Atypical antipsychotic Lumateperone Beyond Schizophrenia: Seeking clarity in a time of Uncertainty

Lumateperone (ITI-007) is a serotonin 5HT2A tosylate salt with high affinity for dopamine D2 and D1 receptors and the serotonin transporter. It is unusual in that it controls serotonin, dopamine, and glutamate neurotransmission concurrently, all of which have been implicated in severe mental illness. Consider it a multi-targeted ligand and multifunctional modulator of the serotoninergic system with possible precognitive, antipsychotic, antidepressant, and anxiolytic properties. While lumateperone has been explored as a new agent for schizophrenia therapy, it also provides a unique therapeutic option for a range of other psychiatric and neurological diseases, including behavioural signs of dementia or Alzheimer's disease, sleep problems, and bipolar depression. Additionally, it had a better safety profile than placebo, with no significant extrapyramidal side effects, hyperprolactinemia, or changes in cardiometabolic or endocrine characteristics. Additional study is needed to validate and analyse lumateperone's effectiveness, as well as to identify prospective therapeutic targets. This article gives a comprehensive overview of the most notable results and potential future applications of this chemical in personalised medicine, particularly for neurodegenerative diseases.

Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumor cells, including glioma cells, in vitro. The developing CNS of fetus and newborn is particularly susceptible to the deleterious effects of neurotoxic substances in our environment, and perinatal exposure could result in the later development of diseases, a hypothesis known as the developmental origin of health and disease. Some of these substances affect the serotoninergic system and could therefore be the source of a silent pandemic of neurodevelopmental toxicity. This review presents the available data that are contributing to the appreciation of the effects of the exposome on the serotoninergic system and their potential link with brain pathologies (neurodevelopmental, neurodegenerative, neurobehavioral disorders, and glioblastoma).

Increasing Serotonin to Reduce Parkinsonian Tremor

While current dopamine-based drugs seem to be effective for most Parkinson's disease (PD) motor dysfunctions, they produce variable responsiveness for resting tremor. This lack of consistency could be explained by considering recent evidence suggesting that PD resting tremor can be divided into different partially overlapping phenotypes based on the dopamine response. These phenotypes may be associated with different pathophysiological mechanisms produced by a cortical-subcortical network involving even non-dopaminergic areas traditionally not directly related to PD. In this study, we propose a bio-constrained computational model to study the neural mechanisms underlying a possible type of PD tremor: the one mainly involving the serotoninergic system. The simulations run with the model demonstrate that a physiological serotonin increase can partially recover dopamine levels at the early stages of the disease before the manifestation of overt tremor. This result suggests that monitoring serotonin concentration changes could be critical for early diagnosis. The simulations also show the effectiveness of a new pharmacological treatment for tremor that acts on serotonin to recover dopamine levels. This latter result has been validated by reproducing existing data collected with human patients.

Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

The treatment of neuropathic pain remains a clinical challenge. Analgesic drugs and antidepressants are frequently ineffective, and opioids may induce side effects, including hyperalgesia. Recent results on brainstem pain modulatory circuits may explain those clinical challenges. The dual action of noradrenergic (NA) modulation was demonstrated in animal models of neuropathic pain. Besides the well-established antinociception due to spinal effects, the NA system may induce pronociception by directly acting on brainstem pain modulatory circuits, namely, at the locus coeruleus (LC) and medullary dorsal reticular nucleus (DRt). The serotoninergic system also has a dual action depending on the targeted spinal receptor, with an exacerbated activity of the excitatory 5-hydroxytryptamine 3 (5-HT3) receptors in neuropathic pain models. Opioids are involved in the modulation of descending modulatory circuits. During neuropathic pain, the opioidergic modulation of brainstem pain control areas is altered, with the release of enhanced local opioids along with reduced expression and desensitization of μ-opioid receptors (MOR). In the DRt, the installation of neuropathic pain increases the levels of enkephalins (ENKs) and induces desensitization of MOR, which may enhance descending facilitation (DF) from the DRt and impact the efficacy of exogenous opioids. On the whole, the data discussed in this review indicate the high plasticity of brainstem pain control circuits involving monoaminergic and opioidergic control. The data from studies of these neurochemical systems in neuropathic models indicate the importance of designing drugs that target multiple neurochemical systems, namely, maximizing the antinociceptive effects of antidepressants that inhibit the reuptake of serotonin and noradrenaline and preventing desensitization and tolerance of MOR at the brainstem.

