Abstract Somatostatin analogues (SSAs) are the cornerstone of treatment for patients with neuroendocrine tumours (NETs), with established anti‐secretory activity in functioning NETs and anti‐proliferative activity in grade 1 and 2 (Ki‐67 levels, up to 10%) gastro‐entero‐pancreatic NETs. However, several clinically relevant scenarios regarding their role still remain insufficiently addressed by available guidance, including the following: patient selection for dose‐escalation or interval‐shortening after disease progression, their anti‐proliferative effect in tumours with a > 10% Ki‐67 index, their role in pulmonary carcinoids, Multiple Endocrine Neoplasia (MEN1)‐related pancreatic NETs and uncommon neuroendocrine neoplasms (NENs), their adjuvant use after surgery, and their continuation beyond disease progression, as well as the presence of predictive biomarkers, quality‐of‐life endpoints, and emerging somatostatin receptor (SSTR)‐targeted strategies. This manuscript addresses 10 practical questions regarding SSA use beyond established indications. The available evidence supports dose‐intensification mainly for improved hormonal symptom control and, in selected patients, temporary disease stabilisation, while objective tumour responses remain uncommon. Anti‐proliferative effects may also be observed in some grade 2 NETs with a Ki‐67 index higher than 10%, albeit with diminishing activity in the presence of increasing proliferative activity, whereas it is limited in grade 3 tumours. Evidence in pulmonary carcinoids, MEN1‐related pancreatic NETs, and other uncommon somatostatin receptor (SSTR)‐positive NETs remains heterogeneous, and mostly based on small or non‐randomised studies. In contrast, routine adjuvant treatment after complete tumour resection is not currently supported, although retrospective studies suggest a potential benefit in selected patients with resected pancreatic NETs at high risk of recurrence. Quantitative SSTR imaging, tissue SSTR2 expression and circulating molecular markers are promising tools for patient selection, but none is currently validated for routine predictive use. New formulations and SSTR‐directed agents with receptor‐binding properties distinct from those of conventional SSAs are expected to broaden future treatment options, although their clinical value will require prospective confirmation.
Human binge eating disorder is characterized by recurrent episodes of excessive food consumption accompanied by loss of control and is strongly associated with alterations in reward processing and emotional regulation. Ayahuasca, a psychoactive botanical preparation traditionally used in Amazonian medicine, has been shown to modulate serotonergic signaling and reward-related behaviors and has emerged as a potential therapeutic tool for mood and substance use disorders. However, its effects on binge-like eating behavior remain largely unexplored. In the present study, we evaluated the behavioral and metabolic consequences of a binge-like eating model in mice and investigated the effects of a single administration of ayahuasca on food intake, sucrose consumption, and anxiety-like behavior. Male C57BL/6 mice were subjected to an intermittent fasting protocol combined with restricted access to a standard diet and a sucrose solution for 10 days. On the eleventh day, a subgroup of binge-exposed mice received a single oral dose of ayahuasca (1.76 mg/kg of N, N-dimethyltryptamine). Food and sucrose intake were quantified during refeeding periods; anxiety-like behavior was assessed using the elevated plus maze; and the expression of hypothalamic genes POMC and CART was evaluated by RT-PCR. Mice exposed to the binge-like eating protocol exhibited increased food and sucrose intake during restricted access periods, reduced body weight, anxiogenic-like behavior, and reduced hypothalamic CART gene expression. Ayahuasca administration selectively reduced food and sucrose intake during the initial hour of refeeding without affecting later intake, reversed anxiety-like behavior, and increased hypothalamic CART expression. These findings support the notion that ayahuasca acutely attenuates binge-like eating and anxiety-related behaviors in mice, supporting its potential relevance for investigating psychedelic-based approaches targeting compulsive eating and associated emotional dysregulation.
