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Post-trial administration of vasopressin in humans does not enhance memory formation (vasopressin and memory consolidation)
Peptides 23 (2002) 581–583
Short Communication
Post-trial administration of vasopressin in humans does not enhance memory formation (vasopressin and memory consolidation) Steffen Gais, Marcel Sommer, Stefan Fischer, Boris Perras, Jan Born* Clinical Neuroendocrinology, University of Lu¨beck, Lu¨beck, Germany Received 16 July 2001; accepted 28 September 2001
Abstract Many animal studies show an enhancing effect of vasopressin (VP) on memory, but not all human studies could confirm this finding. This study examined the influence of post-learning administration of VP (40 IU, intranasally) on the consolidation of declarative memories in healthy humans during different intervals of sleep and waking. We could not find any effect of VP on memory consolidation, but EEG activity indicated a significant arousing influence of VP. Results suggest that if VP affects memory function it might do so primarily at the stage of encoding of the materials to be learned but it leaves unaffected processes of consolidation. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Vasopressin; Memory consolidation; Sleep
1. Introduction Vasopressin (VP) has become linked to a prolonged discussion about its influence on memory consolidation [2,5]. Studies show memory enhancing effects of VP administration on declarative, i.e. hippocampus dependent, memory in rodents [1,8,9] and, more recently, in monkeys [20]. However, in healthy young human subjects, the evidence is less clear cut. Part of these studies did not find any enhancing effect of VP on memory [10,14] or at least understand unspecific arousal and attention effects to be the primary cause of performance gains after administration of VP [19]. Other studies found improved recall of memory contents after VP administration [16,22]. One source of variance in the experimental results is that the effects on learning, memory consolidation, and recall are mixed up. VP administered shortly before a learning task with immediate recall testing, as it was done in many human studies, can exert influences at each of these stages of acquisition, consolidation, and retrieval. A second possible explanation for the discrepant results refers to the diversity of memory * Corresponding author. Medizinische Universita¨t Lu¨beck, Klinische Forschergruppe Neuroendokrinologie, Ratzeburger Allee 160, Haus 23a, D-23538 Lu¨beck, Germany. Tel.: ⫹49 (451) 500-3641; fax: ⫹49 (451) 500-3640. E-mail address: [email protected] (J. Born).
tasks employed in those studies. Memory tests address several anatomically and neurophysiologically distinct memory systems – most importantly organized into declarative and non-declarative memory. Here, we concentrate on effects of VP on declarative memory consolidation. Since sleep is considered to particularly support memory consolidation [7,13,17], effects of VP and placebo on memory consolidation during different times of the night were compared while subjects were either sleeping or awake. Periods of early and late retention sleep were compared in light of evidence for differential influences of VP on memory consolidation during these sleep periods [17]. VP was administered after learning; it was given intranasally, in order to facilitate passage of the peptide to the brain [18].
2. Methods Subjects were healthy non-smoking males, aged 19 –27. Experiments were implemented according to a three factorial design with one within-subject factor (VP vs. placebo) and two between subject factors (sleep vs. wake, first vs. second half of the night). A detailed description of the sleep/wake procedures and the task employed is given in Ref. 17. Briefly, 23 subjects were tested across the first half of the night with learning (pretest) between 22.20 h and 22.40 h, substance administration at 22.50 h and recall
0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 6 2 5 - 8
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S. Gais et al. / Peptides 23 (2002) 581–583
(posttest) at 02.15 h. Thirteen of these subjects slept for 3 h starting from 23.00 h while the rest remained awake. Nineteen subjects were tested across the second half of the night after having slept for 3 h between 23.00 h and 02.00 h. These subjects had their learning session between 02.20 h and 02.40 h, substance administration at 02.50 h and recall at 06.15 h. Ten of these subjects slept for 3 h during the retention phase starting from 03.00 h, nine stayed awake during this interval. After getting used to sleeping under laboratory conditions during one night, each subject participated in two experimental nights, with intranasal administration of VP (40 IU Arginine-Vasopressin, Sigma, Germany) and placebo according to a double-blind cross-over design. To test memory performance, subjects learned one of two lists of 36 category-instance word-pairs to a criterion of 60% before the administration of VP at the beginning of the first or the second half of the night, respectively. After the 3-h retention period, recall was measured as the percentage of paired words remembered correctly upon presentation of the first word of each pair. Before and after learning and recall testing, a sample of subjects’ saliva was taken to allow the determination of free cortisol levels by radioimmunoassay (Coat-A-Count, DPCBiermann, Germany). Sleep was monitored electrophysiologically and scored according to standard criteria. Statistics relied on the General Linear Model (GLM) with the three above-mentioned factors. During the wake retention interval 1 min of spontaneous EEG activity during eyes closed was recorded for 13 channels in a subsample of 9 subjects. EEG was sampled digitally at 100 Hz and power spectra were computed by means of Fast Fourier Transform. Band-power was calculated for delta (0.5– 4 Hz), theta (4.5– 8 Hz), alpha1 (8.5–10 Hz), alpha2 (10.5–12.5 Hz), beta1 (13–17.5 Hz), and beta2 (18 –30 Hz) bands. Significance was tested with two factor GLM (channels ⫻ substance) for each band.
