitate retention when administered centrally rather than subcuta-neously different doses of the dihydropyridine amlodipine were administered to groupsof mice following training in the passive avoidance task. Mice were transported to anadjacent room immediately after training and the drug was administered intracerebroven-tricularly using the methods described above. Mice were given 0 (n 5 13), 10 (n 5 12),20 (n 5 12), 30 (n = 9), or 50 (n 5 13) mg of amlodipine in a volume of 3 ml of distilledwater. As a control for possible nonspecific effects of higher doses, the 50-mg dose wasadministered to a group (n 5 13) of mice who were not shocked during passive avoidancetraining. Retention was tested 24 h later using methods described above.

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RESULTS

Passive Avoidance

Median test latencies for all of the drug and dose groups are shown in Fig. 1. Kruskal–Wallis one-way ANOVAs were computed for each drug group followed by plannedcomparisons using the Mann–Whitney U test. Figure 1 indicates that all of the CCAsexcept verapamil facilitated retention of passive avoidance learning in a dose-dependentmanner. The minimum effective dose was lowest for the dihydropyridines nifedipine andnimodipine (0.1 mg/kg) and highest for the benzothiazapine diltiazem (5mg/kg).

Linear Maze Retention

Figure 2 shows the effects of the same agents on the retention of linear maze learning.The data for each drug group were analyzed by a one-way ANOVA followed by comparisonof the dose groups with each vehicle group using Dunnett’s test. As indicated in Fig. 2all of the CCAs produced robust facilitation of retention. The effective memory-enhancingconcentrations were similar to those observed for passive avoidance retention with thedihydropyridines overall effective at lower doses than the benzothiazepine or phenylalky-lamine representatives. The most conspicuous discrepancy between the data from the twotasks was the ineffectiveness of verapamil in passive avoidance and its strong enhancementeffects in linear maze retention. The three concentrations which produced significant(P , .01) facilitation of maze learning were without effect in the passive avoidance task.

Linear Maze Acquisition

The effects of selected single doses of each of the CCAs on acquisition of the spatialmaze habit is shown in Fig. 3. A one-way ANOVA computed for these data indicated asignificant difference among the treatment groups [F(6, 76) 5 8.538; P , .0001]. Com-parison of each treatment group with the vehicle group using Dunnett’s test revealed thatall of the groups with the exception of verapamil reached the learning criterion significantlyfaster than the vehicle controls.

Effect of Intracerebroventricular Administration of Amlodipine

Results are shown in Fig. 4. A Kruskal–Wallis one-way ANOVA carried out on thelatencies of the shock groups revealed a significant difference among the five amlodipineconcentration groups [H(4, 61) 5 9.515; P , .05]. Comparisons of the individual druggroups with the vehicle controls using the Mann–Whitney U test revealed that both the30- and the 50-mg groups exhibited significantly (P , .02) facilitated retention of passiveavoidance learning. The nonshocked group receiving the 50-mg dose exhibited test latenciescomparable to the nonshock group treated with the vehicle.

FIG. 1. Median test latencies (and semi-interquartile ranges) to reenter the shock compartment on the 24-h retention test. P values for the Kruskal–Wallis one-way ANOVA by ranks for each drug group are shown inthe upper left corner of each graph. Mann–Whitney P values: *P , .05; **P , .01; ***P , .001.

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DISCUSSION

The results of this study convincingly demonstrate that calcium channel antagonistscan facilitate retention in young adult mice in at least two types of learning task. Severalearly studies (e.g., Deyo, Staube, & Disterhoft, 1989) indicated that some CCAs hadessentially no effects in young animals, suggesting that memory enhancement may berestricted to old animals with impaired intracellular calcium regulation. However, thepresent results as well as many of the studies reviewed under the Introduction have shownthat memory facilitation can be reliably obtained in young animals of several species,thereby demonstrating that the phenomenon is independent of chronological age. In thepresent study all representatives of the three classes of CAAs facilitated retention in atleast one of the learning tasks. Verapamil is clearly the most inconsistent in its effects onmemory retention. It was totally without effect on the passive avoidance task and showedstrong enhancement effects at three concentrations in the linear maze retention task butsurprisingly failed to facilitate acquisition when the most effective dose was administered1 h prior to training in the linear maze. An explanation for such inconsistency is notreadily apparent. Verapamil is known to be a powerful vasodilator but it differs from theother CCAs in that it also has depressant effects on heart rate (van Zwieten & Pfaffendorf,1993). Verapamil is a potent antagonist of 5HT2 receptors and has interactions with bothalpha-1 and -2 adrenoceptors (Defeudis, 1987). It has also been shown to inhibit uptakeof 5-HT, DA, and NE into rat forebrain synaptosomes (Defeudis, 1987). These findingsindicate that verapamil has a number of side effects not shared by the other CCAs.

Despite the biochemical and pharmacokinetic heterogeneity of the CCAs employedthere is a marked similarity in the shape of the dose–response effects which is particularlyapparent in the linear maze retention data. All of the effective drugs with the exceptionof amlodipine exhibit the inverted U function that is typical of most centrally activememory-enhancing drugs (White & Salinas, 1998). Amlodipine does not appear to diminishin effectiveness at high doses, as is the case with all of the other agents used in the linearmaze task. In informal experiments we have observed that in both passive avoidance andlinear maze learning, doses as high as 40–50 mg/kg continue to produce strong enhance-ment of memory in the 60% of animals who typically survive such high concentrations.This raises the possibility that the mechanisms mediating amlodipine-induced memoryfacilitation may be different from those of the other dihydropyridines. Amlodipine, awater-soluble dihydropyridine, differs structurally from the other dihydropyridines byvirtue of a basic side chain at the two carbon position of the dihydropyridine ring. As a resultof this feature more than 90% of amlodipine molecules are ionized under physiologicalconditions (Burges & Dodd, 1990; Nayler, 1994). The drug has a slow association withand dissociation from peripheral dihydropyridine receptor sites, which results in a longduration of drug action. Although amlodipine binds principally to dihydropyridine recep-tors some binding also occurs to benzothiazapine and phenylalkylamine recognition sites(Nayler, 1994). Amlodipine does not cross the blood–brain barrier as easily as the other

FIG. 2. Mean (1SEM) trials to reach a criterion of four correct runs in a block of five trials on a 24-hretention test for individual dose groups in each drug condition. One-way ANOVA P values for each drug areshown in the upper left corner of each graph. Dunnett’s test P values: *P , .05; **P , .01; ***P , .001.


