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Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Humans
EXPERIMENTAL NEUROLOGY ARTICLE NO.
145, 89–92 (1997)
EN976447
Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Humans Gary Lynch, Richard Granger, Jose Ambros-Ingerson, C. Mike Davis, Markus Kessler, and Robert Schehr1 Cortex Pharmaceuticals, Inc., 15241 Barranca Parkwy, Irvine, California 92718
at various times after ingesting placebo or drug; the subjects rested in bed during the posttreatment period. Blood pressure and heart rate were monitored throughout the session and blood samples were collected at regular intervals. Behavioral results are described here for self-assessment of psychological variables and for delayed recall of nonsense syllables from tests conducted immediately before and during a 2.5-h period after administration of drug or placebo. The EWL 60-S instrument is a set of 60 adjectives, each associated with a 1 to 4 scale; these scales are grouped into 15 categories (4 adjectives each) related to different psychological states (8). Subjects are asked to rate themselves from low to high on each scale. Tests for recall involved playing a tape of 10 three-letter nonsense syllables to the subjects and then asking them to recall as many syllables as possible, first with minimal delay and then again after 5 min. Different lists of syllables matched for difficulty were used for successive testing but all subjects (placebo and drug) within a given test period (e.g., pretreatment) were read the same list. Subjects were administered the recall test prior to treatment and again 75 and 135 min after ingesting placebo or drug. Psychological self-assessment (EWL) scores were also collected prior to and 60 min after treatment. The subjects were tested in groups of 10 (6 drug and 4 placebo) over a period of 3 months. In all cases, they were fasted for 10 h before and 3 h after treatment. The study was conducted in a double-blind fashion. The ampakine used was CX516 (1-(quinoxalin6-ylcarbonyl)piperidine), a compound shown to enhance memory in a number of animal experiments (5, 9, 13, 15, 17, 18). Plasma concentrations of CX516 determined by a chromatographic procedure from samples collected shortly before and after each of the two posttreatment memory tests are summarized in Table 1. Values for the 900-mg group were almost three times those of the 600-mg subjects; note also that blood concentrations dropped by more than 50% between the two behavioral tests. Delayed recall scores were not correlated within subjects across the memory tests administered before
Elderly subjects (65–76 years) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors. A significant and positive drug effect was found for delayed (5 min) recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables. r 1997 Academic Press
Ampakines are a family of small benzoylpiperidine compounds that selectively enhance currents gated by AMPA-type glutamate receptors (1, 2). As expected from this, the drugs facilitate fast excitatory transmission and promote the induction of long-term potentiation (18). Ampakines freely cross the blood–brain barrier (17) and have been shown in a number of animal studies to improve the encoding of memory (5, 9, 13, 15, 17, 18). Glutamatergic synapses are lost with age (11) and a recent experiment demonstrated that ampakines greatly reduce the memory impairments exhibited by middle-aged rats in spatial mazes (6). These results raise the possibility that the drugs may be useful with regard to improving memory in elderly humans. While evidence suggestive of a positive influence of ampakines on human memory has been reported (10), data concerning their effects in older subjects has not been previously available. The results described in the present communication, which were collected as part of a safety trial conducted with 65- to 76-year-old subjects, are pertinent to this issue. Experimental procedures were similar to those described in a previous study (10). Male volunteers (65–76 years) were admitted to the AFB-Parexel clinic (Berlin) the evening before drug testing and administered a series of psychological and psychometric tests. The following morning they were again tested prior to and
1 Current address: Science and Technology Group, P.O. Box 109, Lake Placid, NY 12946.
89
0014-4886/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.
90
LYNCH ET AL.
TABLE 1
TABLE 2
Blood Levels of CX516 (µM) at the Time of Behavioral Testing (Means 6 SD)
Blood Pressure and Heart Rate (Means and SD) Were Measured at 60–90 Min Posttreatment and Average of the Two Values Was Calculated for Each Subject
Sampling times Dosage of CX516 (mg) 60–90 min Dosage 300 mg n56 600 mg n56 900 mg n56
120–150 min
2.0 6 1.1
0.8 6 0.5
2.9 6 1.2
1.2 6 0.7
8.3 6 3.6
4.0 6 2.4
Note. Samples were collected shortly before and shortly after each of two memory tests and an average value for each individual calculated for the indicated time periods.