Fig. 1. Recall (mean ⫾ SEM) after paired-associate wordlist learning as compared to performance at initial learning for a. the first half of the night, and b. the second half of the night. Pairwise comparisons between placebo (filled bars) and VP conditions (open bars) remained non-significant.
(sleep stages 3 and 4) during the first half of the night, and a larger percentage of REM sleep during the second half. Saliva cortisol levels, again as expected, differed between the first and second half of the night (mean ⫾ SEM: 0.09 ⫾ 0.02 g/dl vs. 0.21 ⫾ 0.03 g/dl; F(1,35) ⫽ 26.30, P ⬍ 0.001) and between the sleep and wake condition (0.16 ⫾ 0.03 g/dl vs. 0.12 ⫾ 0.02 g/dl; F(1,35) ⫽ 9.20, P ⬍ 0.01). However, differences between VP and placebo conditions remained non-significant (0.13 ⫾ 0.02 g/dl vs. 0.14 ⫾ 0.02 g/dl; P ⬎ 0.20, for main effect and first and second order interactions). Resting EEG during waking indicated an arousing effect of VP. Power in the beta1 band increased significantly (substance ⫻ channel interaction: F(10,80) ⫽ 2.396, P ⬍ 0.05; significant t tests for frontal [Fz, F3, F4] and central [C3, C4] leads, P ⬍ 0.05) while there were no significant effects of VP in any other frequency band.
3. Results Recall performance did not indicate any effect of VP on memory consolidation. As expected from previous studies [17], recall was best after sleep during the first half of the night (Fig. 1). Sleep significantly enhanced memory consolidation in the early sleep condition (F(1,15) ⫽ 5.30, P ⬍ 0.05) while it has no effect on memory consolidation during the late sleep interval. There is no effect of VP on declarative memory consolidation whatsoever (P ⬎ 0.75 for main effect and first and second order interactions). VP also did not affect sleep during the retention intervals (Table 1). Total sleep time remained constant and the percentage of time spent in the respective sleep stages did not differ significantly between VP and placebo conditions. Differences between the first and second half of the night showed, as expected, a larger percentage of slow wave sleep
Table 1 Percentage of time spent in individual sleep stages during the first and second half of the night
TST Wake S1 S2 S3 S4 REM MT
1st half of the night
2nd half of the night
Placebo
Vasopressin
Placebo
Vasopressin
2:50 ⫾ 0:03 1.7 ⫾ 1.7% 7.0 ⫾ 1.8% 46.8 ⫾ 3.3% 17.5 ⫾ 1.8% 15.0 ⫾ 3.6% 9.0 ⫾ 1.5% 1.0 ⫾ 0.3%
2:55 ⫾ 0:04 1.0 ⫾ 0.3% 2.7 ⫾ 1.7% 46.0 ⫾ 2.5% 15.9 ⫾ 2.0% 17.1 ⫾ 3.1% 9.2 ⫾ 1.7% 1.0 ⫾ 0.3%
2:55 ⫾ 0:03 1.3 ⫾ 0.9% 10.7 ⫾ 2.3% 53.3 ⫾ 4.2% 8.7 ⫾ 3.0% 0.3 ⫾ 0.3% 21.7 ⫾ 2.1% 1.2 ⫾ 0.4%
2:54 ⫾ 0:02 0.3 ⫾ 0.3% 13.3 ⫾ 4.4% 50.8 ⫾ 3.0% 6.8 ⫾ 1.8% 0.5 ⫾ 0.3% 24.3 ⫾ 2.2% 0.7 ⫾ 0.3%
Pairwise comparisons between vasopressin and placebo conditions were non-significant. TST: total sleep time, S1– 4: sleep stages 1– 4, REM: rapid eye movement sleep, MT: movement time.
