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The Post-training Memory Enhancement Induced by Physostigmine and Oxotremorine in Mice Is Not State-Dependent
NEUROBIOLOGY OF LEARNING AND MEMORY ARTICLE NO.
65, 121–124 (1996)
0014
The Post-training Memory Enhancement Induced by Physostigmine and Oxotremorine in Mice Is Not State-Dependent CARLOS M. BARATTI AND SILVIA R. KOPF1 Laboratorio de Neurofarmacologı´a de Procesos de Memoria, Ca´tedra de Farmacologı´a, Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires, Junı´n 956, RA-1113 Buenos Aires, Argentina
cholinergic systems. In general, low to moderate doses of anticholinesterase drugs, as well as muscarinic or nicotinic cholinergic agonists facilitate memory (Baratti, Huygens, Min˜o, Merlo, & Gardella, 1979; Baratti, Introini, & Huygens, 1984; Flood, Landry, & Jarvik, 1981; Faiman, de Erausquin, & Baratti, 1991). Also, the post-training administration of muscarinic receptors, antagonists that block autoreceptor mediating the inhibition of acetylcholine release from cholinergic nerve endings (Kilbinger, 1984), improves memory (Baratti, Opezzo, & Kopf, 1993). On the contrary, the cholinergic nonselective muscarinic antagonist, such as atropine or scopolamine, induce amnesia (Baratti et al., 1984; Drachman and Leavitt, 1974). When administered post-training the effects of cholinergic agonists on retention are time-dependent, supporting the view that the drugs affect memory by modulating the activity in brain systems involved in memory storage (McGaugh, 1992). However, it was recently found that oxotremorine, a muscarinic cholinergic agonist (Choi, Roch, & Jenden, 1973), also enhances memory retrieval (Brioni & Izquierdo, 1988). In addition, the information acquired on training may be stored in the brain state induced by the post-training treatment (Izquierdo, 1984). Therefore, under some particular conditions, the memory enhancement produced by post-training treatments might result from state dependency rather than from a facilitatory effect on memory storage processes. The present results clearly show that the post-training administration of the centrally acting anticholinesterase physostigmine (Taylor, 1990), but not its quaternary analog neostigmine (Taylor, 1990), and the muscarinic agonist oxotremorine enhance retention of a one-trial step-through inhibitory avoidance task in mice and that the effects are not state-dependent.
Immediate post-training subcutaneous administration of either the centrally acting anticholinesterase physostigmine (35, 70, or 150 mg/kg) or the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 mg/kg) significantly enhanced retention of male Swiss mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). Neither physostigmine nor OTM affected latencies to step through in mice not given the footshock on the training trial, suggesting that the effects of both cholinomimetics on retention performance were not due to nonspecific actions on response test latencies. The peripherally acting anticholinesterase neostigmine (35, 70, or 150 mg/kg) did not significantly influence retention latencies of either shocked or unshocked mice. The influences of physostigmine (150 mg/kg) and OTM (100 mg/kg) on retention were time-dependent, which suggests that the drugs facilitated memory storage. Administration of physostigmine (150 mg/kg) or OTM (100 mg/kg) 30 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline, physostigmine (150 mg/kg), or OTM (100 mg/kg). Considered together, these findings indicate that the memory-enhancing effects of post-training administration of physostigmine or OTM are not state-dependent and are consistent with the view that the behavioral effects of the cholinomimetics drugs are mediated through an interaction with the neural processes underlying the storage of acquired information. q 1996 Academic Press, Inc.
INTRODUCTION Numerous studies have reported that memory is influenced by drugs that affect the activity of the 1 This work was supported by Grant 3051/92 from CONICET to Dr. Carlos M. Baratti. Address correspondence and reprint requests to Carlos Baratti. E-mail: [email protected].