(one test) and after (two tests) ingestion of placebo or drug. Group data are summarized in Fig. 1. As shown, a statistically significant drug effect (P 5 0.015, ANOVA) was present in the first posttreatment comparison. This was in the predicted direction in that the 900-mg group had higher recall scores than the placebo or 300-mg groups (P , 0.05, Tukey–Kramer test). Scores for the subjects given 600 mg CX516 were intermediate between those of the placebo and high dose groups. The 600-mg group included the subject with the highest pretreatment score on the recall test; dropping this individual from the analysis had no effect on the posttreatment results summarized in Fig. 1. The improvement in delayed recall obtained 75 min after drug administration appeared to be transient as evidenced by the results collected with a longer posttreatment delay (Fig. 1, right side). Immediate recall scores were 2.37 6 .85 (mean 6 SD) across all subjects before drug administration, versus 2.9 6 1.3 after drug administra-
Systolic (mm Hg) Diastolic (mm Hg) Heart rate (bpm)
0 (n 5 12)
300 (n 5 6)
600 (n 5 6)
900 (n 5 6)
140 6 18 79 6 6 59 6 7
145 6 25 79 6 9 59 6 6
147 6 12 86 6 7 63 6 5
129 6 7 78 6 5 59 6 5
tion; the 900-mg group scored 3.83 6 1.17, but this improvement did not reach statistical significance (P 5 0.079; Kruskal–Wallis ANOVA). Table 2 summarizes heart rate and blood pressure data collected at about the time of the first posttreatment memory test. There was no evidence for group differences in heart rate or diastolic pressure. Systolic values tended to be lower in the 900-mg group but this did not approach statistical significance; moreover, the average for the four placebo controls tested together with the 900-mg subjects was very close to that of the drug-treated individuals (129 6 15 vs 129 6 7). Results for a self-assessment inventory of psychological variables administered within minutes of the first posttreatment memory test are presented in Table 3. There were no evident placebo-drug differences. The above described results for delayed recall of nonsense syllables were obtained as part of a study to evaluate the safety of CX516 in elderly subjects; under these circumstances, it was not possible to optimize testing for possible memory enhancing influences of the drug. It is noteworthy, however, that drug effects were obtained at the expected time point and in the expected group. That is, blood levels of the test compound
FIG. 1. Delayed recall in syllable test. Different lists of 10 nonsense syllables were read to subjects prior to, 75 min, and 135 min after ingestion of placebo or the drug dose indicated underneath the columns. The number of syllables correctly recalled after a 5-min delay is plotted on the vertical axis. The data are means and SEM from 12 subjects in the control group and 6 subjects in each of the drug groups. Scores in the first posttreatment comparison (75 min) showed a significant drug effect (P 5 0.015, ANOVA) in the predicted direction, and subjects in the 900-mg group had higher recall scores than those in the placebo or 300-mg groups (P , 0.05, Tukey–Kramer test).
