Somatostatin interneurons activated by 5-HT2A receptor suppress slow oscillations in medial entorhinal cortex

Serotonin (5-HT) is one of the major neuromodulators present in the mammalian brain and has been shown to play a role in multiple physiological processes. The mechanisms by which 5-HT modulates cortical network activity, however, are not yet fully understood. We investigated the effects of 5-HT on slow oscillations (SOs), a synchronized cortical network activity universally present across species. SOs are observed during anesthesia and are considered to be the default cortical activity pattern. We discovered that (±)3,4-methylenedioxymethamphetamine (MDMA) and fenfluramine, two potent 5-HT releasers, inhibit SOs within the entorhinal cortex (EC) in anesthetized mice. Combining opto- and pharmacogenetic manipulations with in vitro electrophysiological recordings, we uncovered that somatostatin-expressing (Sst) interneurons activated by the 5-HT2A receptor (5-HT2AR) play an important role in the suppression of SOs. Since 5-HT2AR signaling is involved in the etiology of different psychiatric disorders and mediates the psychological effects of many psychoactive serotonergic drugs, we propose that the newly discovered link between Sst interneurons and 5-HT will contribute to our understanding of these complex topics.

Increasing central serotonin with 5-HTP disrupts the inhibition of social gaze in non-human primates

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted in patient populations treated with serotonergic drugs. However, the field lacks a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-Hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze responses, making them worse at flexibly switching between orientating and inhibiting behaviors. Furthermore, the effects of 5-HTP on performance correlated with a constriction of the pupil, an increased time to initiate trials, and an increased reaction time, suggesting that the disruptive effects of 5-HTP on social gaze behaviors are likely driven by a downregulation of arousal and motivational states. Taken together, these findings provide causal evidence for a modulatory relationship between 5-HTP and social gaze behaviors in non-human primates and offer translational insights for the role of the serotonergic system in social gaze.

Toxicological Findings in a Possible Drug-drug Interaction Death: A Case Report

Synergistic effects are the most encountered types of drug-drug interaction in post-mortem toxicology. Concomitant use of fentanyl, tramadol and carbamazepine may increase the risk of severe serotonin toxicity. The decedent was a 32-year-old black man, with a history of severe migraine headaches. He died after being administered several drugs to treat the migraine. For fentanyl identification and quantification, samples were extracted using solid phase extraction and analyzed by GC-MS. For carbamazepine and tramadol identification and quantification, samples were extracted by liquid-liquid extraction and analyzed by LC-QTOF. Toxicology showed post-mortem concentrations of fentanyl 0.033, 0.025, 0.005, 0.0127, and 0.005 mg/L; tramadol 0.143, 0.093, 0.043, 0.09, and 0.08 mg/L; carbamazepine 1.6, 1.04, 0.3, 0.83, and 0.18 mg/L in the blood, brain, liver, kidney and stomach, respectively. In this case report, the combination of serotonergic drugs can contribute to synergistic serotonergic effects. Therefore, drug-drug interaction is expected, and the cause of death may be attributed to toxic synergistic drug-drug interaction including fentanyl, tramadol and carbamazepine.

Focus on Depression in Parkinson’s Disease: A Delphi Consensus of Experts in Psychiatry, Neurology, and Geriatrics

Major and minor forms of depression are significant contributors to Parkinson’s disease morbidity and caregiver burden, affecting up to 50% of these patients. Nonetheless, symptoms of depression are still underrecognized and undertreated in this context due to scarcity of evidence and, consequently, consistent clinical guideline recommendations. Here, we carried out a prospective, multicentre, 2-round modified Delphi survey with 49 questions about the aetiopathological mechanisms of depression in Parkinson’s disease (10), clinical features and connections with motor and nonmotor symptoms (10), diagnostic criteria (5), and therapeutic options (24). Items were assessed by a panel of 37 experts (neurologists, psychiatrists, and a geriatrist), and consensus was achieved in 81.6% of them. Depressive symptoms, enhanced by multiple patient circumstances, were considered Parkinson’s disease risk factors but not clinical indicators of motor symptom and disease progression. These patients should be systematically screened for depression while ruling out both anhedonia and apathy symptoms as they are not necessarily linked to it. Clinical scales (mainly the Geriatric Depression Scale GDS-15) can help establishing the diagnosis of depression, the symptoms of which will require treatment regardless of severity. Efficacious and well-tolerated pharmacological options for Parkinson’s comorbid depression were selective serotonin reuptake inhibitors (especially sertraline), dual-action serotonin and norepinephrine reuptake inhibitors (venlafaxine, desvenlafaxine, and duloxetine), multimodal (vortioxetine, bupropion, mirtazapine, and tianeptine), and anti-Parkinsonian dopamine agonists (pramipexole, ropinirole, and rotigotine). Tricyclic antidepressants and combining type B monoamine oxidase inhibitors with serotonergic drugs have serious side effects in these patients and therefore should not be prescribed. Electroconvulsive therapy was indicated for severe and drug-refractory cases. Cognitive behavioural therapy was recommended in cases of mild depression. Results presented here are useful diagnostic and patient management guidance for other physicians and important considerations to improve future drug trial design.