121 1074-7427/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
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MATERIALS AND METHODS Adult male Swiss mice furnished by Roux-Ocefa Laboratories (Argentina) were used (age, 60–70 days; weight, 25–30 g). The mice were trained in a step-through inhibitory avoidance task using 0.80 mA, 50 Hz, 1 s foot-shock (Baratti et al., 1984) and were tested for retention 48 h later. A ceiling score of 300 s was recorded on the retention trial. The doses of the drugs were calculated as the free base and were selected on the basis of previous results (Baratti et al. 1979, 1984). All drugs were dissolved in saline inmediately before being used, and were given subcutaneously (10 ml/kg). Data are expressed as means { SEM of the latencies to step-through during the retention test. They were analyzed using a one- or a two-way ANOVA (Winer, 1971), and post hoc analysis with the Newman–Keuls test was made. In all cases, p values less than .05 were considered significant. RESULTS In the first experiment we studied the effects of the immediate post-training injections of saline, physostigmine salicilate (Sigma) (35, 70, or 150 mg/kg), neostigmine bromide (Sigma) (35, 70, or 150 mg/kg), or oxotremorine sesquifumarate (Aldrich) (OTM; 25, 50, or 100 mg/kg) to mice that had (N Å 20 per group) or had not (N Å 10 per group) received a footshock during training. A one-way ANOVA revealed that both physostigmine (F(3, 76) Å 5.03; p õ .01) (Fig. 1A) and OTM (F(3, 76) Å 5.79; p õ .01) (Fig. 1B) markedly influenced the latencies to step through during the retention test of mice given a footshock on the training trial. The low doses of physostigmine and OTM had a small nonsignificant effect on retention (p ú .05, in both cases), whereas the two higher doses of the cholinomimetics significantly enhanced retention (p õ .01, in both cases). Neostigmine did not modify retention latencies (saline, 164 { 22 s; neostigmine, 35 mg/kg, 152 { 18 s; neostigmine, 70 mg/kg, 160 { 21 s; and neostigmine, 150 mg/kg, 155 { 20 s; F(3, 76) Å 0.06, p ú .05). Finally, retention performance of mice given post-training injections of physostigmine (F(3, 36) Å 0.16; p ú .05) (Fig. 1A), OTM (F(3, 36) Å 0.18; p ú .05) (Fig. 1B), or neostigmine (F(3, 36) Å 0.14 p ú .05) (data not shown) in the absence of the footshock did not differ from those of mice given saline when the mice were tested 48 h later. In a second experiment, different groups of 20 mice each were submitted to the training procedure
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FIG. 1. Effects of post-training injections of physostigmine (A) or oxotremorine (B) on the retention latencies of mice that had received a footshock (FS) or had received no footshock (NS) during training. The treatments were given immediately after training. Each bar represents the mean { SEM for 20 mice (shocked) or 10 mice (not shocked) per group. **põ.01, compared with saline control group (Newman–Keuls test).
and received saline, physostigmine (150 mg/kg), or OTM (100 mg/kg) immediately, 30, or 180 min after training. Table 1 shows the results of these experiments. A 3 (saline–physostigmine–OTM) 1 3 (training–treatment interval) ANOVA showed significant interaction of treatment 1 time (F(4, 171) Å 8.90; p õ .01). Both physostigmine and OTM administered immediately or 30 min after training significantly increased retention latencies (p õ .01, in all cases). However, when the injections were given 180 min after training, retention latencies did not differ significantly compared with their control groups.
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TABLE 1 Effect of Delayed Injections of Saline Physostigmine or OTM on Retention (Latency to Step Through(s) Treatments Training–treatment interval (min)
Saline
Physostigmine (150 mg/kg)
OTM (100 mg/kg)
0 30 180
136 { 22 135 { 21 146 { 20
249 { 12** 230 { 16** 144 { 18
259 { 19** 260 { 18** 155 { 19
Note. Data are expressed as means { SEM. ** p õ .01, as compared with its respective saline-injected control group (Newman–Keuls test). N Å 20 mice per group.