MODULATOR OF GLUTAMATE RECEPTORS IMPROVES RECALL
TABLE 3 Psychological Self-Assessment Scores in 15 Categories (A–O) of the EWL Test, Measured 60 Min after Treatment with Drug or Placebo (Mean 6 SD) 0
300
B 11.1 6 1.7 11.2 6 2.0 A 10.4 6 2.2 10.0 6 3.0 H 10.3 6 1.4 10.7 6 2.6 F 9.3 6 2.7 11.8 6 2.0 I 7.9 6 2.7 9.8 6 3.0 D 6.2 6 1.7 4.7 6 1.0 E 5.3 6 1.5 4.0 6 0 G 5.2 6 1.6 4.0 6 0 O 5.2 6 1.6 4.5 6 1.2 J 4.9 6 1.5 4.0 6 0 K 4.9 6 0.9 4.7 6 1.6 C 4.8 6 1.3 4.2 6 0.4 M 4.4 6 0.9 4.0 6 0 L 4.3 6 0.9 4.0 6 0 N 4.3 6 0.9 4.0 6 0
600
900
12.8 6 2.9 11.8 6 2.7 10.8 6 1.6 10.8 6 2.3 10.2 6 3.1 4.8 6 1.3 4.7 6 1.0 4.8 6 1.3 5.7 6 1.6 5.2 6 1.8 4.8 6 1.3 4.2 6 0.4 4.0 6 0 4.0 6 0 4.2 6 0.4
11.8 6 2.9 12.0 6 2.9 10.8 6 1.8 11.5 6 2.3 9.5 6 2.3 5.3 6 1.5 4.8 6 1.3 4.7 6 1.6 5.0 6 1.5 4.8 6 1.6 4.8 6 1.6 4.7 6 1.6 4.7 6 1.6 4.5 6 1.2 4.7 6 1.2
(Attentiveness) (Activity) (Confidence) (Extraversion) (Elevated mood) (Fatigue) (Drowsiness) (Introversion) (Dreaminess) (Agitation) (Emotionality) (Inactivity) (Anxiety) (Anger) (Depression)
Note. Maximum and minimum values for each category are 16 and 4, respectively. The scales are listed from high to low scores as recorded in the placebo group.
decayed steadily after 1 h postingestion; its direct actions should therefore be more evident in psychological tests administered shortly after treatment than in those given after longer delays. Furthermore, blood concentrations at the time of behavioral testing were related to dosage levels, suggesting that the effects of the CX516 should be most evident in the high dose group. That the present findings are in accord with these points strengthens the conclusion that CX516 promotes the encoding/recall of verbal material in aged subjects. A previous study found evidence that CX516 in the dosage range of 600–1200 mg had a positive effect on delayed recall in young, adult subjects (10). Other work using a much more extensive battery of tests also obtained results indicative of a memory enhancing effect of the drug in young individuals (7). The results described here are in agreement with these observations and, in addition, suggest that ampakines may be effective against a background of reduced memory processing. The number of items recalled by the subjects receiving 900 mg of CX516 more than doubled (3.0 6 0.68 with drug vs 1.2 6 0.31 before drug). Moreover, the mean predrug delayed recall scores for all of the 65- to 76-year-old people in the present experiment (1.4 6 1.0 items) were substantially lower than those of young subjects (4.48 6 1.8 items) in a similar study (10), except for the majority of the individuals tested 75 min after 900 mg of CX516. Although the size of the test groups in the present study are too small for strong conclusions, the size of the effects, the correspondence of scores with blood levels of the drug, the comparisons
91
with young subjects from previous studies, and the selectivity of the effects all suggest that the ampakine improved memory in these elderly subjects. Experiments with animals have also found that ampakines offset memory deficits that occur with age (6). CX516 had no evident effects on heart rate or blood pressure, measures that are presumably sensitive to changes in arousal (4, 12, 14). Drug-treated subjects also had scores similar to controls on self-rating tests for alertness, mood, and a variety of other psychological variables. It would appear then that the drug’s effects on memory were not secondary to generalized changes in behavior. Neurophysiological studies have shown that ampakines have much greater effects in complex, polysynaptic networks than they do on monosynaptic responses (2, 16). The relative selectivity of CX516 may thus reflect a greater influence in elaborate cortical circuitries required for processing verbal material than in simpler lower brain networks. It should also be noted that ampakines were developed using AMPA receptors in the cortical telencephalon as test systems and it remains possible that the drugs have lesser effects on receptor subtypes found outside cortical structures. Finally, recent work has resulted in ampakines that are considerably more potent than CX516 in physiological and behavioral assays and that, in some cases, have substantially greater half-lives (2, 3). If these compounds have appropriate toxicological profiles, it will be of considerable interest to determine if they have greater effects on memory in the elderly than CX516. REFERENCES 1.