Differential localization of serotoninergic system elements in human amniotic epithelial cells†

Serotonin or 5-hydroxytryptamine (5-HT) is a biogenic amine involved in regulating several functions, including development. However, its impact on human embryo development has been poorly studied. The present work investigated the expression and distribution of the main components of the serotoninergic system in human amniotic tissue and in human amniotic epithelial cells (hAEC) in vitro, as an alternative model of early human embryo development. Amniotic membranes from full-term healthy pregnancies were used. Human amnion tissue or hAEC isolated from the amnion were processed for RT-PCR and immunofluorescence analyses of the main components of the serotoninergic system. We found the expression of tryptophan hydroxylase type 1 (TPH1), type 2 (TPH2), serotonin transporter (SERT), monoamine oxidase-A (MAO-A) as well as HTR1D and HTR7 receptors at mRNA level in amnion tissue as well in hAEC. Interestingly, we found the presence of 5-HT in the nucleus of the cells in amnion tissue, whereas it located in the cytoplasm of isolated hAEC. We detected TPH1, TPH2 and HTR1D receptor in both the nucleus and cytoplasm. SERT, MAO-A and HTR7 receptor were only observed in the cytoplasm. The results presented herein show, for the first time, the presence of the serotoninergic system in human amnion in vivo and in vitro.

Roles of the Serotoninergic System in Coping with Traumatic Stress

Post-Traumatic Stress Disorder (PTSD) is characterized by substantial physiological and/or psychological distress following exposure to trauma. Intrusive fear memories often lead to persistent avoidance of stimuli associated with the trauma, detachment from others, irritability and sleep disturbances. Different key structures in the brain are involved with fear conditioning, fear extinction and coping. The limbic system, namely, the amygdala complex in close relationship with the hippocampal hub and the prefrontal cortex play central roles in the integration and in coping with fear memories. Serotonin acting both as a neurotransmitter and as a neurohormone participates in regulating the normal and pathological activity of these anatomic structures. We review the literature analyzing how the different actors of the serotoninergic system (5-HT receptors, transporters and anabolic and catabolic pathways) may be involved in regulating the sensitivity to highly stressful events and hopefully coping with them.

Peripheral Modulators of the Central Fatigue Development and Their Relationship with Athletic Performance in Jumper Horses

The current study aimed to investigate whether peripheral modulators of serotoninergic function and neurohumoral factors’ changes in athletic horses during an official jumping competition, and to evaluate their relationship with the physical performance of competing horses. From 7 Italian Saddle mares (6–9 years; mean body weight 440 ± 15 kg), performing the same standardized warm-up and jumping course during an official class, heart rate (HR) was monitored throughout the competition. Rectal temperature (RT) measurement, blood lactate and glucose concentration, serum tryptophan, leucine, valine, the tryptophan/branched-chain amino-acids ratio (Try/BCAAs), dopamine, prolactin, and non-esterified fatty acids (NEFAs) were assessed before the exercise event (T0), at the end of the competition stage (5 min ± 10 s following the cessation of the exercise, TPOST5), and 30 min after the end of competition (TPOST30). Highest HR values were recorded during the course and at the outbound (p < 0.0001); blood lactate concentration and RT increased after exercise with respect to the rest condition (p < 0.0001). Lower leucine and valine levels (p < 0.01), and higher tryptophan, Try/BCAAs ratio, and NEFAs values were found at TPOST5 and TPOST30 with respect to T0 (p < 0.0001). A higher prolactin concentration was found at TPOST5 and TPOST30 compared to T0 (p < 0.0001), whereas dopamine showed decreased values after exercise compared to rest (p < 0.0001). Statistically significant correlations among the peripheral indices of serotoninergic function, neurohumoral factors, and athletic performance parameters were found throughout the monitoring period. The findings provide indirect evidence that the serotoninergic system may be involved in fatigue during jumper exercise under a stressful situation, such as competition, in which, in addition to physical effort, athletic horses exhibit more passive behavior.