Social withdrawal during cocaine abstinence is a significant predictor of relapse, yet the neuroendocrine mechanisms underlying this vulnerability remain poorly understood, particularly in females. Estradiol, a potent neuromodulator of mesocorticolimbic circuitry, regulates dopamine-dependent processes that encode social motivation. L-type calcium channels (LTCCs) similarly regulate neuronal excitability and plasticity in corticolimbic regions implicated in addiction and affective regulation, and estradiol interacts with LTCC signaling through both membrane-initiated and transcriptional mechanisms. However, whether estradiol and LTCCs functionally converge to regulate social behavior during cocaine abstinence is unknown. Here, we used a preclinical behavioral pharmacology approach to examine this interaction in female Sprague-Dawley rats. Ovariectomized (OVX) rats with or without 17 beta-estradiol replacement underwent jugular catheterization and self-administered cocaine (0.5 mg/kg/inf, FR1) or saline for 10 days, followed by 17 days of forced abstinence. Social preference was assessed using a three-chamber social interaction test, with systemic isradipine (1.2 mg/kg, i.p.) administered 15 min prior to testing. Cocaine abstinence significantly reduced social preference in intact females. LTCC blockade with isradipine restored social preference, but this effect was dependent on ovarian hormone status: isradipine normalized social behavior in sham-operated and OVX + E2 rats but not in OVX rats lacking estradiol. Multiple linear regression confirmed that ovarian hormone status and isradipine treatment, but not total cocaine intake, significantly predicted social preference, with a robust hormone & times; isradipine interaction explaining 44.6% of behavioral variance. These findings demonstrate that estradiol does not simply protect against abstinence-related social deficits but rather biases neural signaling such that social behavior becomes sensitive to LTCC-dependent mechanisms. This work identifies a functional estradiol-LTCC interaction regulating social motivation during cocaine abstinence and highlights the importance of hormonal state in shaping sex-specific addiction vulnerability.
Abstract The perinatal period is characterized by profound psychological, physiological, and behavioral changes that may increase sleep, circadian, and affective disturbances. While sleep disruption across pregnancy and postpartum has been widely documented, far less is known about how this transition shapes circadian health and whether circadian characteristics during pregnancy predict postpartum circadian and affective outcomes. In this study, we characterize circadian preference, circadian phase, circadian function, and light exposure across the transition from late pregnancy to early postpartum, and examine their predictive value for postpartum circadian function and depressive and anxiety symptomatology. Women were followed from the third trimester of pregnancy to 1 month postpartum. At both time points, participants wore a wrist actigraph to derive circadian parameters including the circadian function index (CFI) and circadian phase (L5c), and to quantify mean light exposure. Circadian preference and affective states were also assessed by questionnaires (MEQ, EPDS, STAI‐T). Within‐subject changes from pregnancy to postpartum were examined, and regression models were used to test whether prenatal circadian and affective measures predicted postpartum circadian function and depressive symptomatology. The transition to postpartum was marked by a significant reduction in CFI and mean light exposure, whereas circadian preference and L5c remained largely stable. During pregnancy, higher CFI was associated with morningness and greater light exposure; however, these associations were no longer evident postpartum. Postpartum CFI was predicted by prenatal CFI and circadian preference, with lower values observed among women with more evening‐oriented profiles. In parallel, prenatal affective symptoms showed continuity into the postpartum period, and both prenatal CFI and circadian preference contributed to the prediction of postpartum depressive symptoms. Together, these findings indicate that early postpartum is characterized by a decay in circadian function rather than a shift in circadian phase, identify eveningness as a vulnerability factor during the transition to motherhood, support the use of CFI as an integrative marker of maternal circadian health, and highlight pregnancy as a potential window for circadian‐informed interventions aimed at improving postpartum circadian and mood outcomes.
Abstract Early‐life adversity increases risk for disease with sex‐specific effects on brain development. While the association between early‐life stress and neuropsychiatric disorders is well established, its impact on respiratory health is poorly documented, particularly in females. Here, we review recent studies using neonatal maternal separation (NMS) to examine the long‐term consequences of early‐life stress on cardiorespiratory function in females. Panic disorder (PD) is an anxiety disorder that is ⁓2 times more prevalent in women. The respiratory subtype is characterised by an exaggerated ventilatory response to CO 2 . NMS augmented the response to 5% CO 2 of adult female rats; this effect was most pronounced during proestrus and absent in males. Orexin (ORX) neurons potentiate the CO 2 response and are normally inhibited by 17β‐estradiol (E2). Electrophysiological measurements showed that in control females, excitatory postsynaptic current frequency varied inversely with E2 levels. However, NMS disrupted this E2‐mediated inhibition, particularly during proestrus, implicating impaired estrogen action in PD‐related respiratory dysfunction. Age‐related ovarian decline increases the risk of sleep apnea and associated comorbidities. Whereas apnea frequency decreased with age in control females, 1 year‐old NMS females exhibited a 75% higher apnea index than age‐matched controls, together with greater adiposity and hypertension. Arterial pressure was inversely correlated with circulating E2 levels only in NMS females, indicating heightened vulnerability to age‐related estrogen decline. Although physiological fluctuations in E2 levels exert modest effects in healthy females, we propose that early‐life stress persistently alters responsiveness to E2 and acts synergistically with ageing to increase cardiovascular vulnerability throughout the female lifespan.