In the last experiment eight different groups of 20 mice each were injected immediately after training with saline, physostigmine (150 mg/kg), or OTM (100 mg/kg). Forty-eight hours later, these mice received, 30 min before testing, saline, physostigmine (150 mg/ kg), or OTM (100 mg/kg). The results are shown in Table 2. A two-way ANOVA indicated nonsignificant interaction between physostigmine administered after training and before the retention test (F(1, 76) Å 1.00; p ú .05). The same interaction occurred with the OTM treatment (F(1, 76) Å .96, p ú .05). The post-training administration of physostigmine or OTM enhanced retention in mice given saline prior to testing (p õ .01, in both cases). These effects were not modified by the administration, prior to testing, of the same doses of physostigmine or OTM, respectively (p õ .01, in both cases, as compared with saline–saline-injected control group). Neither physostigmine nor OTM given 30 min before testing affected the retention latencies of mice that received saline immediately after training ( p ú .05, in both cases, as compared with saline–salineinjected control group). DISCUSSION Extensive evidence indicates that cholinergic systems are involved in memory processes (Fibiger, 1991). The results of these experiments confirm and extend previous obsevations about the effects of two cholinomimetics drugs, physostigmine (Taylor, 1990) and oxotremorine (Choi et al., 1973), on retention of an inhibitory avoidance response in mice (Baratti et al., 1979; Baratti et al., 1984). Thus, physostigmine and OTM enhanced retention in a dosedependent manner. The inverted-U dose–response
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curve, which appears to be characteristic of nearly all treatments that can retroactively enhance retention (Gold, 1989), was not found in the present studies. However, higher doses of the cholinomimetics were not tested since they may produce several peripheral autonomic effects that, in turn, might affect retention performance in a nonspecific way. In the dose range employed this may not be the case, since post-training administration of physostigmine or OTM to unshocked mice did not modify their latencies to step through 48 h later. The effects of physostigmine and OTM on retention were time-dependent, which is another common feature to memorymodulating agents (Gold, 1989; McGaugh, 1992), suggesting an action on mechanisms involved in memory storage (McGaugh, 1992). However, the information acquired on training may be stored in the brain state induced by the post-training treatment (Izquierdo, 1984). Therefore, under some conditions, the retrograde modulation of memory might result from state-dependency rather than from an influence of a particular pharmacological treatment on memory storage processes (Izquierdo, 1984, 1986). The evidence supporting this suggestion has come primarily from studies of the retrograde amnesia induced by endogenous opioids (b-endorphin and enkephalins) or by the post-training administration of high doses of epinephrine in rats (Izquierdo, 1984). The findings of these studies raise the question of whether retention enhancement produced by different post-training pharmacological treatments may
TABLE 2 Effects of Physostigmine and OTM Administered Post-training and prior to Retention Test Treatment Immediately after training Saline Physostigminea Saline Physostigmine Saline OTMb Saline OTM
Thirty minutes prior to retention test Saline Saline Physostigminea Physostigmine Saline Saline OTMb OTM
a
Retencion latencies (s, mean { SEM) 140 240 148 248 141 250 147 257
{ { { { { { { {
21 14** 22 22** 20 20** 24 22**
150 mg/kg, sc. 100 mg/kg, sc. ** p õ .01, as compared with saline–saline-injected control group (Newman–Keuls test). N Å 20 mice per group. b