FIG. 3. Mean (1SEM) trials to reach a criterion of four correct runs in a block of five trials in acquisitionfor mice treated 1 h before training with selected doses of the six CCAs. Dunnett’s P values: **P , .01.

dihydropyridines (see below) and this may be the major reason for the different shape ofthe dose–response curve.

Differences in the minimum effective concentrations among the CCAs probably reflectdifferences in the ease with which they penetrate the blood–brain barrier. Nimodipineand its structural analog nifedipine, which have the lowest effective concentration (0.1mg/kg), penetrate the blood–brain barrier freely. A recent study of the pharmacokineticsof calcium antagonists in the mouse (Uchida, Yamada, Nagai, Deguchi, & Kimura, 1997)indicated that brain concentrations of nimodipine and nifedipine were 6–9 times higherthan amlodipine following intravenous injection. This study also showed that a significantamount of in vivo binding to 1,4-dihydropyridine antagonist receptors occurred in mousebrain following intravenous injections with [3H]nimodipine and [3H]nifedipine but notwith [3H] amlodipine. This and other studies (e.g., Yamamoto et al., 1995) suggest thatamlodipine may penetrate the brain less readily than other dihydropyridines probablybecause of the structural characteristics described above.

What similarities might this heterogeneous group of drugs share that could account fortheir effects on memory processes? In the periphery they all inhibit the influx of calciuminto vascular smooth muscle and myocardium and this action provides the rationale fortheir clinical use as vasodilators in treatment of hypertension, unstable angina, and coronaryspasm. Cerebral vasodilation has been the rationale for the use of nimodipine for thetreatment of subarachnoid hemorrhage and brain ischemia (Golden et al., 1996) andflunarazine for the treatment of migraine headaches (Lamsudin & Sadjimin, 1993). Thepotent vasodilating potential of the three classes of CCAs has suggested the hypothesisthat they may be influencing memory processing by enhancing blood flow (Deyo &Hittner, 1995). Some support for this explanation was provided by studies reported byDeyo and colleagues (Deyo & Hittner 1993, 1995) which showed that memory facilitationoccurred when CCAs were administered peripherally but not when the vascular systemwas bypassed by injecting the drugs directly into the brain. However, studies have recentlyappeared reporting memory enhancement following central administration of CCAs. Inthe present study the results depicted in Fig. 4 clearly indicate that amlodipine enhancesretention of passive avoidance learning when the drug is administered via the cerebralventricular system. The effective doses are high but this may be the result of poor


FIG. 4. Median test latencies (and semi-interquartile ranges) to reenter the shock compartment on the 24-h retention test for mice treated intracerebroventricularly with different doses of amlodipine posttraining.

penetration of the brain from the ventricles. We are currently examining the effects ofadministering amlodipine directly into neural centers such as the hippocampus and amyg-dala. Quevedo, Vianna, Daroit, Born, Kuyven, Roesler, and Quillfeldt (1998) infusednifedipine bilaterally into the dorsal hippocampus of rats immediately after step-downinhibitory avoidance training and showed facilitated retention at a 24-h retention test.These findings do not necessarily argue against enhanced blood flow as the mechanismmediating memory enhancement. L-type calcium channels are present in the cerebralvasculature so it is possible that local vasodilator effects in the brain may underlie theCCA-induced retention enhancement.

Another possibility is that the CCAs may enhance retention via a direct blockadeof L-type calcium channels on neurons. Disterhoft and his associates have shown thatconcentrations of nimodipine which facilitate eye-blink conditioning in rabbits reducethe after-hyperpolarization which follows bursts of action potentials, thereby increasingneuronal firing rate (Thompson, Deyo, & Disterhoft, 1990; Disterhoft, Moyer, & Thomp-son, 1994; Disterhoft, Thompson, Weiss, Moyer, Van der Zee, Carrillo, Kronforst-Collins, & Power, 1995). These data raise the possibility that the facilitation of retentioninduced by CCAs in this study could be the result of their enhancement of neuronalexcitability.

The role of calcium channel blockade in mediating the retention-enhancing effects ofCCAs can be investigated pharmacologically by the use of enantiomers which are inactiveor less active than the racemate at calcium channels. Inactive enantiomers are availablefor amlodipine and nifedipine and a less active form of verapamil has been synthesized.We are presently carrying out an experiment comparing the effects of administering theinactive (1) and the active (2) enantiomers of amlodipine immediately following activeavoidance and linear maze training. Since it has been established that the affinity of thelevorotatory (2) enantiomer for the calcium channels is 1000 times greater than thedextrorotary (1) enantiomer (Arrowsmith, Campbell, Cross, Stubbs, Burges, Gardiner, &Blackbum, 1986), the results of this experiment may indicate the extent to which amlodi-pine-induced memory facilitation is mediated by calcium channel blockade.


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calcium channel antagonists enhance retention of passive avoidance and maze learning in mice

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