S. Gais et al. / Peptides 23 (2002) 581–583
4. Discussion Memory consolidation was unchanged after intranasal administration of VP. This finding supports the view that the effects on memory function found in several other studies resulted mainly from changes in arousal and attention at the time of acquisition of the materials to be learned [10,19]. Whereas in those studies, VP was administered before learning, here the post-learning administration of the peptide enabled to separate effects on consolidation from those on processes activated at acquisition. However, one animal study showed an effect of VP administered after learning [12]. While this discrepancy is difficult to interpret, differences in the type of task, the species, the dose, and the exact timing of VP administration are to be taken into consideration. Notably, the animal study employed an aversiveconditioning task while we used a non-emotional declarative learning task. This is especially relevant, because VP is released in response to a variety of emotional stimuli [15]. Sleep parameters were unchanged under VP conditions. At first glance, this deviates from former studies [4], where VP after i.v. administration significantly shortened REM sleep and increased time in stage 2 sleep. However, another study using the same intranasal route for substance administration as used here did not reveal changes in sleep architecture after VP [21]. Since the intranasal route provides more direct access of the peptide to the cerebrospinal fluid compartment [11] acute reductions in REM sleep after VP previously observed with the i.v. route of administration probably represent effects mediated via systemic action of the peptide [5]. VP induced a significant change in the power distribution in the resting EEG during the wake state, notably in the lower beta band. This can be seen as an indication for an arousing effect of VP and it is consistent with other studies relating the effects of VP to signs of attention and arousal [3,19,21]. Together, these results speak against a substantial central nervous effect of VP on the consolidation of declarative memories in humans and thus favor the view that VP influences memory function primarily at the stage of the encoding process. However, several factors may modulate the effect of VP on memory consolidation that have not been tested here. Notably these are the dose of VP, the type of memory task, different times of day, and the subjects’ sex [6].
References [1] Alescio-Lautier B, Paban V, Soumireu-Mourat B. Neuromodulation of memory in the hippocampus by vasopressin. Eur J Pharmacol 2000;405:63–72.
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[2] Bohus B, Ader R, de Wied D. Effects of vasopressin on active and passive avoidance behavior. Horm Behav 1972;3:191–7. [3] Born J, Fehm-Wolfsdorf G, Lutzenberger W, Voigt KH, Fehm HL. Vasopressin and electrophysiological signs of attention in man. Peptides 1986;7:189 –93. [4] Born J, Kellner C, Uthgenannt D, Kern W, Fehm HL. Vasopressin regulates human sleep by reducing rapid-eye-movement sleep. Am J Physiol 1992;262:E295–300. [5] Born J, Pietrowsky R, Fehm HL. Neuropsychological effects of vasopressin in healthy humans. Prog Brain Res 1998;119:619 – 43. [6] Bruins, J. Desglycinamide-(ARG8)-Vasopressin, and Cognitive Processes in Healthy Subjects. PhD Thesis, Rijksuniversiteit te Utrecht, The Netherlands, 1991. [7] Buzsaki G. Memory consolidation during sleep: a neurophysiological perspective. J Sleep Res 1998;7:17–23. [8] Dietrich A, Allen JD. Vasopressin and memory. I. The vasopressin analogue AVP4 –9 enhances working memory as well as reference memory in the radial arm maze. Behav Brain Res 1997;87:195– 200. [9] Dietrich A, Allen JD. Vasopressin and memory. II. Lesions to the hippocampus block the memory enhancing effects of AVP4 –9 in the radial maze. Behav Brain Res 1997;87:201– 8. [10] Fehm-Wolfsdorf G, Born J. Behavioral effects of neurohypophyseal peptides in healthy volunteers: 10 years of research. Peptides 1991; 12:1399 – 406. [11] Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology? Eur J Pharmacol 2000;405:43–54. [12] Gaffori OJ, de Wied D. Time-related memory effects of vasopressin analogues in rats. Pharmacol Biochem Behav 1986;25:1125–9. [13] Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective. Trends Neurosci 2001;24:237– 43. [14] Jenkins JS, Mather HM, Coughlan AK. Effect of desmopressin on normal and impaired memory. J Neurol Neurosurg Psychiatry 1982; 45:830 –1. [15] Landgraf R, Wotjak CT, Neumann ID, Engelmann M. Release of vasopressin within