An opponent process for alcohol addiction based on changes in endocrine gland mass

SummaryConsuming addictive drugs is often initially pleasurable, but escalating drug intake eventually recruits physiological “anti-reward” systems called opponent processes that cause tolerance and withdrawal symptoms. Opponent processes are fundamental for the addiction process, but their physiological basis is not fully characterized. Here, we propose an opponent processes mechanism centered on the endocrine stress-response, the HPA axis. We focus on alcohol addiction, where the HPA axis is activated and secretes β-endorphin, causing euphoria and analgesia. Using a mathematical model, we show that slow changes in HPA glands act as an opponent process for β-endorphin secretion. The model explains hormone dynamics in alcohol addiction, and experiments on alcohol preference in rodents. The opponent process is based on fold-change detection (FCD) where β-endorphin responses are relative rather than absolute; FCD confers vulnerability to addiction but has adaptive roles for learning. Our model suggests gland-mass changes as potential targets for intervention in addiction.

Prelimbic cortex glucocorticoid receptors regulate the stress-mediated inhibition of pain contagion in male mice

Experiencing pain with a familiar individual can enhance one’s own pain sensitivity, a process known as pain contagion. When experiencing pain with an unfamiliar individual, pain contagion is suppressed in males by activating the endocrine stress response. Here, we coupled a histological investigation with pharmacological and behavioral experiments to identify enhanced glucocorticoid receptor activity in the prelimbic subdivision of the medial prefrontal cortex as a candidate mechanism for suppressing pain contagion in stranger mice. Acute inhibition of glucocorticoid receptors in the prelimbic cortex was sufficient to elicit pain contagion in strangers, while their activation prevented pain contagion in cagemate dyads. Slice physiology recordings revealed enhanced excitatory transmission in stranger mice, an effect that was reversed by pre-treating mice with the corticosterone synthesis inhibitor metyrapone. Following removal from dyadic testing, stranger mice displayed enhanced affective-motivational pain behaviors when placed on an inescapable thermal stimulus, which were reversed by metyrapone. Together, our data suggest that the prelimbic cortex may play an integral role in modulating pain behavior within a social context and provide novel evidence towards the neural mechanism underlying the prevention of pain contagion.

Effects of sugar and sweetener on the acute endocrine stress response in fasted women

The endocrine stress response helps to maintain homeostasis at times of increased demand and supports survival through energy mobilization. Paradoxically, low blood glucose levels impede the endocrine stress response, yet increasing blood glucose levels through sugar consumption prior to stress restores it. This suggests that glucose availability may play a causal role in the endocrine stress response. However, sugar has other distinct properties beyond the raise of blood glucose concentration. Here, we investigated the potential role of sweetness in restoring the cortisol stress reactivity after fasting. N=152 women (mean(age)=21.53, sd(age)=2.61) participated in a psychosocial stress test for groups in the morning after an overnight fast. Prior to stress induction, participants either consumed a drink that contained a caloric sweetener (sugar, n=51), an equally sweet drink containing non-caloric sweetener (sweetener, n=46), or water (n=56). Salivary cortisol and blood glucose levels were assessed repeatedly. Former studies suggested that sugar load prior to stress leads to increased cortisol responses compared to water, and sweetener. The effects of the consumed drinks on cortisol trajectories were tested using multilevel mixed models. Unexpectedly, we found that sugar and sweetener each significantly increased cortisol stress reactivity compared to water. Indeed, sweetener lead to cortisol increases comparable to sugar. Changes in blood glucose levels after drink consumption were not significantly associated with stress-induced increases in cortisol. This suggests that not the metabolic properties of sugar, but properties of sweet taste prior to stress are critical to boost the endocrine stress response to stress.

Dietary antioxidants attenuate the endocrine stress response during long-duration flight of a migratory bird

Glucocorticoids (GCs) are metabolic hormones that promote catabolic processes, which release stored energy and support high metabolic demands such as during prolonged flights of migrating birds. Dietary antioxidants (e.g. anthocyanins) support metabolism by quenching excess reactive oxygen species produced during aerobic metabolism and also by activating specific metabolic pathways. For example, similar to GCs' function, anthocyanins promote the release of stored energy, although the extent of complementarity between GCs and dietary antioxidants is not well known. If anthocyanins complement GCs functions, birds consuming anthocyanin-rich food can be expected to limit the secretion of GCs when coping with a metabolically challenging activity, avoiding the exposure to potential hormonal detrimental effects. We tested this hypothesis in European starlings ( Sturnus vulgaris ) flying in a wind tunnel. We compared levels of corticosterone, the main avian GC, immediately after a sustained flight and at rest for birds that were fed diets with or without an anthocyanin supplement. As predicted, we found (i) higher corticosterone after flight than at rest in both diet groups and (ii) anthocyanin-supplemented birds had less elevated corticosterone after flight than unsupplemented control birds. This provides novel evidence that dietary antioxidants attenuate the activation of the HPA axis (i.e. increased secretion of corticosterone) during long-duration flight.