2.
3.
4.
5.
6.
7.
Arai, A., Kessler, M., Xiao, P., Ambros-Ingerson, J., Rogers, G., and Lynch, G. 1994. A centrally active drug that modulates AMPA receptor gated currents. Brain Res. 638: 343–346. Arai, A., Kessler, M., Rogers, G., and Lynch, G. 1996. Effects of a memory enhancing drug on AMPA receptor currents and synaptic transmission in hippocampus. J. Pharm. Exp. Ther. 278: 627–638. Davis, C. M., Moskovitz, B., Nguyen, M. A., Arai, A., Lynch, G., and Granger, R. A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors. Psychopharmacology, in press. France, C., and Ditto, B. 1992. Cardiovascular responses to the combination of caffeine and mental arithmetic, cold pressor, and static exercise stressors. Psychophysiology 29: 272–282. Granger, R., Staubli, U., Davis, M., Perez, Y., Nilsson, L., Rogers, G. A., and Lynch, G. 1993. A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning dependent task. Synapse 15: 326–329. Granger, R., Deadwyler, S., Davis, M., Moskovitz, B., Rogers, G., and Lynch, G. 1996. Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse 22: 332–337. Ingvar, M., Ambros-Ingerson, J., Davis, M., Granger, R., Kessler, M., Rogers, G. A., Schehr, R. S., and Lynch, G. Enhancement by an ampakine of memory encoding in humans. Exper. Neurol., in press.
92 8. 9.
10.
11.
12.
13.
LYNCH ET AL. Janke, W., and Debus, G. 1978. Die Eigenschaftswo¨rterliste. Hogrefe, Go¨ttingen. Larson, J., Lieu, T., Petchpradub, V., LeDuc, B., Ngo, H., Rogers, G. A., and Lynch, G. 1995. Facilitation of olfactory learning by a modulator of AMPA receptors. J. Neurosci. 15: 8023–8030. Lynch, G., Kessler, M., Rogers, G., Ambros-Ingerson, J., Granger, R., and Schehr, R. S. 1996. Psychological effects of a drug that facilitates brain AMPA receptors. Intl. Clin. Psychopharm. 11: 13–19. Masliah, E., Mallory, M., Hansen, L., DeTeresa, R., and Terry, R. D. 1993. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43: 192–197. McGlynn, F., Moore, P., Rose, M., and Lazarte, A. 1995. Effects of relaxation training on fear and arousal during in vivo exposure to a caged snake among DSM-III-R simple (snake) phobics. J. Behav. Ther. Exp. Psychiatry 26: 1–8. Rogan, M., Staubli, U., and LeDoux, J. E. 1994. Facilitation of AMPA receptors accelerates classical fear conditioning in rats. Soc. Neurosci. Abstr. 20: 1007.
14.
15.
16.
17.
18.
Rose, R., and Fogg, J. 1993. Definition of a responder: analysis of behavioral, cardiovascular, and endocrine responses to varied workload in air traffic controllers. Psychosomatic Med. 55: 325–338. Shors, T. J., Servatius, R. J., Thompson, R. F., Rogers, G., and Lynch, G. 1995. Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely-moving rat. Neurosci. Lett. 186: 153–156. Sirvio, J., Larson, J., Quach, C. N., Rogers, G. A., and Lynch, G. 1996. Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit.Neuroscience 74: 1025–1035. Staubli, U., Rogers, G., and Lynch, G. 1994a. Facilitation of glutamate receptors enhances memory. Proc. Natl. Acad. Sci. USA 91: 777–781. Staubli, U., Perez, Y., Xu, F., Rogers, G., Ingvar, M., StoneElander, S., and Lynch, G. 1994b. Centrally active modulators of glutamate (AMPA) receptors facilitate the induction of LTP in vivo. Proc. Natl. Acad. Sci. USA 91: 11158–11162.