the brain contributes to neuroendocrine and behavioral regulation. Prog Brain Res 1998;119:201–20. [16] Medvedev VI, Bakharev VD, Grechko AT, Nezovibat’ko VN. Effect of vasopressin and adrenocorticotrophic hormone fragment ACTH(4)-(7) on human memory. Hum Physiol 1980;6:307–10. [17] Plihal W, Born J. Effects of early and late nocturnal sleep on declarative and procedural memory. J Cogn Neurosci 1997;9:534 – 47. [18] Riekkinen P, Legros JJ, Sennef C, Jolkkonen J, Smitz S, Soininen H. Penetration of DGAVP (Org 5667) across the blood-brain barrier in human subjects. Peptides 1987;8:261–5. [19] Snel J, Taylor J, Wegman, M. Does DGAVP influence memory, attention, and mood in young healthy men? Psychopharmacology (Berl) 1987;92:224 – 8. [20] Sollertinskaya TN. Comparative physiological features of the regulatory effect of vasopressin on higher nervous activity in an ascending series of mammals. Neurosci Behav Physiol 1997;27:734 – 42. [21] Timsit-Berthier M, Mantanus H, Devos JE, Spiegel R. Action of lysine-vasopressin on human electroencephalographic activity. Night sleep pattern, auditory evoked potential, contingent negative variation. Neuropsychobiology 1982;8:248 –58. [22] Weingartner H, Gold P, Ballenger JC, Smallberg SA, Summers R, Rubinow DR, Post RM, Goodwin FK. Effects of vasopressin on human memory functions. Science 1981;211:601–3.
Short Communication
Post-trial administration of vasopressin in humans does not enhance memory formation (vasopressin and memory consolidation) Steffen Gais, Marcel Sommer, Stefan Fischer, Boris Perras, Jan Born* Clinical Neuroendocrinology, University of Lu¨beck, Lu¨beck, Germany Received 16 July 2001; accepted 28 September 2001
Abstract Many animal studies show an enhancing effect of vasopressin (VP) on memory, but not all human studies could confirm this finding. This study examined the influence of post-learning administration of VP (40 IU, intranasally) on the consolidation of declarative memories in healthy humans during different intervals of sleep and waking. We could not find any effect of VP on memory consolidation, but EEG activity indicated a significant arousing influence of VP. Results suggest that if VP affects memory function it might do so primarily at the stage of encoding of the materials to be learned but it leaves unaffected processes of consolidation. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Vasopressin; Memory consolidation; Sleep
1. Introduction Vasopressin (VP) has become linked to a prolonged discussion about its influence on memory consolidation [2,5]. Studies show memory enhancing effects of VP administration on declarative, i.e. hippocampus dependent, memory in rodents [1,8,9] and, more recently, in monkeys [20]. However, in healthy young human subjects, the evidence is less clear cut. Part of these studies did not find any enhancing effect of VP on memory [10,14] or at least understand unspecific arousal and attention effects to be the primary cause of performance gains after administration of VP [19]. Other studies found improved recall of memory contents after VP administration [16,22]. One source of variance in the experimental results is that the effects on learning, memory consolidation, and recall are mixed up. VP administered shortly before a learning task with immediate recall testing, as it was done in many human studies, can exert influences at each of these stages of acquisition, consolidation, and retrieval. A second possible explanation for the discrepant results refers to the diversity of memory * Corresponding author. Medizinische Universita¨t Lu¨beck, Klinische Forschergruppe Neuroendokrinologie, Ratzeburger Allee 160, Haus 23a, D-23538 Lu¨beck, Germany. Tel.: ⫹49 (451) 500-3641; fax: ⫹49 (451) 500-3640. E-mail address: [email protected] (J. Born).
tasks employed in those studies. Memory tests address several anatomically and neurophysiologically distinct memory systems – most importantly organized into declarative and non-declarative memory. Here, we concentrate on effects of VP on declarative memory consolidation. Since sleep is considered to particularly support memory consolidation [7,13,17], effects of VP and placebo on memory consolidation during different times of the night were compared while subjects were either sleeping or awake. Periods of early and late retention sleep were compared in light of evidence for differential influences of VP on memory consolidation during these sleep periods [17]. VP was administered after learning; it was given intranasally, in order to facilitate passage of the peptide to the brain [18].
