Peptides, Vol. 3, pp. 627-630, 1982. Printed in the U.S.A.
Vasopressin Analog (DDAVP) Facilitates Concept Learning in Human Males
B I L L E. B E C K W l T H , 1 T O M PETROS, SAMIRA K A N A A N - B E C K W l T H , D E B O R A H I. C O U K A N D R O D N E Y J. H A U G
Department o f Psychology, University of North Dakota, Grand Forks, ND 58202
A N D
C A S E Y R Y A N
Grand Forks Clinic, 1000 South Columbia Road, Grand Forks, ND 58201
Received 23 March 1982
BECKWlTH, B. E., T. PETROS, S. KANAAN-BECKWlTH, D. I. COUK, R. J. HAUG AND C. RYAN. Vasopressin analog (DDA VP) facilitates concept learning in human males. PEPTIDES 3(4) 627-630, 1982.--The effects of desmopres- sin acetate (DDAVP) were studied in normal males. Subjects were given 60/zg of DDAVP, a placebo, or no treatment and were given several behavioral tests. DDAVP enhanced learning of all problems on a concept shift task but had no effect on visual memory, anxiety, blood pressure or heart rate. It was suggested that DDAVP may influence memory via its actions on attention.
The behavioral activating properties of adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (MSH), and vasopressin and their analogues have been well estab- lished [2, 3, 9, 10]. For instance, ACTH-and MSH-like neuropeptides have been found to delay extinction of avoidance [16,24] and to facilitate the reversal of a brightness discrimination [21,25] in male rats. Moreover, peptides re- lated to vasopressin have also been found to delay extinction of avoidance [8] but not to facilitate reversal of a brightness discrimination [6]. The primary difference between the ac- tions of these neuropeptides upon the extinction of con- ditioned avoidance responding appears to be that the effects of MSH/ACTH-Iike peptides are temporary whereas the ef- fects of vasopressin are relatively enduring in most test situ- ations [7,8]; however there are exceptions to this generaliza- tion [6]. Several reviewers have suggested that these actions may be best explained by assuming that MSH/ACTH-Iike peptides influence "short term" memory [8] whereas vaso- pressin influences "long term" memory [9,10]. However, an alternative explanation has been forwarded for the actions of these MSH/ACTH-Iike peptides based upon their influence upon reversal of a brightness discrimination [2, 3, 25]. Ac- cording to this view, these peptides do not directly influence memory processes but rather they mediate selective atten- tion.
Several studies have also demonstrated that MSH/ ACTH-Iike peptides influence attention in man. For ex- ample, these neuropeptides have been shown to prolong
alpha-blocking of the EEG [17], increase somatosensory evoked potentials [ 13], augment heart-rate deceleration dur- ing the presentation of a novel stimulus [22], faciliate visual memory of geometric designs on a Benton Visual Retention Test [13, 17, 23] and improve concept shifts during a visual discrimination procedure [22,23]. Additionally, several in- vestigators have demonstrated that vasopressin is also be- haviorally active in humans. For example, vasopressin has been found to improve memory performance of Korsakoff patients [14], to facilitate attention and memory in amnesic patients [20] and to enhance serial learning, prompted recall, and recall of semantically related words in college students [28].
The purpose of the present study was to explore the ef- fects of vasopressin (desmopressin acetate, an analogue of 8-argininevasopressin) when administered prior to learning on (1) a visual discrimination procedure which requires that subjects distinguish relevant from irrelevant information and (2) a visual memory task that requires subjects to hold geometric forms in short term memory for 30 seconds. In short, the design of the present study was intended to pro- vide evidence regarding the actions of desmopressin acetate (DDAVP) on selective attention [2,3] in human males.
METHOD
Subjects
Fifty-four normal healthy male volunteers between the
1Address all correspondence to Bill E. Beckwith, Psychology Department, University of North Dakota, Grand Forks, ND 58202.
ages of 18-25 years participated in this experiment. Subjects were currently enrolled in undergraduate psychology courses at UND and were given course credit for their par- ticipation. All subjects gave informed, written consent and were tested between 1600 hr and 1900 hr. No subject was taking prescribed or nonprescribed medications, was ill, or had a blood pressure above 139/89 at the time of testing.