145, 89–92 (1997)
EN976447
Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Humans Gary Lynch, Richard Granger, Jose Ambros-Ingerson, C. Mike Davis, Markus Kessler, and Robert Schehr1 Cortex Pharmaceuticals, Inc., 15241 Barranca Parkwy, Irvine, California 92718
at various times after ingesting placebo or drug; the subjects rested in bed during the posttreatment period. Blood pressure and heart rate were monitored throughout the session and blood samples were collected at regular intervals. Behavioral results are described here for self-assessment of psychological variables and for delayed recall of nonsense syllables from tests conducted immediately before and during a 2.5-h period after administration of drug or placebo. The EWL 60-S instrument is a set of 60 adjectives, each associated with a 1 to 4 scale; these scales are grouped into 15 categories (4 adjectives each) related to different psychological states (8). Subjects are asked to rate themselves from low to high on each scale. Tests for recall involved playing a tape of 10 three-letter nonsense syllables to the subjects and then asking them to recall as many syllables as possible, first with minimal delay and then again after 5 min. Different lists of syllables matched for difficulty were used for successive testing but all subjects (placebo and drug) within a given test period (e.g., pretreatment) were read the same list. Subjects were administered the recall test prior to treatment and again 75 and 135 min after ingesting placebo or drug. Psychological self-assessment (EWL) scores were also collected prior to and 60 min after treatment. The subjects were tested in groups of 10 (6 drug and 4 placebo) over a period of 3 months. In all cases, they were fasted for 10 h before and 3 h after treatment. The study was conducted in a double-blind fashion. The ampakine used was CX516 (1-(quinoxalin6-ylcarbonyl)piperidine), a compound shown to enhance memory in a number of animal experiments (5, 9, 13, 15, 17, 18). Plasma concentrations of CX516 determined by a chromatographic procedure from samples collected shortly before and after each of the two posttreatment memory tests are summarized in Table 1. Values for the 900-mg group were almost three times those of the 600-mg subjects; note also that blood concentrations dropped by more than 50% between the two behavioral tests. Delayed recall scores were not correlated within subjects across the memory tests administered before
Elderly subjects (65–76 years) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine (CX516), a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors. A significant and positive drug effect was found for delayed (5 min) recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables. r 1997 Academic Press
Ampakines are a family of small benzoylpiperidine compounds that selectively enhance currents gated by AMPA-type glutamate receptors (1, 2). As expected from this, the drugs facilitate fast excitatory transmission and promote the induction of long-term potentiation (18). Ampakines freely cross the blood–brain barrier (17) and have been shown in a number of animal studies to improve the encoding of memory (5, 9, 13, 15, 17, 18). Glutamatergic synapses are lost with age (11) and a recent experiment demonstrated that ampakines greatly reduce the memory impairments exhibited by middle-aged rats in spatial mazes (6). These results raise the possibility that the drugs may be useful with regard to improving memory in elderly humans. While evidence suggestive of a positive influence of ampakines on human memory has been reported (10), data concerning their effects in older subjects has not been previously available. The results described in the present communication, which were collected as part of a safety trial conducted with 65- to 76-year-old subjects, are pertinent to this issue. Experimental procedures were similar to those described in a previous study (10). Male volunteers (65–76 years) were admitted to the AFB-Parexel clinic (Berlin) the evening before drug testing and administered a series of psychological and psychometric tests. The following morning they were again tested prior to and
1 Current address: Science and Technology Group, P.O. Box 109, Lake Placid, NY 12946.
89
0014-4886/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.
90
LYNCH ET AL.
TABLE 1
TABLE 2
Blood Levels of CX516 (µM) at the Time of Behavioral Testing (Means 6 SD)
Blood Pressure and Heart Rate (Means and SD) Were Measured at 60–90 Min Posttreatment and Average of the Two Values Was Calculated for Each Subject
Sampling times Dosage of CX516 (mg) 60–90 min Dosage 300 mg n56 600 mg n56 900 mg n56
120–150 min
2.0 6 1.1
0.8 6 0.5
2.9 6 1.2
1.2 6 0.7
8.3 6 3.6
4.0 6 2.4
Note. Samples were collected shortly before and shortly after each of two memory tests and an average value for each individual calculated for the indicated time periods.