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be also due to a state dependency. According to McGaugh (1992), a state-dependency interpretation of a retroactively memory enhancement would require an ‘‘assumption that the state normally occurring at the time of the retention test is similar to that induced by the drugs following the training.’’ If that is true, the administration of the same drug prior to testing should decrease the similarity of the states and, thus, block, or at least attenuate, the memory enhancement (McGaugh, 1992). Our findings with physostigmine and OTM have provided no evidence for these possibilities. In fact, the administration of physostigmine or OTM prior to the retention test did not affect retention latencies of mice given either physostigmine or OTM immediately after training. Furthermore, our results also indicate that both cholinomimetics do not influence memory retrieval when given prior to retention test. These results, considered together with those obtained in other studies (Castellano & McGaugh, 1989, 1990; Kopf, Opezzo, & Baratti, 1993), do not support the view that memory facilitation produced by post-training treatments, in general, are due to the induction of state-dependency and clearly indicate that both physostigmine and OTM influence memory storage. Finally, the lack of effects of neostigmine, a peripheral anticholinesterase (Taylor, 1990), on retention suggests that peripheral cholinergic mechanisms do not participate in the behavioral actions of cholinomimetic drugs (but see Rush & Streit, 1992). REFERENCES Baratti, C. M., Huygens, P., Min˜o, J., Merlo, A., & Gardella, J. (1979). Memory facilitation with post-trial injection of physostigmine and oxotremorine in mice. Psychopharmacology, 64, 85–88. Baratti, C. M., Introini, I. B., & Huygens, P. (1984). Possible interaction between central cholinergic muscarinic and opiod peptidergic systems during memory consolidation in mice. Behavioral and Neural Biology, 40, 155–169. Baratti, C. M., Opezzo, J. W., & Kopf, S. R. (1993). Facilitation of memory storage by the acethylcholine M2 muscarinic receptor antagonist AF-DX 116. Behavioral and Neural Biology, 60, 69–74. Brioni, J. D., & Izquierdo, I. (1988). Retention enhancement by pretest b-endorphin and oxotremorine and its reversal by scopolamine. Behavioral and Neural Biology, 50, 251–254.
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Castellano, C., & McGaugh, J. L. (1989). Retention enhancement with post-training picrotoxin: Lack of state-dependency. Behavioral and Neural Biology, 51, 165–170. Castellano, C., & McGaugh, J. L. (1990). Effects of post-raining bicuculline and muscimol on retention: Lack of state dependency. Behavioral and Neural Biology, 54, 156–164. Choi, R. L., Roch, M., & Jenden, D. J. (1973). A regional study of acetylcholine turnover in rat brain and the effects of oxotremorine. Proceedings of West Pharmacology Society, 16, 188– 190. Drachman, D. A., & Leavitt, J. (1974). Human memory and the cholinergic system. Archives of Neurology, 30, 113–121. Faiman, C. P., de Erausquin, G. A., & Baratti, C. M. (1991). The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms. Behavioral and Neural Biology, 56, 183– 199. Fibiger, H. C. (1991). Cholinergic mechanisms in learning, memory and dementia: A review of recent evidence. Trends in Neurosciences, 14, 220–223. Flood, J. F., Landry, D. W., & Jarvik, M. E. (1981). Cholinergic receptor interactions and their effects on long-term memory. Brain Research, 215, 177–185. Gold, P. E. (1989). Neurobiological features common to memory modulation by many treatments. Animal Learning and Behavior, 17, 94–100. Izquierdo, I. (1984). Endogenous state dependency: Memory depends on the relation between the neurohumoral and hormonal states present after training and at the time of testing. In G. Lynch, J. L. McGaugh, & N. M. Weinberger (Eds.), Neurobiology of learning and memory (pp. 333–350). New York: Guilford Press. Izquierdo, I. (1986). Memory consolidation is not a useful hypothesis in the search for memory-enhancing drugs. Trends in Pharmacological Sciences, 7, 476–477. Kilbinger, H. (1984). Presynaptic muscarinic modulating acetylcholine release. Trends in Pharmacological Sciences, 5, 103– 105. Kopf, S. R., Opezzo, J. W., & Baratti, C. M. (1993). Glucose enhancement of memory is not state-dependency. Behavioral and Neural Biology, 60, 192–195. McGaugh, J. L. (1992). Neuromodulatory systems and the regulation of memory storage. In L. R. Squire and N. Butters (Eds.), Neuropsychology of memory (pp. 386–401). New York: Guildford Press. Rush, D. K., & Streit, K. (1992). Memory modulation with peripherally acting cholinergic drugs. Psychopharmacology, 106, 375–382. Taylor, P. (1990). Anticholinesterase agents. In A. Goodman Gilman, T. W. Rall, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (pp. 131–149). New York: Pergamon. Winer, B. J. (1971). Statistical principles in experimental design. New York: McGraw–Hill.
