Selective amnesic effects of oxytocin on human memory
Introduction
Four decades ago, David de Wied [1], one of the pioneers in behavioral neuroscience, showed that in the rat, the neuropeptide oxytocin plays a central role in behavioral regulation in general, and in learning and memory in particular. Subsequently, numerous studies went on to demonstrate that in addition to its most well-known peripheral role in parturition and lactation, oxytocin promotes positive social interaction (e.g., pair bonding, maternal behavior, sexual behavior, social attachment), inhibits stress-responsive neuroendocrine systems (e.g., hypothalamic–pituitary–adrenal axis), and modulates cognitive performance (e.g., learning, memory) [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14].
Oxytocin belongs to a family of nine-amino-acid peptides that have been identified in all classes of vertebrates and many invertebrate species [15]. Oxytocin and the closely related nonapeptide arginine-vasopressin are the only members of this family of peptides that are identified in mammals. Oxytocin is synthesized in magnocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus [16], [17]. The peptide is processed from its precursor form, together with the carrier protein, along the axonal projection to the posterior pituitary, from which it is secreted into the systemic circulation [18]. In addition, oxytocin is widely distributed throughout the central nervous system from smaller parvocellular neurons, influencing many neurobehavioral functions [10], [19], [20], [21]. Prominent oxytocin receptor binding has been found in various brain regions, in particular the hippocampus and the septum [19], [22], [23], [24], [25], [26], [27]. These findings suggest that the brain is a target organ for oxytocin and that this peptide may function as a neurotransmitter or neuromodulator in the central nervous system.
The neuropeptides oxytocin and arginine-vasopressin may have opposite roles, the former impairing memory and learning processes, and the latter improving cognitive performance [28], [29]. However, recent studies in animals suggest that oxytocin and vasopressin may be differentially involved in cognitive behavioral regulation depending on the behavioral test, the application or endogenous stimulation of the peptide, and the area of the brain under study [30]. Similar to the studies in animals, studies in healthy humans also showed inconsistent effects of oxytocin on memory function. Whereas some studies report impaired memory following oxytocin administration [31], [32], others were not able to confirm such memory effects [33], [34], [35].
Human memory has been subdivided into two categories, implicit and explicit [36]. Whereas explicit tests require subjects to retrieve previously studied items, implicit tests do not mention the study episode and measure retention indirectly as a facilitation of performance in a seemingly unrelated task. This facilitation is known as priming. Direct tests of memory, such as recall or recognition tasks, are used to measure explicit memory, while indirect tests of memory, such as word stem completion, are used to measure implicit memory. Implicit tests of memory can further be classified as perceptual or conceptual. While the cues in perceptual tests have a perceptual relation with their studied targets (e.g., din- for dinosaur within a word stem completion task), the cues in conceptual tests have a conceptual or semantic relation (e.g., reptiles within a category-cued association task). The distinction between implicit and explicit tests is supported by numerous findings of dissociations between performance under implicit and explicit conditions [36], [37]. For example, amnesic patients are severely impaired in explicit tests but not in most of the implicit measures of memory [38].
In the present study, we investigated the effects of oxytocin on implicit and explicit memory functions in healthy men. It should be noted within this context that neuropharmacological research has demonstrated that several pathways to the brain pass the blood–brain barrier, and there is convincing evidence that peptides gain access to the brain after intranasal administration in humans [6], [39], [40], [41], [42], [43]. In the present study, we therefore used double-blind, placebo-controlled intranasal administration of the neuropeptide to induce central nervous effects. Due to the reproductive role of oxytocin and the impact of adequate environmental conditions for the stimulation of behavioral effects of oxytocin, as known from animal research [12], [44], [45], [46], we used semantic word stimuli with and without reproduction-related meaning.
Section snippets
Subjects
A total of 38 healthy men (mean age=23.7 years, S.D.=3.0) were recruited by local advertisements for paid participation in the study. The study was conducted at the University of Trier, Germany. Before entering the study, all subjects underwent a standardized interview to screen out chronic diseases, mental disorders, medication, and drug or alcohol abuse. Subjects were instructed to abstain from food and drink (other than water) for 2 h before they reported to the laboratory, and from alcohol,
Description of subjects
As described in Methods, participants were randomly assigned to either the oxytocin or placebo group. Groups did not differ significantly in age and education. In addition, there were no significant differences between the two groups (mean±S.D.) with respect to anxiety (38.10±9.78 vs. 36.33±7.81; t(36)=−.61, p=.55) or depression (34.00±6.46 vs. 33.10±4.87; t(36)=−.48, p=.64). Trait anxiety (37.26±8.83) and depression scores (33.58±5.70) of all subjects were within the normal range of the
Discussion
The effects of intranasally administered oxytocin reported above suggest that central oxytocin in humans selectively influences memory performance depending on the kind of memory test and the psychobiological relevance of stimuli. There was a memory impairing effect on recall performance of studied words in the cued recall test in those who received oxytocin relative to the placebo group. However, the impaired cued recall performance was unrelated to the meaning of words, i.e., neutral and
Acknowledgments
The authors would like to thank Ines Simbrig, MS, and Sabine Wagner, MS, for research assistance. We thank Dr. Beate Ditzen and Ulrike Rimmele, MS, for helpful discussions and Anuschka Enzler and Sarah Mannion for editing assistance.