2. Methods Subjects were healthy non-smoking males, aged 19 –27. Experiments were implemented according to a three factorial design with one within-subject factor (VP vs. placebo) and two between subject factors (sleep vs. wake, first vs. second half of the night). A detailed description of the sleep/wake procedures and the task employed is given in Ref. 17. Briefly, 23 subjects were tested across the first half of the night with learning (pretest) between 22.20 h and 22.40 h, substance administration at 22.50 h and recall
0196-9781/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 6 - 9 7 8 1 ( 0 1 ) 0 0 6 2 5 - 8
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S. Gais et al. / Peptides 23 (2002) 581–583
(posttest) at 02.15 h. Thirteen of these subjects slept for 3 h starting from 23.00 h while the rest remained awake. Nineteen subjects were tested across the second half of the night after having slept for 3 h between 23.00 h and 02.00 h. These subjects had their learning session between 02.20 h and 02.40 h, substance administration at 02.50 h and recall at 06.15 h. Ten of these subjects slept for 3 h during the retention phase starting from 03.00 h, nine stayed awake during this interval. After getting used to sleeping under laboratory conditions during one night, each subject participated in two experimental nights, with intranasal administration of VP (40 IU Arginine-Vasopressin, Sigma, Germany) and placebo according to a double-blind cross-over design. To test memory performance, subjects learned one of two lists of 36 category-instance word-pairs to a criterion of 60% before the administration of VP at the beginning of the first or the second half of the night, respectively. After the 3-h retention period, recall was measured as the percentage of paired words remembered correctly upon presentation of the first word of each pair. Before and after learning and recall testing, a sample of subjects’ saliva was taken to allow the determination of free cortisol levels by radioimmunoassay (Coat-A-Count, DPCBiermann, Germany). Sleep was monitored electrophysiologically and scored according to standard criteria. Statistics relied on the General Linear Model (GLM) with the three above-mentioned factors. During the wake retention interval 1 min of spontaneous EEG activity during eyes closed was recorded for 13 channels in a subsample of 9 subjects. EEG was sampled digitally at 100 Hz and power spectra were computed by means of Fast Fourier Transform. Band-power was calculated for delta (0.5– 4 Hz), theta (4.5– 8 Hz), alpha1 (8.5–10 Hz), alpha2 (10.5–12.5 Hz), beta1 (13–17.5 Hz), and beta2 (18 –30 Hz) bands. Significance was tested with two factor GLM (channels ⫻ substance) for each band.
Fig. 1. Recall (mean ⫾ SEM) after paired-associate wordlist learning as compared to performance at initial learning for a. the first half of the night, and b. the second half of the night. Pairwise comparisons between placebo (filled bars) and VP conditions (open bars) remained non-significant.
(sleep stages 3 and 4) during the first half of the night, and a larger percentage of REM sleep during the second half. Saliva cortisol levels, again as expected, differed between the first and second half of the night (mean ⫾ SEM: 0.09 ⫾ 0.02 g/dl vs. 0.21 ⫾ 0.03 g/dl; F(1,35) ⫽ 26.30, P ⬍ 0.001) and between the sleep and wake condition (0.16 ⫾ 0.03 g/dl vs. 0.12 ⫾ 0.02 g/dl; F(1,35) ⫽ 9.20, P ⬍ 0.01). However, differences between VP and placebo conditions remained non-significant (0.13 ⫾ 0.02 g/dl vs. 0.14 ⫾ 0.02 g/dl; P ⬎ 0.20, for main effect and first and second order interactions). Resting EEG during waking indicated an arousing effect of VP. Power in the beta1 band increased significantly (substance ⫻ channel interaction: F(10,80) ⫽ 2.396, P ⬍ 0.05; significant t tests for frontal [Fz, F3, F4] and central [C3, C4] leads, P ⬍ 0.05) while there were no significant effects of VP in any other frequency band.
