Macaque study explores best route of oxytocin administration

Oxytocin is a natural brain peptide most commonly thought of as the “love hormone” for its role in social bonding: it spikes during social contact, play, cuddling, and sex. Because of extensive research in animals including prairie voles, sheep, and monkeys demonstrating that oxytocin promotes affiliative behaviors and social bonding1,2, oxytocin is increasingly being studied for its effects on humans3. The jury is still out here: some studies show that oxytocin has no effect on social behavior, whereas others show a negative effect. The most attention, however, is given to those studies showing a positive effect, particularly in individuals with social deficits like those with autism spectrum disorder (ASD)4.

Consequently, oxytocin nasal sprays are increasingly being advertised as treatments for ASD, despite the inconclusive results from clinical trials and a lack of studies showing their long-term efficacy and side effects. These sprays are available online without a prescription but they are not regulated by the FDA. Thus little is known about the quantity of oxytocin they contain, their efficacy, or possible side effects.

Though nasal sprays are commonly used in clinical trials for ASD, oxytocin is often administered intravenously (IV). In both cases, study designs differ in the amount of oxytocin they use, the duration of treatment, and the delivery method, so it is no surprise that they have yielded conflicting results. Thus, the mechanisms by which oxytocin administered in different ways may act in the brain are unclear.

Macaque Monkey

Image Credit: Amanda M. Dettmer

An important and timely study just published online in Psychoneuroendocrinology by researchers at the California National Primate Center and the University of California-Davis tackles some of these methodological questions. Rhesus monkeys were implanted with intrathecal catheters to allow for repeated sampling of cerebrospinal fluid (CSF) in awake animals, and were treated with either intranasal (IN) or IV oxytocin at three different doses in a randomized, crossover study design (meaning animals were randomly assigned to IN, then IV, or vice versa). Blood and CSF samples were collected from awake animals (thus eliminating possible confounds of anesthesia) pre-dose (0 minutes), and at 5, 15, 30, 60, and 120 minutes after oxytocin administration. Importantly, this is the first study to use awake monkeys for oxytocin administration and sample collection, to directly compare more than two different doses of oxytocin in the same subjects, and to collect five concurrent post-oxytocin blood and CSF samples in a relatively short period. These methods would be extremely difficult, if not impossible, to carry out in human subjects.

The researchers found that blood and CSF levels of oxytocin were higher after IV vs. IN administration. Furthermore, they found that IV-administered oxytocin elevated blood and CSF oxytocin for a period of up to 30 minutes, whereas IN oxytocin had no effect on blood levels of oxytocin, regardless of the dose – an unexpected finding because IV oxytocin does not cross the blood-brain barrier5. The authors postulate that elevated levels of oxytocin in the bloodstream after IV oxytocin treatment might result in the release of oxytocin in the brain (as observed in CSF) via mechanisms that have yet to be identified, but which studies using nonhuman primate models will be critical for disentangling. They also argue that humans can be instructed to inhale deeply during IN administration, whereas animals cannot, yielding important methodological implications for studies relying on animal models of human behavior. Finally, the group reported that blood oxytocin cannot be used as a reference for CSF oxytocin (thus supporting earlier findings), yet most human studies rely on measuring blood oxytocin after oxytocin treatment.

The authors conclude that, “…it is…critical to use nonhuman primate models to better evaluate the effectiveness of the delivery method most commonly used in human studies and clinical use – the nasal spray.”6 Indeed, studies like this one are critical for informing dosing regimens and administration methods of oxytocin in humans, as we cannot conduct such detailed studies without animal models. Ultimately, animals – specifically nonhuman primates – will be key for identifying and understanding the mechanisms by which oxytocin and other drugs act to affect brain and behavioral responses.

Amanda M. Dettmer

References

  1. Stoesz, Hare & Snow, 2013, Neurosci Biobehav Rev, 37(2):123-32.
  2. Lim & Young, 2006, Hormones & Behavior, 50:506-17.
  3. Kuehn, 2011, JAMA, 305(7):659-61.
  4. Young & Barrett, 2015, Science, 347(6224):825-26.
  5. Ermisch et al., J Cereb. Blood Flow Metab, 5:350-57.
  6. Freeman et al., 2016, PNEC, 66:185-94.

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