DDAVP and MEMORY

by Bill E. Beckwith, Ph.D.
Memory Disorders Clinic
and
Center for Psychology and Neuropsychiatry
Fort Myers, FL 33907

Hormones are chemical messengers that are synthesized in ductless glands and neurons and serve as signaling factors for endocrine glands as well as the nervous and immune systems. For example, arginine vasopressin is synthesized in the hypothalamus and secreted into the general circulation to regulate kidney and cardiovascular function. Additionally, vasopressin serves as a putative neurotransmitter in the central nervous system. Added to its classical endocrine effects are actions in such functions as pain tolerance, temperature regulation, learning and memory.

Descriptions of the effects of hormones on behavior probably began with Aristotle’s description of castration in birds where he drew parallels with human castration. There is also a long and rich history of information on eunuchs. For example, the penalty for adultery in ancient Egypt was castration. Eunuchs also served as guards for harems and servants for rulers (e.g., Mardian served Cleopatra). Religious sects such as the Skoptsi in Russia practiced castration to "purify" their thoughts of sexual desires. It has been estimated that 4,000 prepubescent boys were castrated as musici in Italy and were extensively used as choir members in the Roman Catholic Church despite prohibition of such practices.

Early behavioral descriptions of the effects of hormones centered on emotional disorders. For example, Harvey Cushing speculated on the association of endocrine glands with psychiatric disorders such as depression. Indeed, it was the fashion of the mid-1900s to treat psychiatric patients with surgical removal of endocrine glands and administration of hormones. However, it was not until the 1950s and 1960s that it was appreciated that hormones of the pituitary gland influence learning and memory. David DeWied and others demonstrated that removal of the pituitary disrupts learning and memory in laboratory animals and that replacement of posterior pituitary extract corrected the deficits. Subsequently, vasopressin was found to be the active consistent of posterior pituitary extract that restored learning in neurohypophysectomized animals. Numerous later studies with nonhuman animals have shown that vasopressin improves learning and memory in normal as well as surgically altered animals.

Several studies published in the late 1970s through the early 1980s demonstrated that patients suffering from diabetes insipidus displayed deficits in learning and memory. Administration of vasopressin and its analogue not only improved learning and memory in these patients but improved memory operations to "above normal" in some of the studies . Studies conducted in the early 1980s with healthy, young volunteers demonstrated that treatment with vasopressin analogues improved the consistency, organization, and completeness of recall of lists of words.

One approach to investigate the effects of vasopressin on human memory is to administer the hormone or one of its analogues to healthy, young volunteers and measure its actions on memory and related mechanisms. DDAVP is an excellent compound for these studies. It is easy to administer, is devoid of cardiovascular effects, and has few side effects in acute administration. We conducted a number of studies in the 1980s and early 1990s on the effects to DDAVP on human learning and memory while I was at the University of North Dakota. These experiments were motivated, in part, by my work with a graduate student who had a pituitary adenoma which was removed and left her with DI. As she was on replacement with DDAVP, we began a number of studies to better understand the effects of this compound on cognitive processes. Most of the experiments were performed with a single, intranasal administration of 60 micrograms of DDAVP to healthy young college students. We determined that treatment has no obvious effects on cardiovascular functions (e.g., blood pressure and heart rate) or psychological variables (e.g., anxiety and depression) and that students could not subjectively distinguish the active treatment from the placebo (saline solution in a double blind design).

Our initial study focused on the effects of DDAVP on attention. Twenty minutes after administration of DDAVP, we had students perform a concept learning task. They were given pictures of two geometric forms in two colors and asked to determine which was the correct kind. The first problem demanded that they ignore form and respond to color as correct. As soon as they learned to respond to one of the colors, we "reversed" the solution and had them respond to the earlier incorrect color. We then presented two new geometric forms with two new colors and the correct solution was again one of the colors. Finally, we switched the correct solution to form. Students treated with DDAVP solved all four problems more quickly than those treated with a placebo. The results suggest that treatment improved attention in learning.

We followed this with several experiments designed to determine the effects of DDAVP on memory for verbally presented materials. We had students learn verbal materials (e.g., lists of words, sentences, or prose) in an attempt to determine the specific cognitive process influenced by treatment. DDAVP improved the learning of lists of words but did not appear to influence any specific cognitive process (e.g., serial position effects which would suggest distinctions between influence on short-term versus long-term memory systems). We also had students learn inferential sentences. In this experiment, we tested both male and female students. We found that DDAVP enhanced learning in the male volunteers but had no effect on female volunteers. We followed this with a study of the effect of DDAVP on recall of narrative prose but used only males. DDAVP augmented recall of the most important idea units from the passages but had no effect on recall of trivial detail.

A follow up study explored the effects of DDAVP on immediate versus delayed recall (retention interval of one week). However, an unexpected finding arose from exploration of the effects of DDAVP in students with high versus low vocabulary ability. Students with low vocabulary ability benefited from treatment only for immediate recall of sentences. Students with high vocabulary ability benefited from treatment for delayed but not for immediate recall. We also performed a study comparing the effects of DDAVP on memory for sentences in college aged and elderly volunteers. Treatment improved recall for sentences in both groups of volunteers but did not appear to have differential effects based on age.

These studies suggest that treatment with DDAVP improves attention and memory in healthy young and elderly volunteers. This is especially interesting in that the subjects we used have very efficient memory operations as suggested by their pursuit of higher education. We would hope that we could have shown greater effects in subjects with memory impairments such as individuals inflicted with DI. However, we did not have access to these individuals. Additionally, this series of studies indicated that the effects of DDAVP on cognitive operations are complex. For example, it appears that treatment is influenced by such factors such as sex of individual treated and verbal ability. It also appears that treatment influences a subset of cognitive processes such as attention to important rather than trivial details that are to be learned and remembered.

It is clear that the actions of DDAVP are complex and determined by both the task at hand and factors that psychologists describe as individual differences (e.g., sex and verbal ability). The effects are subtle rather than dramatic and may be compared to fine tuning rather than channel selection of cognitive processes. There is a great deal of work that still needs to be performed to better understand the effects of DDAVP on learning and memory in humans. Further studies also need to explore the potential of DDAVP in clinical populations in complex designs that disentangle factors such as individual differences, duration and timing of treatment, and dose and analogue used.