Comprehensive analysis of the range of serotonergic agents and substances for their production registered in Russia

The article presents the characteristics of serotonergic drugs (mode of action, classifi cation, pharmacodynamic and pharmacokinetic properties, drug interactions with medicinal products of other pharmacological groups). The domestic pharmaceutical market of serotonergic drug products (DP) and substances for their production registered in the Russian Federation (RF) was analyzed. It was established that the pharmaceutical market of serotonergic agents in the RF is quite diverse. Various pharmacological groups of drugs (anxiolytic, antiemetic, vasodilatory and peripheral circulation improving, evacuant, hemostatic and anti-migraine agents) are presented in various dosage forms (tablets — 5.71%; fi lm-coated tablets — 41.43%; injectable solution for intravenous and intramuscular use — 34.28%; concentrate for preparation of solution for injections — 8.57%; solutions for intravenous administration and rectal suppositories — by 2.86%; syrup, freeze-dried tablets and capsules — by 1.43%). The leading role in the Russian pharmaceutical market belongs to domestic manufacturers of serotonergic DP (59.70%), which are mainly presented by generic drugs. Foreign manufacturers own 40.30% of the market for serotonergic DP, with the leading positions held by manufacturers of India (8.96%), Switzerland (5.97%), Israel (4.48%). The analysis of the range of pharmaceutical substances for the production of serotonergic DP showed that the Russian pharmaceutical market is dominated by foreign manufacturers (52.38%). The proportion of domestic providers accounts for 47.62% of the manufacturers of substances registered in the Russian Federation.

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

In the last few years, there have been significant advances in migraine management and prevention. Lasmiditan, ubrogepant, rimegepant and monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) are new drugs that were launched on the US pharmaceutical market; some of them also in Europe. This publication reviews the available worldwide references on the safety of these anti-migraine drugs with a focus on the possible drug–drug (DDI) or drug–food interactions. As is known, bioavailability of a drug and, hence, its pharmacological efficacy depend on its pharmacokinetics and pharmacodynamics, which may be altered by drug interactions. This paper discusses the interactions of gepants and lasmiditan with, i.a., serotonergic drugs, CYP3A4 inhibitors, and inducers or breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) inhibitors. In the case of monoclonal antibodies, the issue of pharmacodynamic interactions related to the modulation of the immune system functions was addressed. It also focuses on the effect of monoclonal antibodies on expression of class Fc gamma receptors (FcγR).

Clinical Relevance of Pharmacogenetics in Serotonin Syndrome

Serotonin syndrome is a predictable life-threatening condition that is caused by serotonergic stimulation of the central and peripheral nervous systems. A patient’s genetic profile can amplify exposure risk as many serotonergic drugs are metabolized by CYP450 enzymes, and these enzymes may be altered in functionality. We report a case of an elderly man who presented with serotonin syndrome after a dose change in valproic acid 5 weeks prior. His medication list consisted of low-dose serotonergic agents, which is unusual as most cases of serotonin syndrome involve higher doses. A review of his pharmacogenetic profile is presented to retrospectively evaluate the additive risk for serotonin syndrome and implications on resuming serotonergic agents.

Phasic activation of dorsal raphe serotonergic neurons increases pupil-linked arousal

SUMMARYVariations in pupil size under constant luminance are closely coupled to changes in arousal state [1–5]. It is assumed that such fluctuations are primarily controlled by the noradrenergic system [6–9]. Phasic activity of noradrenergic axons precedes pupil dilations associated with rapid changes in arousal [7,9], and is believed to be driven by unexpected uncertainty [1,10–16]. However, the role of other modulatory pathways in the control of pupil-linked arousal has not been as thoroughly investigated, but evidence suggests that noradrenaline may not be alone [7,17,18]. Administration of serotonergic drugs seems to affect pupil size [19–23], but these effects have not been investigated in detail. Here, we show that transient serotonin (5-HT) activation, like noradrenaline, causes pupil-size changes. We used phasic optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) in head-fixed mice locomoting in a foraging task. 5-HT-driven modulations of pupil size were maintained throughout the photostimulation period and sustained for several seconds after the end of the stimulation. The activation of 5-HT neurons increased pupil size additively with locomotor speed, suggesting that 5-HT transients affect pupil-linked arousal independently from locomotor states. We found that the effect of 5-HT on pupil size depended on the level of environmental uncertainty, consistent with the idea that 5-HT may report a salience or surprise signal [24]. Together, these results challenge the classic view of the neuromodulatory control of pupil-linked arousal, revealing a tight relationship between the activation of 5-HT neurons and changes in pupil size.