(one test) and after (two tests) ingestion of placebo or drug. Group data are summarized in Fig. 1. As shown, a statistically significant drug effect (P 5 0.015, ANOVA) was present in the first posttreatment comparison. This was in the predicted direction in that the 900-mg group had higher recall scores than the placebo or 300-mg groups (P , 0.05, Tukey–Kramer test). Scores for the subjects given 600 mg CX516 were intermediate between those of the placebo and high dose groups. The 600-mg group included the subject with the highest pretreatment score on the recall test; dropping this individual from the analysis had no effect on the posttreatment results summarized in Fig. 1. The improvement in delayed recall obtained 75 min after drug administration appeared to be transient as evidenced by the results collected with a longer posttreatment delay (Fig. 1, right side). Immediate recall scores were 2.37 6 .85 (mean 6 SD) across all subjects before drug administration, versus 2.9 6 1.3 after drug administra-
Systolic (mm Hg) Diastolic (mm Hg) Heart rate (bpm)
0 (n 5 12)
300 (n 5 6)
600 (n 5 6)
900 (n 5 6)
140 6 18 79 6 6 59 6 7
145 6 25 79 6 9 59 6 6
147 6 12 86 6 7 63 6 5
129 6 7 78 6 5 59 6 5
tion; the 900-mg group scored 3.83 6 1.17, but this improvement did not reach statistical significance (P 5 0.079; Kruskal–Wallis ANOVA). Table 2 summarizes heart rate and blood pressure data collected at about the time of the first posttreatment memory test. There was no evidence for group differences in heart rate or diastolic pressure. Systolic values tended to be lower in the 900-mg group but this did not approach statistical significance; moreover, the average for the four placebo controls tested together with the 900-mg subjects was very close to that of the drug-treated individuals (129 6 15 vs 129 6 7). Results for a self-assessment inventory of psychological variables administered within minutes of the first posttreatment memory test are presented in Table 3. There were no evident placebo-drug differences. The above described results for delayed recall of nonsense syllables were obtained as part of a study to evaluate the safety of CX516 in elderly subjects; under these circumstances, it was not possible to optimize testing for possible memory enhancing influences of the drug. It is noteworthy, however, that drug effects were obtained at the expected time point and in the expected group. That is, blood levels of the test compound
FIG. 1. Delayed recall in syllable test. Different lists of 10 nonsense syllables were read to subjects prior to, 75 min, and 135 min after ingestion of placebo or the drug dose indicated underneath the columns. The number of syllables correctly recalled after a 5-min delay is plotted on the vertical axis. The data are means and SEM from 12 subjects in the control group and 6 subjects in each of the drug groups. Scores in the first posttreatment comparison (75 min) showed a significant drug effect (P 5 0.015, ANOVA) in the predicted direction, and subjects in the 900-mg group had higher recall scores than those in the placebo or 300-mg groups (P , 0.05, Tukey–Kramer test).
