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Background: Drugs that act on the central nervous system (CNS) and have sedative effects can lead to abuse in humans. New CNS-active drugs often require evaluation of their abuse potential in dedicated animal models before marketing approval. Daridorexant is a new dual orexin receptor antagonist (DORA) with sleep-promoting properties in animals and humans. It was approved in 2022 in the United States and Europe for the treatment of insomnia disorder., Aims: Nonclinical evaluation of abuse potential of daridorexant using three specific rat models assessing reinforcement, interoception, and withdrawal., Methods: Reinforcing effects of daridorexant were assessed in an operant rat model of intravenous drug self-administration. Similarity of interoceptive effects to those of the commonly used sleep medication zolpidem was tested in an operant drug discrimination task. Withdrawal signs indicative of physical dependence were evaluated upon sudden termination of chronic daridorexant treatment. Rat experiments were conducted at a dose range resulting in daridorexant plasma concentrations equaling or exceeding those achieved at the clinically recommended dose of 50 mg in humans., Results: Daridorexant had no reinforcing effects, was dissimilar to zolpidem in the drug discrimination task, and did not induce any withdrawal-related signs upon treatment discontinuation that would be indicative of physical dependence., Outcomes: Daridorexant showed no signs of abuse or dependence potential in rats. Our data indicate that daridorexant, like other DORAs, has a low potential for abuse in humans., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAS and MTS were employees and shareholders of Idorsia Pharmaceuticals Ltd at the time the study was conducted. Idorsia has developed daridorexant as a treatment for insomnia and is selling the drug under the trade name Quviviq®. MT, LD, and MEG have no conflicting interests to declare.

For abuse potential assessment, U.S. Food and Drug Administration (FDA) requests that new, brain-penetrating drugs are ideally compared with approved drugs that share the mechanism of action and are judged to have abuse liability by the Drug Enforcement Agency. For development of the dual orexin receptor antagonist (DORA) daridorexant, the FDA recommended conducting a rat drug discrimination paradigm against the approved, schedule IV, DORA suvorexant. Surprisingly, at suvorexant plasma levels up to three-fold the maximum concentration at the highest approved human dose, rats did not learn to discriminate the suvorexant stimulus from vehicle., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MAS and MTS were employees and shareholders of Idorsia Pharmaceuticals Ltd at the time the study was conducted. Idorsia has developed daridorexant as a treatment for insomnia and is selling the drug under the trade name Quviviq®. MT and LD have no conflicting interests to declare.

This essay considers the pursuits and occupational trajectory of the Parisian anatomical modeler Marie Marguerite Biheron (1719-95), who was celebrated for her anatomical cabinet. It highlights the role of Biheron's circle of friends and supporters in nourishing her place in the anatomical world. I argue that a focus on social and affective relations, such as friendship, can enhance our understanding of the careers of female medical practitioners and medical artists like Biheron. Her case provides a useful vantage point to reconstruct how a woman, who could not rely on the support of her family nor, for most of her life, on royal patronage, could successfully engage in anatomical practice and become renowned. Casting light on early modern economies of care, Biheron's story also helps illuminate the broader significance of amicable and affective relations in the histories of medicine and natural inquiry.

This essay examines the historical fortunes of an image that throughout the seventeenth and eighteenth centuries became a landmark of the medical doctrine and practice of static medicine advanced by the physician Santorio Santorio (1561-1636). The image depicted a man sitting on a large Roman steelyard, which allowed the weighing of bodily discharges and gave guidance on the intake of food. Well into the eighteenth century, the image of the weight-watching man accompanied Santorio's work on the art of static medicine and, most likely, contributed to its success. It appeared in a variety of medical works and navigated across competing medical theories and different medical genres, while remaining largely unscathed. This essay explores the success and the historical agency of this image. Focusing on the history of its copies and variants, it investigates how the image came to symbolize the attempt to transform dietetics into an experimental practice, and accordingly preserve its pivotal significance in the medical world., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.

Anatomical waxworks lay at the centre of a composite world of social interaction in mid-18th-century Bologna. Sponsored by Pope Benedict XIV and included among Grand Tour attractions, they earned fame and authority for wax-modellers such as Anna Morandi, Giovanni Manzolini and Ercole Lelli. By dissecting bodies, making waxwork models of them and demonstrating their anatomical collections, these artificers became protagonists of the world of anatomy. Offering representations of the inner body some thought more faithful than the real thing, their collections gave expression to a new set of relations between the role of artefacts in the production and communication of knowledge, the emergence of new apparatuses for viewing and investigating the human body, the legacy of codified visual conventions and the authenticating power of natural spectacle.

This paper investigates the debate on the nature of dreams that took place in eighteenth-century Britain. Focusing on the increasingly popular view of the time that perfect sleep was sleep without dreams, it examines the medicalization of dreaming that developed alongside the conceptualization of dreams as instances of mental derangement. At the end of the seventeenth century, John Locke had likened dreaming to madness and drunkenness, and characterized it as a disturbance of the self. In the course of the eighteenth century, physicians, religious preachers, champions of politeness and moral philosophers all provided competing accounts of the doubling of consciousness which was incidental to dreaming. This paper situates their attempts in the context of re-assessment of the authorities that defined what constituted credible and reliable thinking. It does so by drawing attention to the body as one of the crucial sites in which changing attitudes towards dreaming were discussed and negotiated.