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0014
The Post-training Memory Enhancement Induced by Physostigmine and Oxotremorine in Mice Is Not State-Dependent CARLOS M. BARATTI AND SILVIA R. KOPF1 Laboratorio de Neurofarmacologı´a de Procesos de Memoria, Ca´tedra de Farmacologı´a, Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires, Junı´n 956, RA-1113 Buenos Aires, Argentina
cholinergic systems. In general, low to moderate doses of anticholinesterase drugs, as well as muscarinic or nicotinic cholinergic agonists facilitate memory (Baratti, Huygens, Min˜o, Merlo, & Gardella, 1979; Baratti, Introini, & Huygens, 1984; Flood, Landry, & Jarvik, 1981; Faiman, de Erausquin, & Baratti, 1991). Also, the post-training administration of muscarinic receptors, antagonists that block autoreceptor mediating the inhibition of acetylcholine release from cholinergic nerve endings (Kilbinger, 1984), improves memory (Baratti, Opezzo, & Kopf, 1993). On the contrary, the cholinergic nonselective muscarinic antagonist, such as atropine or scopolamine, induce amnesia (Baratti et al., 1984; Drachman and Leavitt, 1974). When administered post-training the effects of cholinergic agonists on retention are time-dependent, supporting the view that the drugs affect memory by modulating the activity in brain systems involved in memory storage (McGaugh, 1992). However, it was recently found that oxotremorine, a muscarinic cholinergic agonist (Choi, Roch, & Jenden, 1973), also enhances memory retrieval (Brioni & Izquierdo, 1988). In addition, the information acquired on training may be stored in the brain state induced by the post-training treatment (Izquierdo, 1984). Therefore, under some particular conditions, the memory enhancement produced by post-training treatments might result from state dependency rather than from a facilitatory effect on memory storage processes. The present results clearly show that the post-training administration of the centrally acting anticholinesterase physostigmine (Taylor, 1990), but not its quaternary analog neostigmine (Taylor, 1990), and the muscarinic agonist oxotremorine enhance retention of a one-trial step-through inhibitory avoidance task in mice and that the effects are not state-dependent.
Immediate post-training subcutaneous administration of either the centrally acting anticholinesterase physostigmine (35, 70, or 150 mg/kg) or the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 mg/kg) significantly enhanced retention of male Swiss mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). Neither physostigmine nor OTM affected latencies to step through in mice not given the footshock on the training trial, suggesting that the effects of both cholinomimetics on retention performance were not due to nonspecific actions on response test latencies. The peripherally acting anticholinesterase neostigmine (35, 70, or 150 mg/kg) did not significantly influence retention latencies of either shocked or unshocked mice. The influences of physostigmine (150 mg/kg) and OTM (100 mg/kg) on retention were time-dependent, which suggests that the drugs facilitated memory storage. Administration of physostigmine (150 mg/kg) or OTM (100 mg/kg) 30 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline, physostigmine (150 mg/kg), or OTM (100 mg/kg). Considered together, these findings indicate that the memory-enhancing effects of post-training administration of physostigmine or OTM are not state-dependent and are consistent with the view that the behavioral effects of the cholinomimetics drugs are mediated through an interaction with the neural processes underlying the storage of acquired information. q 1996 Academic Press, Inc.
INTRODUCTION Numerous studies have reported that memory is influenced by drugs that affect the activity of the 1 This work was supported by Grant 3051/92 from CONICET to Dr. Carlos M. Baratti. Address correspondence and reprint requests to Carlos Baratti. E-mail: [email protected].
121 1074-7427/96 $18.00 Copyright q 1996 by Academic Press, Inc. All rights of reproduction in any form reserved.