MODULATOR OF GLUTAMATE RECEPTORS IMPROVES RECALL
TABLE 3 Psychological Self-Assessment Scores in 15 Categories (A–O) of the EWL Test, Measured 60 Min after Treatment with Drug or Placebo (Mean 6 SD) 0
300
B 11.1 6 1.7 11.2 6 2.0 A 10.4 6 2.2 10.0 6 3.0 H 10.3 6 1.4 10.7 6 2.6 F 9.3 6 2.7 11.8 6 2.0 I 7.9 6 2.7 9.8 6 3.0 D 6.2 6 1.7 4.7 6 1.0 E 5.3 6 1.5 4.0 6 0 G 5.2 6 1.6 4.0 6 0 O 5.2 6 1.6 4.5 6 1.2 J 4.9 6 1.5 4.0 6 0 K 4.9 6 0.9 4.7 6 1.6 C 4.8 6 1.3 4.2 6 0.4 M 4.4 6 0.9 4.0 6 0 L 4.3 6 0.9 4.0 6 0 N 4.3 6 0.9 4.0 6 0
600
900
12.8 6 2.9 11.8 6 2.7 10.8 6 1.6 10.8 6 2.3 10.2 6 3.1 4.8 6 1.3 4.7 6 1.0 4.8 6 1.3 5.7 6 1.6 5.2 6 1.8 4.8 6 1.3 4.2 6 0.4 4.0 6 0 4.0 6 0 4.2 6 0.4
11.8 6 2.9 12.0 6 2.9 10.8 6 1.8 11.5 6 2.3 9.5 6 2.3 5.3 6 1.5 4.8 6 1.3 4.7 6 1.6 5.0 6 1.5 4.8 6 1.6 4.8 6 1.6 4.7 6 1.6 4.7 6 1.6 4.5 6 1.2 4.7 6 1.2
(Attentiveness) (Activity) (Confidence) (Extraversion) (Elevated mood) (Fatigue) (Drowsiness) (Introversion) (Dreaminess) (Agitation) (Emotionality) (Inactivity) (Anxiety) (Anger) (Depression)
Note. Maximum and minimum values for each category are 16 and 4, respectively. The scales are listed from high to low scores as recorded in the placebo group.
decayed steadily after 1 h postingestion; its direct actions should therefore be more evident in psychological tests administered shortly after treatment than in those given after longer delays. Furthermore, blood concentrations at the time of behavioral testing were related to dosage levels, suggesting that the effects of the CX516 should be most evident in the high dose group. That the present findings are in accord with these points strengthens the conclusion that CX516 promotes the encoding/recall of verbal material in aged subjects. A previous study found evidence that CX516 in the dosage range of 600–1200 mg had a positive effect on delayed recall in young, adult subjects (10). Other work using a much more extensive battery of tests also obtained results indicative of a memory enhancing effect of the drug in young individuals (7). The results described here are in agreement with these observations and, in addition, suggest that ampakines may be effective against a background of reduced memory processing. The number of items recalled by the subjects receiving 900 mg of CX516 more than doubled (3.0 6 0.68 with drug vs 1.2 6 0.31 before drug). Moreover, the mean predrug delayed recall scores for all of the 65- to 76-year-old people in the present experiment (1.4 6 1.0 items) were substantially lower than those of young subjects (4.48 6 1.8 items) in a similar study (10), except for the majority of the individuals tested 75 min after 900 mg of CX516. Although the size of the test groups in the present study are too small for strong conclusions, the size of the effects, the correspondence of scores with blood levels of the drug, the comparisons
91
with young subjects from previous studies, and the selectivity of the effects all suggest that the ampakine improved memory in these elderly subjects. Experiments with animals have also found that ampakines offset memory deficits that occur with age (6). CX516 had no evident effects on heart rate or blood pressure, measures that are presumably sensitive to changes in arousal (4, 12, 14). Drug-treated subjects also had scores similar to controls on self-rating tests for alertness, mood, and a variety of other psychological variables. It would appear then that the drug’s effects on memory were not secondary to generalized changes in behavior. Neurophysiological studies have shown that ampakines have much greater effects in complex, polysynaptic networks than they do on monosynaptic responses (2, 16). The relative selectivity of CX516 may thus reflect a greater influence in elaborate cortical circuitries required for processing verbal material than in simpler lower brain networks. It should also be noted that ampakines were developed using AMPA receptors in the cortical telencephalon as test systems and it remains possible that the drugs have lesser effects on receptor subtypes found outside cortical structures. Finally, recent work has resulted in ampakines that are considerably more potent than CX516 in physiological and behavioral assays and that, in some cases, have substantially greater half-lives (2, 3). If these compounds have appropriate toxicological profiles, it will be of considerable interest to determine if they have greater effects on memory in the elderly than CX516. REFERENCES 1.