References (69)
- et al.
Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress
Biol. Psychiatry
(2003) - et al.
Role of oxytocin in memory and amnesia
Pharmacol. Ther.
(1982) Inhibitory effect of oxytocin on corticotroph function in humans: are vasopressin and oxytocin ying-yang neurohormones?
Psychoneuroendocrinology
(2001)- et al.
Central nervous system actions of oxytocin and modulation of behavior in humans
Mol. Med. Today
(1997) Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo–pituitary–adrenal axis
Prog. Brain Res.
(2002)Oxytocin may mediate the benefits of positive social interaction and emotions
Psychoneuroendocrinology
(1998)Neuropeptide families and their receptors: evolutionary perspectives
Brain Res.
(1999)- et al.
Central nervous system effects of the neurohypophyseal hormones and related peptides
Front. Neuroendocrinol.
(1993) - et al.
Neurohypophyseal hormone receptors: relation to behavior
Prog. Brain Res.
(1992) - et al.
Central functions of oxytocin
Neurosci. Biobehav. Rev.
(1991)
Localization of high-affinity binding sites for oxytocin and vasopressin in the human brain. An autoradiographic study
Brain Res.
The brain oxytocin receptor(s)?
Front. Neuroendocrinol.
Behavioral effects of neurohypophyseal peptides in healthy volunteers: 10 years of research
Peptides
Behavioral consequences of intracerebral vasopressin and oxytocin: focus on learning and memory
Neurosci. Biobehav. Rev.
Effect of a single dose of des-glycinamide-[Arg8]vasopressin or oxytocin on cognitive processes in young healthy subjects
Peptides
Influence of oxytocin on human memory processes
Life Sci.
Human memory and neurohypophyseal hormones: opposite effects of vasopressin and oxytocin
Psychoneuroendocrinology
Inhibitory influence of oxytocin infusion on contingent negative variation and some memory tasks in normal men
Psychoneuroendocrinology
A nose–brain pathway for psychotropic peptides: evidence from a brain evoked potential study with cholecystokinin
Psychoneuroendocrinology
Penetration of DGAVP (Org 5667) across the blood–brain barrier in human subjects
Peptides
Oxytocin and sexual behavior
Neurosci. Biobehav. Rev.
Neural control of maternal behavior and olfactory recognition of offspring
Brain Res. Bull.
Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder
Psychiatry Res.
Effects of a single administration of oxytocin or vasopressin and their interactions with two selective receptor antagonists on memory storage in mice
Neurobiol. Learn. Mem.
Oxytocin, vasopressin and memory: opposite effects on consolidation and retrieval processes
Brain Res.
The social deficits of the oxytocin knockout mouse
Neuropeptides
The neuroendocrine basis of social recognition
Front. Neuroendocrinol.
Social modulation of stress responses
Physiol. Behav.
Cellular mechanisms of social attachment
Horm. Behav.
Motherhood and memory: a review
Psychoneuroendocrinology
Explicit memory in pregnant women
Am. J. Obstet. Gynecol.
Temporary peripartal impairment in memory and attention and its possible relation to oxytocin concentration
Life Sci.
The influence of posterior and intermediate lobe of the pituitary and pituitary peptides on the maintenance of a conditioned avoidance response in rats
Int. J. Neuropharmacol.
Neuroendocrine perspectives on social attachment and love
Psychoneuroendocrinology
Cited by (154)
The effect of intranasal oxytocin on neurocognition in people with schizophrenia: A randomized controlled trial
2024, Journal of Psychiatric ResearchExogenous estradiol and oxytocin modulate sex differences in hippocampal reactivity during the encoding of episodic memories
2022, NeuroImageCitation Excerpt :Furthermore, conditional deletion of OXT receptors in the hippocampus of male mice impaired the persistence of long-term social recognition memory (Lin et al., 2018), and treatment with OXTint after experiencing a stressful event rescued recognition memory and hippocampal long-term potentiation in male rats (Park et al., 2017). In humans, some studies found improved recognition memory after an OXTint administration before encoding (Guastella et al., 2008; Rimmele et al., 2009), while other studies observed the opposite effect (Heinrichs et al., 2004; Herzmann et al., 2012). In our study, the behavioral effect of the OXTint administration did not survive correction for multiple comparisons, indicating that the mnemonic effects of 24IU OXTint administration in men are not very robust.
Effects of intranasal oxytocin on tactile perception
2019, Neuroscience LettersThe Causal Role Of Temporoparietal Junction In Mediating Self-Other Mergence During Mentalizing
2023, Journal of Neuroscience