3. Results Recall performance did not indicate any effect of VP on memory consolidation. As expected from previous studies [17], recall was best after sleep during the first half of the night (Fig. 1). Sleep significantly enhanced memory consolidation in the early sleep condition (F(1,15) ⫽ 5.30, P ⬍ 0.05) while it has no effect on memory consolidation during the late sleep interval. There is no effect of VP on declarative memory consolidation whatsoever (P ⬎ 0.75 for main effect and first and second order interactions). VP also did not affect sleep during the retention intervals (Table 1). Total sleep time remained constant and the percentage of time spent in the respective sleep stages did not differ significantly between VP and placebo conditions. Differences between the first and second half of the night showed, as expected, a larger percentage of slow wave sleep
Table 1 Percentage of time spent in individual sleep stages during the first and second half of the night
TST Wake S1 S2 S3 S4 REM MT
1st half of the night
2nd half of the night
Placebo
Vasopressin
Placebo
Vasopressin
2:50 ⫾ 0:03 1.7 ⫾ 1.7% 7.0 ⫾ 1.8% 46.8 ⫾ 3.3% 17.5 ⫾ 1.8% 15.0 ⫾ 3.6% 9.0 ⫾ 1.5% 1.0 ⫾ 0.3%
2:55 ⫾ 0:04 1.0 ⫾ 0.3% 2.7 ⫾ 1.7% 46.0 ⫾ 2.5% 15.9 ⫾ 2.0% 17.1 ⫾ 3.1% 9.2 ⫾ 1.7% 1.0 ⫾ 0.3%
2:55 ⫾ 0:03 1.3 ⫾ 0.9% 10.7 ⫾ 2.3% 53.3 ⫾ 4.2% 8.7 ⫾ 3.0% 0.3 ⫾ 0.3% 21.7 ⫾ 2.1% 1.2 ⫾ 0.4%
2:54 ⫾ 0:02 0.3 ⫾ 0.3% 13.3 ⫾ 4.4% 50.8 ⫾ 3.0% 6.8 ⫾ 1.8% 0.5 ⫾ 0.3% 24.3 ⫾ 2.2% 0.7 ⫾ 0.3%
Pairwise comparisons between vasopressin and placebo conditions were non-significant. TST: total sleep time, S1– 4: sleep stages 1– 4, REM: rapid eye movement sleep, MT: movement time.
S. Gais et al. / Peptides 23 (2002) 581–583
4. Discussion Memory consolidation was unchanged after intranasal administration of VP. This finding supports the view that the effects on memory function found in several other studies resulted mainly from changes in arousal and attention at the time of acquisition of the materials to be learned [10,19]. Whereas in those studies, VP was administered before learning, here the post-learning administration of the peptide enabled to separate effects on consolidation from those on processes activated at acquisition. However, one animal study showed an effect of VP administered after learning [12]. While this discrepancy is difficult to interpret, differences in the type of task, the species, the dose, and the exact timing of VP administration are to be taken into consideration. Notably, the animal study employed an aversiveconditioning task while we used a non-emotional declarative learning task. This is especially relevant, because VP is released in response to a variety of emotional stimuli [15]. Sleep parameters were unchanged under VP conditions. At first glance, this deviates from former studies [4], where VP after i.v. administration significantly shortened REM sleep and increased time in stage 2 sleep. However, another study using the same intranasal route for substance administration as used here did not reveal changes in sleep architecture after VP [21]. Since the intranasal route provides more direct access of the peptide to the cerebrospinal fluid compartment [11] acute reductions in REM sleep after VP previously observed with the i.v. route of administration probably represent effects mediated via systemic action of the peptide [5]. VP induced a significant change in the power distribution in the resting EEG during the wake state, notably in the lower beta band. This can be seen as an indication for an arousing effect of VP and it is consistent with other studies relating the effects of VP to signs of attention and arousal [3,19,21]. Together, these results speak against a substantial central nervous effect of VP on the consolidation of declarative memories in humans and thus favor the view that VP influences memory function primarily at the stage of the encoding process. However, several factors may modulate the effect of VP on memory consolidation that have not been tested here. Notably these are the dose of VP, the type of memory task, different times of day, and the subjects’ sex [6].