2.
3.
4.
5.
6.
7.
Arai, A., Kessler, M., Xiao, P., Ambros-Ingerson, J., Rogers, G., and Lynch, G. 1994. A centrally active drug that modulates AMPA receptor gated currents. Brain Res. 638: 343–346. Arai, A., Kessler, M., Rogers, G., and Lynch, G. 1996. Effects of a memory enhancing drug on AMPA receptor currents and synaptic transmission in hippocampus. J. Pharm. Exp. Ther. 278: 627–638. Davis, C. M., Moskovitz, B., Nguyen, M. A., Arai, A., Lynch, G., and Granger, R. A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors. Psychopharmacology, in press. France, C., and Ditto, B. 1992. Cardiovascular responses to the combination of caffeine and mental arithmetic, cold pressor, and static exercise stressors. Psychophysiology 29: 272–282. Granger, R., Staubli, U., Davis, M., Perez, Y., Nilsson, L., Rogers, G. A., and Lynch, G. 1993. A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning dependent task. Synapse 15: 326–329. Granger, R., Deadwyler, S., Davis, M., Moskovitz, B., Rogers, G., and Lynch, G. 1996. Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse 22: 332–337. Ingvar, M., Ambros-Ingerson, J., Davis, M., Granger, R., Kessler, M., Rogers, G. A., Schehr, R. S., and Lynch, G. Enhancement by an ampakine of memory encoding in humans. Exper. Neurol., in press.
92 8. 9.
10.
11.
12.
13.
LYNCH ET AL. Janke, W., and Debus, G. 1978. Die Eigenschaftswo¨rterliste. Hogrefe, Go¨ttingen. Larson, J., Lieu, T., Petchpradub, V., LeDuc, B., Ngo, H., Rogers, G. A., and Lynch, G. 1995. Facilitation of olfactory learning by a modulator of AMPA receptors. J. Neurosci. 15: 8023–8030. Lynch, G., Kessler, M., Rogers, G., Ambros-Ingerson, J., Granger, R., and Schehr, R. S. 1996. Psychological effects of a drug that facilitates brain AMPA receptors. Intl. Clin. Psychopharm. 11: 13–19. Masliah, E., Mallory, M., Hansen, L., DeTeresa, R., and Terry, R. D. 1993. Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43: 192–197. McGlynn, F., Moore, P., Rose, M., and Lazarte, A. 1995. Effects of relaxation training on fear and arousal during in vivo exposure to a caged snake among DSM-III-R simple (snake) phobics. J. Behav. Ther. Exp. Psychiatry 26: 1–8. Rogan, M., Staubli, U., and LeDoux, J. E. 1994. Facilitation of AMPA receptors accelerates classical fear conditioning in rats. Soc. Neurosci. Abstr. 20: 1007.
14.
15.
16.
17.
18.
Rose, R., and Fogg, J. 1993. Definition of a responder: analysis of behavioral, cardiovascular, and endocrine responses to varied workload in air traffic controllers. Psychosomatic Med. 55: 325–338. Shors, T. J., Servatius, R. J., Thompson, R. F., Rogers, G., and Lynch, G. 1995. Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely-moving rat. Neurosci. Lett. 186: 153–156. Sirvio, J., Larson, J., Quach, C. N., Rogers, G. A., and Lynch, G. 1996. Effects of pharmacologically facilitating glutamatergic transmission in the trisynaptic intrahippocampal circuit.Neuroscience 74: 1025–1035. Staubli, U., Rogers, G., and Lynch, G. 1994a. Facilitation of glutamate receptors enhances memory. Proc. Natl. Acad. Sci. USA 91: 777–781. Staubli, U., Perez, Y., Xu, F., Rogers, G., Ingvar, M., StoneElander, S., and Lynch, G. 1994b. Centrally active modulators of glutamate (AMPA) receptors facilitate the induction of LTP in vivo. Proc. Natl. Acad. Sci. USA 91: 11158–11162.