AID
NLM 3677
/
m4708$$$17
02-19-96 09:23:31
nlmas
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MATERIALS AND METHODS Adult male Swiss mice furnished by Roux-Ocefa Laboratories (Argentina) were used (age, 60–70 days; weight, 25–30 g). The mice were trained in a step-through inhibitory avoidance task using 0.80 mA, 50 Hz, 1 s foot-shock (Baratti et al., 1984) and were tested for retention 48 h later. A ceiling score of 300 s was recorded on the retention trial. The doses of the drugs were calculated as the free base and were selected on the basis of previous results (Baratti et al. 1979, 1984). All drugs were dissolved in saline inmediately before being used, and were given subcutaneously (10 ml/kg). Data are expressed as means { SEM of the latencies to step-through during the retention test. They were analyzed using a one- or a two-way ANOVA (Winer, 1971), and post hoc analysis with the Newman–Keuls test was made. In all cases, p values less than .05 were considered significant. RESULTS In the first experiment we studied the effects of the immediate post-training injections of saline, physostigmine salicilate (Sigma) (35, 70, or 150 mg/kg), neostigmine bromide (Sigma) (35, 70, or 150 mg/kg), or oxotremorine sesquifumarate (Aldrich) (OTM; 25, 50, or 100 mg/kg) to mice that had (N Å 20 per group) or had not (N Å 10 per group) received a footshock during training. A one-way ANOVA revealed that both physostigmine (F(3, 76) Å 5.03; p õ .01) (Fig. 1A) and OTM (F(3, 76) Å 5.79; p õ .01) (Fig. 1B) markedly influenced the latencies to step through during the retention test of mice given a footshock on the training trial. The low doses of physostigmine and OTM had a small nonsignificant effect on retention (p ú .05, in both cases), whereas the two higher doses of the cholinomimetics significantly enhanced retention (p õ .01, in both cases). Neostigmine did not modify retention latencies (saline, 164 { 22 s; neostigmine, 35 mg/kg, 152 { 18 s; neostigmine, 70 mg/kg, 160 { 21 s; and neostigmine, 150 mg/kg, 155 { 20 s; F(3, 76) Å 0.06, p ú .05). Finally, retention performance of mice given post-training injections of physostigmine (F(3, 36) Å 0.16; p ú .05) (Fig. 1A), OTM (F(3, 36) Å 0.18; p ú .05) (Fig. 1B), or neostigmine (F(3, 36) Å 0.14 p ú .05) (data not shown) in the absence of the footshock did not differ from those of mice given saline when the mice were tested 48 h later. In a second experiment, different groups of 20 mice each were submitted to the training procedure
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FIG. 1. Effects of post-training injections of physostigmine (A) or oxotremorine (B) on the retention latencies of mice that had received a footshock (FS) or had received no footshock (NS) during training. The treatments were given immediately after training. Each bar represents the mean { SEM for 20 mice (shocked) or 10 mice (not shocked) per group. **põ.01, compared with saline control group (Newman–Keuls test).
and received saline, physostigmine (150 mg/kg), or OTM (100 mg/kg) immediately, 30, or 180 min after training. Table 1 shows the results of these experiments. A 3 (saline–physostigmine–OTM) 1 3 (training–treatment interval) ANOVA showed significant interaction of treatment 1 time (F(4, 171) Å 8.90; p õ .01). Both physostigmine and OTM administered immediately or 30 min after training significantly increased retention latencies (p õ .01, in all cases). However, when the injections were given 180 min after training, retention latencies did not differ significantly compared with their control groups.
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TABLE 1 Effect of Delayed Injections of Saline Physostigmine or OTM on Retention (Latency to Step Through(s) Treatments Training–treatment interval (min)
Saline
Physostigmine (150 mg/kg)
OTM (100 mg/kg)
0 30 180
136 { 22 135 { 21 146 { 20
249 { 12** 230 { 16** 144 { 18
259 { 19** 260 { 18** 155 { 19
Note. Data are expressed as means { SEM. ** p õ .01, as compared with its respective saline-injected control group (Newman–Keuls test). N Å 20 mice per group.