Procedure
Subjects were first given a preliminary blood pressure check with a mercury sphygmomanometer (all blood pres- sure recording was done with the subject sitting in a chair) to determine if they were hypertensive. Following this they completed the vocabulary subtest of the Wechsler Adult In- telligence Scale (WAIS) and a Spielberger State-Trait Anx- iety Inventory [27]. Next they were given either 0.6 ml of DDAVP (60 /~g) intranasally (N-18) , 0.6 ml of saline intranasally (N=21), or no treatment (N= 15) while reclining on a couch. Fluids were slowly instilled into one nostril in a double blind procedure. Subjects remained supine during the next 20 min and were then sat up to obtain the final meas- urement of blood pressure. Finally, subjects were taken in- dividually to a quiet room where behavioral tasks were completed. All stimulus materials were presented by means of a carousel projector and a rear projection screen.
Visual discrimination. Subjects were shown slides of colored geometric forms which differed in shape and color (e.g., red, black, blue, and white circles, squares, crosses, and triangles). He was instructed to select the object he thought was correct. During each separate component of the discrimination procedure the subject was given a two-choice discrimination problem.
After acquiring the original discrimination (9 consecutive correct responses), the subject learned in succession rever- sal, intradimensional, and extradimensional shifts. For example, if he was first reinforced (i.e., told he was "cor- rect") for responding to red, during the reversal he was rein- forced for responding to black (the color opposite that rein- forced during original learning). On the intradimensional shift a new set of stimuli were presented that differed in both color and shape but color was still reinforced (e.g., blue). Finally, during the extradimensional shift a value on the heretofore irrelevant dimension of shape was reinforced (e.g., triangle). Order of stimulus (color and shape) presen- tation was counterbalanced across subjects.
Visual memory. This was assessed with the Benton Vis- ual Retention Test (BVRT) [5]. During this task subjects were shown ten slides picturing geometric forms of varying complexity one at a time for 1 sec. After each slide was no longer viewable, the subject was required to wait 30 sec and was then given paper and a pencil and asked to reproduce the figure. All slides were photographed from form C of the BVRT.
Finally, subjects were again given the state form of the Spielberger State Trait Anxiety Inventory, had their blood pressure measured, and were debriefed regarding experi- mental protocol.
RESULTS
Visual Discrimination
Number of trials to criterion excluding the nine criterion trials was recorded for each subject on all four tasks. Number of trials to criterion was subjected to a 3 (peptide-
10 / - - 7 DDAVP
• -~ 1 Placebo
,~ 8 ~ Control
6 "6
E 4 z
0
OL RE IDS EDS
Problem
FIG. 1. Mean trials to criterion for solution of original learning (OL), reversal learning (RE), intradimensional (IDS), and extradimen- sional (EDS) problems.
placebo-control) × 4 (discrimination problem) mixed analysis of variance. There were significant main effects due to treatment, F(2,51)=3.92, p=0.027, and task, F(3, 153)=4.67, p=0.004, and there was a marginally signifi- cant interaction between treatment and task, F(6,153)=2.11, p =0.055. However, the interaction appeared to be mainly a result of two extreme scores in the control group. Therefore, the data were subjected to a logarithmic (x+ l) transforma- tion [19] and a similar analysis was completed. Again there were significant main effects for treatment, F(2,51)=4.331, p=0.01, and task, F(6,153)= 14.533, p=0.001; however, the interaction was no longer significant (F<I .00) suggesting that the interaction present in the raw data was due to the extreme scores in the control group and not a robust effect.
Further analysis of the transformed data was made by means of the Newman-Keuls technique [18] with the critical value selected with a=0.01. As may be seen in Figure 1, this analysis indicated that the group treated with DDAVP solved all problems significantly faster than either the placebo or no treatment control groups. Furthermore, there were no differences in problem solving efficiency between the two control groups. The same result was obtained using the Newman-Keuls technique to evaluate the raw data.
A final analysis of the concept learning data was per- formed in conjunction with the WAIS vocabulary scores. This was done to assess possible effects of verbal ability on the concept learning procedure. The groups did not differ in WAIS score (F<I .00) and there were no first (F<I .00) or second ( F < 1.00) order interactions with either treatment or problem type. Therefore, it appears that the facilitation of DDAVP on concept learning was not a function of differ- ences in subjects ' verbal ability.
Visual Memory
Both a total number correct and a total number of errors score was calculated. These data are presented in Table 1 and as may be seen there was no effect of peptide treatment on visual memory (F<I .00) .
VASOPRESSIN A N A L O G FACILITATES 629
TABLE 1 SUMMARY OF MEANS AND STANDARD DEVIATIONS FOR VARIOUS PHYSIOLOGICAL AND
Benton Visual Retention Test Number Correct 6.70 (0.67) 6.70 (0.48) 6.30 (0.82) Number Errors 5.20 (1.23) 5.10 (2.08) 6.70 (2.41)
*Standard deviation is given in parentheses.
