Chronic use of benzodiazepines: The problem that persists.

Though clinical guidelines and policies discourage the chronic prescribing of benzodiazepines, rates of prescribing have continued to rise in the United States with an estimated 65.9 million office visits per year made for this purpose. Quietly, we have become a nation on benzodiazepines. There are numerous reasons for this discrepancy between official recommendations on the one hand, and actual clinical practice on the other. Drawing from the literature, we argue that while patients and providers both shoulder some of the responsibility, they cannot be solely blamed. Rather, policies and guidelines regarding benzodiazepine prescribing have become out of touch with the clinical reality that benzodiazepines are now deeply entrenched in modern medicine. We propose that guidelines regarding benzodiazepines need to reconsider how to apply concepts such as harm reduction and other lessons learned in the opioid epidemic in order to help physicians manage this increasingly pressing problem affecting millions of Americans.

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors.

In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.

Isolation and the timing of mammary gland development, gonadarche, and ovarian senescence: implications for mammary tumor burden.

In this study of Norway rats, we hypothesized that lifelong psychosocial experiences, social isolation or group living, trigger different developmental trajectories in the ovarian system, contributing to predisease pathways for spontaneous mammary tumors. Epidemiological studies indicate that early puberty and delayed menopause are risk factors for breast cancer. To that end, we took a cross-sectional, prospective approach and examined the ovarian system at two developmental points, young adulthood and middle age. We assessed ovarian function at both points, as well as mammary gland development at puberty and mammary tumor burden in middle age. Social isolation dissociated two components of puberty; it accelerated maturation of ovarian function while it simultaneously delayed mammary tissue development thereby increasing the exposure of developing breast parenchyma to high levels of estrogen. By mid-life, socially isolated rats had greater tumor burden despite having entered estropause prematurely, demonstrating that isolation did not increase tumorigenesis by prolonging ovarian function. These findings are discussed in the context of facultative lifespan strategies for rats born at different times of year and those living in isolation or in a large burrow community.

Social isolation and the inflammatory response: sex differences in the enduring effects of a prior stressor.

Numerous epidemiological studies have demonstrated an association between persistent social isolation and "all-cause" morbidity and mortality. To date, no causal mechanism for these findings has been established. Whereas animal studies have often reported short-term effects of social isolation on biological systems, the long-term effects of this adverse psychological state have been understudied. This is the first animal study to examine the effects of long-term social isolation from weaning through young adulthood on an innate inflammatory response linked to numerous disease processes. Results presented here offer a plausible link between vulnerability to disease and social neglect. For socially isolated male and female Sprague-Dawley rats, a naturally gregarious species, formation of a granuloma in response to a subcutaneous injection of carrageenin (seaweed) was significantly delayed compared with the response of animals housed in single-sex groups of five. Significant sex differences, however, emerged when an acute prior stressor was superimposed on the experience of chronic social isolation. In this context, isolated females produced a more robust inflammatory response than isolated males. This sexual dimorphism at the nexus of chronic social isolation, acute stress, and inflammatory processes may account for the observation in humans that men with low levels of social integration are more vulnerable to disease and death than women.

The sectored foraging field: a novel design to quantify spatial strategies, learning, memory, and emotion.

Although Norway rats are naturally gregarious, males typically live alone at some point during adulthood. Different social ecologies often require different learning strategies and also modulate response to stressors and gonadal development. To measure effects of the social environment on the interaction between cognition and emotion during aging, we focused on a natural learning context and devised the sectored foraging field, a progressively difficult spatial navigation task. Here, we describe how this apparatus and protocol permits multiple learning strategies in a minimally stressful environment, enabling finely graded analyses of cognition and emotionality. Male Sprague-Dawley rats living alone throughout adulthood adopted a sex-typic discernible spatial strategy. In contrast, males housed in group contexts utilized an algorithmic kinesthetic strategy, repeating the same motor action until they found food. Removal of food and distal, but not local cues, elicited anxious alertness, particularly in group-housed males. Cognitive performance of group-housed rats subsequent to food and cue removal was significantly impaired, yet enhanced in isolates.