In the last experiment eight different groups of 20 mice each were injected immediately after training with saline, physostigmine (150 mg/kg), or OTM (100 mg/kg). Forty-eight hours later, these mice received, 30 min before testing, saline, physostigmine (150 mg/ kg), or OTM (100 mg/kg). The results are shown in Table 2. A two-way ANOVA indicated nonsignificant interaction between physostigmine administered after training and before the retention test (F(1, 76) Å 1.00; p ú .05). The same interaction occurred with the OTM treatment (F(1, 76) Å .96, p ú .05). The post-training administration of physostigmine or OTM enhanced retention in mice given saline prior to testing (p õ .01, in both cases). These effects were not modified by the administration, prior to testing, of the same doses of physostigmine or OTM, respectively (p õ .01, in both cases, as compared with saline–saline-injected control group). Neither physostigmine nor OTM given 30 min before testing affected the retention latencies of mice that received saline immediately after training ( p ú .05, in both cases, as compared with saline–salineinjected control group). DISCUSSION Extensive evidence indicates that cholinergic systems are involved in memory processes (Fibiger, 1991). The results of these experiments confirm and extend previous obsevations about the effects of two cholinomimetics drugs, physostigmine (Taylor, 1990) and oxotremorine (Choi et al., 1973), on retention of an inhibitory avoidance response in mice (Baratti et al., 1979; Baratti et al., 1984). Thus, physostigmine and OTM enhanced retention in a dosedependent manner. The inverted-U dose–response
AID
NLM 3677
/
m4708$$$18
02-19-96 09:23:31
curve, which appears to be characteristic of nearly all treatments that can retroactively enhance retention (Gold, 1989), was not found in the present studies. However, higher doses of the cholinomimetics were not tested since they may produce several peripheral autonomic effects that, in turn, might affect retention performance in a nonspecific way. In the dose range employed this may not be the case, since post-training administration of physostigmine or OTM to unshocked mice did not modify their latencies to step through 48 h later. The effects of physostigmine and OTM on retention were time-dependent, which is another common feature to memorymodulating agents (Gold, 1989; McGaugh, 1992), suggesting an action on mechanisms involved in memory storage (McGaugh, 1992). However, the information acquired on training may be stored in the brain state induced by the post-training treatment (Izquierdo, 1984). Therefore, under some conditions, the retrograde modulation of memory might result from state-dependency rather than from an influence of a particular pharmacological treatment on memory storage processes (Izquierdo, 1984, 1986). The evidence supporting this suggestion has come primarily from studies of the retrograde amnesia induced by endogenous opioids (b-endorphin and enkephalins) or by the post-training administration of high doses of epinephrine in rats (Izquierdo, 1984). The findings of these studies raise the question of whether retention enhancement produced by different post-training pharmacological treatments may
TABLE 2 Effects of Physostigmine and OTM Administered Post-training and prior to Retention Test Treatment Immediately after training Saline Physostigminea Saline Physostigmine Saline OTMb Saline OTM
Thirty minutes prior to retention test Saline Saline Physostigminea Physostigmine Saline Saline OTMb OTM
a
Retencion latencies (s, mean { SEM) 140 240 148 248 141 250 147 257
{ { { { { { { {
21 14** 22 22** 20 20** 24 22**
150 mg/kg, sc. 100 mg/kg, sc. ** p õ .01, as compared with saline–saline-injected control group (Newman–Keuls test). N Å 20 mice per group. b