Blood Pressure, Heart Rate, and Anxiety
As can be seen in Table 1 there were no actions of the peptide on systolic blood pressure (F< 1.00), no changes in systolic blood pressure during 50 min observation period of this study ( F < 1.00) and no interaction between these factors (F< 1.00). Also note that DDAVP did not influence diastolic blood pressure, F(2,27)= 1.26, p=0.30, and diastolic blood pressure also did not change over the observation period, F(3,81)=2.24, p=0.09. There was no interaction between these effects (F<I .00) . Finally, DDAVP had no effect on heart rate (F<I .00) . Heart rate did, however, decrease by the final observation period, F(3,81)=6.46, p=0.001, but there was no interaction between this decrease and peptide treatment, F(6,81)= 1.58,p =0.16. This last effect is probably due to the anxiety reduction inherent in completion of an experiment.
Analysis of the Spielberger State-Trait Anxiety Inventory (STAI) indicated that subjects assigned to the three groups did not differ in terms of their general anxiety scores ( F < 1.00). Finally, treatment with DDAVP had no effect on state anxiety (F<I .00) as determined by measuring the change in state anxiety during the course of this experiment.
DISCUSSION
It is apparent from the evidence accumulated in this study that DDAVP influences the ability of college aged males to make visual discriminations. This peptide, at the dose ad- ministered here, causes a general improvement in ability to learn the required discriminations: original learning, rever- sal, intradimensional shift, and extradimensional shift. Treatment with DDAVP had no effect on visual memory or state anxiety.
Other studies of the effects of DDAVP on human memory function had administered the hormone for periods ranging from 3 days (e.g., [15]) to 7 weeks [12] but, this is the first study, to the authors ' knowledge, to demonstrate a behav- ioral effect of a relatively small, acute dose of DDAVP on human cognitive function. Anderson et al. [1] also demon- strated an effect of a single dose of DDAVP (40I.U) on pas- sive avoidance learning in children with Lesch-Nyhan dis- ease. Together these studies do suggest that longer term
treatment is not a necessary condition for vasopressin to be behaviorally active in humans. Most other studies have in- vestigated the actions of this peptide on memory processes in humans. However, Legros et al. [15] did demonstrate im- proved attention for time and forgotten items on clinical tests as a result of treatment with DDAVP (16 I .U./day for 3 days). The present results also indicate improved attentional performance based upon the fact that DDAVP facilitated performance on all concept shift problems: reversal, intradimensional, and extradimensional shifts. This pattern of results strongly implicates the effect of this peptide upon attention, as described by [19,26]. A similar but nonsignific- ant trend was demonstrated for treatment of a similar popu- lation with another neuropeptide, MSH/ACTH 4-10 [22]. This suggests that either DDAVP has actions similar to MSH/ACTH-Iike peptides or that the known capacity of vasopressin to induce release of ACTH [1 I] may account for the present effects.
Although there is no direct evidence separating the effects of ACTH and vasopressin in this study, three lines of evi- dence suggest that the actions may be different. First, treat- ment with M S H / A C T H has been found to improve visual memory on the BVRT [13,23]. However, treatment with DDAVP in the present situation did not influence perform- ance on the BVRT. Second, treatment with MSH/ACTH has been found to influence the pattern of results on the subprob- lem analysis [5, 22, 23], a refined analysis of the learning processes involved in acquisition of the extradimensional shift. In the present study treatment with DDAVP did not effect performance on subproblems of the extradimensional shift. Furthermore, MSH/ACTH has been shown to produce a reduction in anxiety as measured by the STAI [23]. Treat- ment with DDAVP did not influence anxiety as measured by the STAI.
Finally, treatment with DDAVP did not appear to influ- ence peripheral, autonomically medicated responses: blood pressure and heart rate. This suggests that the current effect is not due to a peripheral action of the peptide (e.g., via vasopressin action as a pressor agent), but rather the present influence is due to alteration of CNS functioning.
In conclusion, acute treatment with DDAVP has a direct effect upon the CNS which induces a facilitation of discrimi- nation learning in humans. This action indicates that this
630 B E C K W I T H E T A L .
neu ropep t i de does not on ly inf luence m e m o r y , at leas t in any s imple way. F u r t h e r r e sea rch shou ld add res s the re la t ive effects o f the neu ropep t i de on a t t en t iona l and m e m o r i c proc-
esses . Indeed , p rev ious f indings re la t ing vasop re s s in to faci l i ta t ion o f m e m o r y may be a resu l t of its i m p r o v e m e n t o f a t t en t ion .
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