References [1] Alescio-Lautier B, Paban V, Soumireu-Mourat B. Neuromodulation of memory in the hippocampus by vasopressin. Eur J Pharmacol 2000;405:63–72.
583
[2] Bohus B, Ader R, de Wied D. Effects of vasopressin on active and passive avoidance behavior. Horm Behav 1972;3:191–7. [3] Born J, Fehm-Wolfsdorf G, Lutzenberger W, Voigt KH, Fehm HL. Vasopressin and electrophysiological signs of attention in man. Peptides 1986;7:189 –93. [4] Born J, Kellner C, Uthgenannt D, Kern W, Fehm HL. Vasopressin regulates human sleep by reducing rapid-eye-movement sleep. Am J Physiol 1992;262:E295–300. [5] Born J, Pietrowsky R, Fehm HL. Neuropsychological effects of vasopressin in healthy humans. Prog Brain Res 1998;119:619 – 43. [6] Bruins, J. Desglycinamide-(ARG8)-Vasopressin, and Cognitive Processes in Healthy Subjects. PhD Thesis, Rijksuniversiteit te Utrecht, The Netherlands, 1991. [7] Buzsaki G. Memory consolidation during sleep: a neurophysiological perspective. J Sleep Res 1998;7:17–23. [8] Dietrich A, Allen JD. Vasopressin and memory. I. The vasopressin analogue AVP4 –9 enhances working memory as well as reference memory in the radial arm maze. Behav Brain Res 1997;87:195– 200. [9] Dietrich A, Allen JD. Vasopressin and memory. II. Lesions to the hippocampus block the memory enhancing effects of AVP4 –9 in the radial maze. Behav Brain Res 1997;87:201– 8. [10] Fehm-Wolfsdorf G, Born J. Behavioral effects of neurohypophyseal peptides in healthy volunteers: 10 years of research. Peptides 1991; 12:1399 – 406. [11] Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology? Eur J Pharmacol 2000;405:43–54. [12] Gaffori OJ, de Wied D. Time-related memory effects of vasopressin analogues in rats. Pharmacol Biochem Behav 1986;25:1125–9. [13] Graves L, Pack A, Abel T. Sleep and memory: a molecular perspective. Trends Neurosci 2001;24:237– 43. [14] Jenkins JS, Mather HM, Coughlan AK. Effect of desmopressin on normal and impaired memory. J Neurol Neurosurg Psychiatry 1982; 45:830 –1. [15] Landgraf R, Wotjak CT, Neumann ID, Engelmann M. Release of vasopressin within the brain contributes to neuroendocrine and behavioral regulation. Prog Brain Res 1998;119:201–20. [16] Medvedev VI, Bakharev VD, Grechko AT, Nezovibat’ko VN. Effect of vasopressin and adrenocorticotrophic hormone fragment ACTH(4)-(7) on human memory. Hum Physiol 1980;6:307–10. [17] Plihal W, Born J. Effects of early and late nocturnal sleep on declarative and procedural memory. J Cogn Neurosci 1997;9:534 – 47. [18] Riekkinen P, Legros JJ, Sennef C, Jolkkonen J, Smitz S, Soininen H. Penetration of DGAVP (Org 5667) across the blood-brain barrier in human subjects. Peptides 1987;8:261–5. [19] Snel J, Taylor J, Wegman, M. Does DGAVP influence memory, attention, and mood in young healthy men? Psychopharmacology (Berl) 1987;92:224 – 8. [20] Sollertinskaya TN. Comparative physiological features of the regulatory effect of vasopressin on higher nervous activity in an ascending series of mammals. Neurosci Behav Physiol 1997;27:734 – 42. [21] Timsit-Berthier M, Mantanus H, Devos JE, Spiegel R. Action of lysine-vasopressin on human electroencephalographic activity. Night sleep pattern, auditory evoked potential, contingent negative variation. Neuropsychobiology 1982;8:248 –58. [22] Weingartner H, Gold P, Ballenger JC, Smallberg SA, Summers R, Rubinow DR, Post RM, Goodwin FK. Effects of vasopressin on human memory functions. Science 1981;211:601–3.