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be also due to a state dependency. According to McGaugh (1992), a state-dependency interpretation of a retroactively memory enhancement would require an ‘‘assumption that the state normally occurring at the time of the retention test is similar to that induced by the drugs following the training.’’ If that is true, the administration of the same drug prior to testing should decrease the similarity of the states and, thus, block, or at least attenuate, the memory enhancement (McGaugh, 1992). Our findings with physostigmine and OTM have provided no evidence for these possibilities. In fact, the administration of physostigmine or OTM prior to the retention test did not affect retention latencies of mice given either physostigmine or OTM immediately after training. Furthermore, our results also indicate that both cholinomimetics do not influence memory retrieval when given prior to retention test. These results, considered together with those obtained in other studies (Castellano & McGaugh, 1989, 1990; Kopf, Opezzo, & Baratti, 1993), do not support the view that memory facilitation produced by post-training treatments, in general, are due to the induction of state-dependency and clearly indicate that both physostigmine and OTM influence memory storage. Finally, the lack of effects of neostigmine, a peripheral anticholinesterase (Taylor, 1990), on retention suggests that peripheral cholinergic mechanisms do not participate in the behavioral actions of cholinomimetic drugs (but see Rush & Streit, 1992). REFERENCES Baratti, C. M., Huygens, P., Min˜o, J., Merlo, A., & Gardella, J. (1979). Memory facilitation with post-trial injection of physostigmine and oxotremorine in mice. Psychopharmacology, 64, 85–88. Baratti, C. M., Introini, I. B., & Huygens, P. (1984). Possible interaction between central cholinergic muscarinic and opiod peptidergic systems during memory consolidation in mice. Behavioral and Neural Biology, 40, 155–169. Baratti, C. M., Opezzo, J. W., & Kopf, S. R. (1993). Facilitation of memory storage by the acethylcholine M2 muscarinic receptor antagonist AF-DX 116. Behavioral and Neural Biology, 60, 69–74. Brioni, J. D., & Izquierdo, I. (1988). Retention enhancement by pretest b-endorphin and oxotremorine and its reversal by scopolamine. Behavioral and Neural Biology, 50, 251–254.
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Castellano, C., & McGaugh, J. L. (1989). Retention enhancement with post-training picrotoxin: Lack of state-dependency. Behavioral and Neural Biology, 51, 165–170. Castellano, C., & McGaugh, J. L. (1990). Effects of post-raining bicuculline and muscimol on retention: Lack of state dependency. Behavioral and Neural Biology, 54, 156–164. Choi, R. L., Roch, M., & Jenden, D. J. (1973). A regional study of acetylcholine turnover in rat brain and the effects of oxotremorine. Proceedings of West Pharmacology Society, 16, 188– 190. Drachman, D. A., & Leavitt, J. (1974). Human memory and the cholinergic system. Archives of Neurology, 30, 113–121. Faiman, C. P., de Erausquin, G. A., & Baratti, C. M. (1991). The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms. Behavioral and Neural Biology, 56, 183– 199. Fibiger, H. C. (1991). Cholinergic mechanisms in learning, memory and dementia: A review of recent evidence. Trends in Neurosciences, 14, 220–223. Flood, J. F., Landry, D. W., & Jarvik, M. E. (1981). Cholinergic receptor interactions and their effects on long-term memory. Brain Research, 215, 177–185. Gold, P. E. (1989). Neurobiological features common to memory modulation by many treatments. Animal Learning and Behavior, 17, 94–100. Izquierdo, I. (1984). Endogenous state dependency: Memory depends on the relation between the neurohumoral and hormonal states present after training and at the time of testing. In G. Lynch, J. L. McGaugh, & N. M. Weinberger (Eds.), Neurobiology of learning and memory (pp. 333–350). New York: Guilford Press. Izquierdo, I. (1986). Memory consolidation is not a useful hypothesis in the search for memory-enhancing drugs. Trends in Pharmacological Sciences, 7, 476–477. Kilbinger, H. (1984). Presynaptic muscarinic modulating acetylcholine release. Trends in Pharmacological Sciences, 5, 103– 105. Kopf, S. R., Opezzo, J. W., & Baratti, C. M. (1993). Glucose enhancement of memory is not state-dependency. Behavioral and Neural Biology, 60, 192–195. McGaugh, J. L. (1992). Neuromodulatory systems and the regulation of memory storage. In L. R. Squire and N. Butters (Eds.), Neuropsychology of memory (pp. 386–401). New York: Guildford Press. Rush, D. K., & Streit, K. (1992). Memory modulation with peripherally acting cholinergic drugs. Psychopharmacology, 106, 375–382. Taylor, P. (1990). Anticholinesterase agents. In A. Goodman Gilman, T. W. Rall, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (pp. 131–149). New York: Pergamon. Winer, B. J. (1971). Statistical principles in experimental design. New York: McGraw–Hill.
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