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Measuring oxytocin and vasopressin: bioassays, immunoassays and random numbers

Gareth Leng and Nancy Sabatier

Journal of Neuroendocrinology, 2016, 28

In this review, we consider the ways in which vasopressin and oxytocin have been measured since their first discovery. Two different ways of measuring oxytocin in widespread use currently give values in human plasma that differ by two orders of magnitude, and the values measured by these two methods in the same samples show no correlation. The notion that we should accept this seems absurd. Either one (or both) methods is not measuring oxytocin, or, by ‘oxytocin’, the scientists that use these different methods mean something very different. If these communities are to
talk to each other, it is important to validate one method and invalidate the other, or else to establish exactly what each community understands by ‘oxytocin’. A similar issue concerns vasopressin: again, different ways of measuring vasopressin give values in human plasma that differ by two orders of magnitude, and it appears that the same explanation for discrepant oxytocin measurements applies to discrepant vasopressin measurements. The first assays for oxytocin and vasopressin measured biological activity directly. When immunoassays were introduced, they
encountered problems: high molecular weight factors in raw plasma interfered with the binding of antibodies to the hormones, leading to high and erroneous readings. When these interfering factors were removed by extraction of plasma samples, immunoassays gave measurements consistent with bioassays, with measures of turnover and with the sensitivity of target tissues to exogenous hormone. However, many recent papers use an enzyme-linked immunoassay to measure plasma levels without extracting the samples. Like the first radioimmunassays of unextracted plasma, this generates impossibly high and wholly erroneous measurements.

 

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Reply To: Intranasal Oxytocin Mechanisms Can Be Better Understood, but Its Effects on Social Cognition and Behavior Are Not to Be Sniffed At

Gareth Leng, Mike Ludwig

Biological Psychiatry Volume 79, Issue 8, 15 April 2016, Pages e51–e52

To the Editor

We are very pleased that Quintana and Woolley (1) have engaged with the issues raised in our review (2); we believe that the field is best advanced by frank exchanges that identify issues of concern and ways to resolve them. We address the points raised in the order that they raise them.
Quintana and Woolley cite three meta-analyses as supporting the ability of intranasal oxytocin (OT) to alter cognition. Although we had suggested the possibility of publication bias in the literature on intranasal OT (reflecting widespread concern about publication bias in clinical and biological research), these meta-analyses reported no evidence for this. However, Walum and Young (3) recently reanalyzed the studies covered by these meta-analyses. They concluded that the studies were seriously underpowered and argued that this is true generally of studies with intranasal OT

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Intranasal Oxytocin: Myths and Delusions

Gareth Leng and Mike Ludwig

Biological Psychiatry Volume 79, Issue 3, 1 February 2016, Pages 243–250

 

Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.

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Insulin Action in the Human Brain: Evidence from Neuroimaging Studies

 S. Kullmann, M. Heni, A. Fritsche and H. Preissl

Journal of Neuroendocrinology: 2015, 27, 419–423

Thus far, little is known about the action of insulin in the human brain. Nonetheless, recent advances in modern neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG), have made it possible to investigate the action of insulin in the brain in humans, providing new insights into the pathogenesis of brain insulin resistance and obesity. Using MEG, the clinical relevance of the action of insulin in the brain was first identified, linking cerebral insulin resistance with peripheral insulin resistance, genetic
predisposition and weight loss success in obese adults. Although MEG is a suitable tool for measuring brain activity mainly in cortical areas, fMRI provides high spatial resolution for cortical as well as subcortical regions. Thus, the action of insulin can be detected within all eating behaviour relevant regions, which include regions deeply located within the brain, such as the hypothalamus, midbrain and brainstem, as well as regions within the striatum. In this review, we outline recent advances in the field of neuroimaging aiming to investigate the action of insulin
in the human brain using different routes of insulin administration.

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Compromised white matter integrity in obesity

S. Kullmann, F. Schweizer, R. Veit, A. Fritsche and H. Preissl

Obesity Reviews: 2015 April 16(4): 273-81

Obesity is associated with both structural and functional changes of the central nervous system. While gray matter alterations in obesity point to a consistent reduction with increasing body mass index (BMI), volumetric changes in white matter are more complex and less conclusive. Hence, more recently, diffusion tensor imaging (DTI) has been employed as a highly sensitive tool to investigate microstructural changes in white matter structure. Parameters of diffusivity and anisotropy are used to evaluate white matter and fibre integrity as well as axonal and myelin degeneration. Fractional anisotropy (FA) is the most commonly used parameter as it is the best estimate of fibre integrity. The focus of this review was on the relationship between obesity and brain alterations assessed by DTI. Altogether, these studies have shown a loss of white matter integrity with obesity related factors, especially in tracts within the limbic system and those connecting the temporal and frontal lobe. More specifically, multiple studies found an inverse association between BMI and FA in the corpus callosum, fornix, cingulum and corona radiata in elderly and young adults as well as children. Furthermore, significant interactions were observed between BMI and age, pointing to accelerated ageing of white matter structure in obese

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Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

M. Perello and S. L. Dickson

Journal of Neuroendocrinology, 2015, 27, 424–434

‘Hunger is the best spice’ is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain’s reward system and the stimulation of this system by the hunger-promoting hormone ghrelin. Ghrelin is produced largely from the stomach and levels are higherpreprandially. The ghrelin receptor is expressed in many brain areas important for feeding control,including not only the hypothalamic nuclei involved in energy balance regulation, but also reward-linked areas such as the ventral tegmental area. By targeting the mesoaccumbal dopamine neurones of the ventral tegmental area, ghrelin recruits pathways important for food reward-related behaviours that show overlap with but are also distinct from those important for food intake. We review a variety of studies that support the notion that ghrelin signalling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways.

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“Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior

Johannes Hebebrand, Özgür Albayrak, Roger Adan, Jochen Antel, Carlos Dieguez,Johannes de Jong, Gareth Leng, John Menzies, Julian G. Mercer, Michelle Murphy,Geoffrey van der Plasse, Suzanne L. Dickson

Neuroscience and Biobehavioral Reviews 47 (2014) 295–306

“Food addiction” has become a focus of interest for researchers attempting to explain certain processesand/or behaviors that may contribute to the development of obesity. Although the scientific discussion on “food addiction” is in its nascent stage, it has potentially important implications for treatment and prevention strategies. As such, it is important to critically reflect on the appropriateness of the term “food addiction”, which combines the concepts of “substance-based” and behavioral addiction. The currently available evidence for a substance-based food addiction is poor, partly because systematic clinical and translational studies are still at an early stage. We do however view both animal and existing human data as consistent with the existence of addictive eating behavior. Accordingly, we stress that similar to other behaviors eating can become an addiction in thus predisposed individuals under specific environmental circumstances. Here, we introduce current diagnostic and neurobiological concepts of substance-related and non-substance-related addictive disorders, and highlight the similarities and dissimilarities between addiction and overeating. We conclude that “food addiction” is a misnomer because of the ambiguous connotation of a substance-related phenomenon. We instead propose the term “eating addiction” to underscore the behavioral addiction to eating; future research should attempt to define the diagnostic criteria for an eating addiction, for which DSM-5 now offers an umbrella via the introduction on Non-Substance-Related Disorders within the category Substance-Related and Addictive Disorders.

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