Repeatable glucocorticoid expression is associated with behavioural syndromes in males but not females in a wild primate

Behavioural syndromes are a well-established phenomenon in human and non-human animal behavioural ecology. However, the mechanisms that lead to correlations among behaviours and individual consistency in their expression at the apparent expense of behavioural plasticity remain unclear. The ‘state-dependent' hypothesis posits that inter-individual variation in behaviour arises from inter-individual variation in state and that the relative stability of these states within an individual leads to consistency of behaviour. The endocrine stress response, in part mediated by glucocorticoids (GCs), is a proposed behavioural syndrome-associated state as GC levels are linked to an individual's behavioural responses to stressors. In this study, in wild Barbary macaques ( Macaca sylvanus ), consistent inter-individual differences were observed in both sexes for GC activity (faecal glucocorticoid, fGC concentrations), but not GC variation (coefficient of variation in fGC concentrations). The expression of the behavioural syndrome ‘Excitability' (characterized by the frequencies of brief affiliation or aggressive interactions) was related to GC activity in males but not in females; more ‘excitable' males had lower GC activity. There was no relationship in females between any of the behavioural syndromes and GC activity, nor in either sex with GC variation. The negative relationship between GC activity and Excitability in males provides some support for GC expression as a behavioural syndrome-generating state under the state-dependent framework. The absence of this relationship in females highlights that state-behavioural syndrome associations may not be generalizable within a species and that broader sex differences in state need to be considered for understanding the emergence and maintenance of behavioural syndromes.

Genetic inheritance and environment determine endocrine plasticity to urban living

As urban areas continue to expand globally, understanding how and why species respond to novel habitats becomes increasingly important. Knowledge of the mechanisms behind observed phenotypic changes in urban animals will enable us to better evaluate the impact of urbanization on current and future generations of wildlife. Physiological changes, such as those involved in the endocrine stress response, may allow individuals to inhabit and thrive in urbanized areas, but it is currently unknown how these changes arise in natural populations. In this study, we performed a four-way cross-foster experiment in free-living house wren chicks, Troglodytes aedon , to disentangle whether differences in baseline corticosterone between urban and rural individuals are a result of genetic and/or plastic mechanisms during development. We found that urban chicks already had higher corticosterone levels than their rural counterparts on the day they hatched, which suggests a possible genetic component to the corticosterone phenotype. However, rural offspring that were moved to an urban environment significantly increased their corticosterone levels, mimicking those of urban offspring. Our findings suggest that, although differences in baseline corticosterone concentrations between urban and rural individuals may have a genetic component, plasticity plays a pivotal role and can modify the corticosterone phenotype in response to the environment experienced in the first two weeks of life.

Differences in stress reactivity between zebrafish with alternative stress coping styles

Animals experience stress in a variety of contexts and the behavioural and neuroendocrine responses to stress can vary among conspecifics. The responses across stressors often covary within an individual and are consistently different between individuals, which represent distinct stress coping styles (e.g. proactive and reactive). While studies have identified differences in peak glucocorticoid levels, less is known about how cortisol levels differ between stress coping styles at other time points of the glucocorticoid stress response. Here we quantified whole-body cortisol levels and stress-related behaviours (e.g. depth preference, movement) at time points representing the rise and recovery periods of the stress response in zebrafish lines selectively bred to display the proactive and reactive coping style. We found that cortisol levels and stress behaviours are significantly different between the lines, sexes and time points. Further, individuals from the reactive line showed significantly higher cortisol levels during the rising phase of the stress response compared with those from the proactive line. We also observed a significant correlation between individual variation of cortisol levels and depth preference but only in the reactive line. Our results show that differences in cortisol levels between the alternative stress coping styles extend to the rising phase of the endocrine stress response and that cortisol levels may explain variation in depth preferences in the reactive line. Differences in the timing and duration of cortisol levels may influence immediate behavioural displays and longer lasting neuromolecular mechanisms that modulate future responses.