Search

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.

Author(s): Argel Aguilar-Valles [sup.1] [sup.2] [sup.3] , Danilo De Gregorio [sup.1] [sup.4] , Edna Matta-Camacho [sup.1] [sup.3] , Mohammad J. Eslamizade [sup.1] [sup.2] , Abdessattar Khlaifia [sup.2] , Agnieszka Skaleka [...], Effective pharmacotherapy for major depressive disorder remains a major challenge, as more than 30% of patients are resistant to the first line of treatment (selective serotonin reuptake inhibitors).sup.1. Sub-anaesthetic doses of ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist.sup.2,3, provide rapid and long-lasting antidepressant effects in these patients.sup.4-6, but the molecular mechanism of these effects remains unclear.sup.7,8. Ketamine has been proposed to exert its antidepressant effects through its metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK).sup.9. The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase.sup.10,11. mTORC1 controls various neuronal functions.sup.12, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs).sup.13. Here we show that 4E-BP1 and 4E-BP2 are key effectors of the antidepressant activity of ketamine and (2R,6R)-HNK, and that ketamine-induced hippocampal synaptic plasticity depends on 4E-BP2 and, to a lesser extent, 4E-BP1. It has been hypothesized that ketamine activates mTORC1-4E-BP signalling in pyramidal excitatory cells of the cortex.sup.8,14. To test this hypothesis, we studied the behavioural response to ketamine and (2R,6R)-HNK in mice lacking 4E-BPs in either excitatory or inhibitory neurons. The antidepressant activity of the drugs is mediated by 4E-BP2 in excitatory neurons, and 4E-BP1 and 4E-BP2 in inhibitory neurons. Notably, genetic deletion of 4E-BP2 in inhibitory neurons induced a reduction in baseline immobility in the forced swim test, mimicking an antidepressant effect. Deletion of 4E-BP2 specifically in inhibitory neurons also prevented the ketamine-induced increase in hippocampal excitatory neurotransmission, and this effect concurred with the inability of ketamine to induce a long-lasting decrease in inhibitory neurotransmission. Overall, our data show that 4E-BPs are central to the antidepressant activity of ketamine. The antidepressant-like effects of ketamine in mice depend on the expression of specific eIF4E-binding proteins in excitatory and inhibitory neurons.

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1 receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1 receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1 pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1 receptors in the LC-NE neurons. In conclusion, MT1 receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia, a complex and debilitating psychiatric disorder, is often comorbid with metabolic syndrome, intertwining the realms of mental health and physiological dysregulation. Serotonin (5-HT), a neurotransmitter derived from tryptophan and implicated in both psychiatric and metabolic regulation, could be a pivotal player in this interplay. Moreover, 5-HT is the precursor of the neuromodulator melatonin (MLT), which is also an important regulator of brain function and metabolism, as well as the circadian system. Dysregulation of the circadian system has been associated with both schizophrenia and metabolic disturbances. However, the specific mechanisms linking schizophrenia, metabolic disturbances, 5-HT, and MLT are still unknown. Aims & Objectives: To unravel the possible neurobiological link among schizophrenia, metabolic disturbances and the tryptophan to 5-HT and MLT pathway. Method: We investigated the activity of dorsal raphe nucleus (DRN) 5-HT neurons in anesthetized mice using single-unit in-vivo electrophysiology in mice considered melatonin proficient (C3H/HeN strain) and melatonin deficient (C57BL/6J strain). We induced metabolic dysfunction by subjecting them to a 10- week high-fat diet (HFD) and schizophrenia-like symptoms by injecting the non-competitive NMDA receptor antagonist MK-801 (0.3 mg/Kg, intraperitoneal). Severity of schizophrenia-like symptoms in the different experimental groups were assessed in the open field test. Results: As expected, in the open field test, we found that in mice of both strains MK-801 induced an increase in the locomotor activity, a measure of the severity of psychotic symptoms. Of interest, the increase in locomotor activity due to MK-801 treatment was lower in animals of both strains undergoing the HFD diet compared to those fed a normal diet. Moreover, while C57BL/6J mice fed a HFD independently of the MK-801 treatment spent less time in the centre of the open field than those fed a normal diet, no dietinduced differences were observed in C3H/HeN mice. These behavioural changes were paralleled by significant effects strain and diet dependent in the DRN 5-HT neural activity. In melatonin-deficient C57BL/6J mice, DRN 5-HT firing activity was higher in HFD than in normal diet mice independently of MK-801 treatment. The coefficient of variation (COV) of the 5-HT neurons, a measure of their regularity, in animals treated with vehicle was higher in HFD than in normal diet animals. In contrast, no effect of diet on the COV was seen in mice treated with MK-801. In melatonin-proficient C3H/HeN mice, DRN 5-HT spontaneous firing activity was also higher in HFD than in normal diet mice independently of MK-801 treatment. However, independently on the diet, MK-801 treatment was reducing DRN 5-HT neural activity. No effect of either diet or MK-801 treatment was observed on the COV of DRN 5-HT. Discussion & Conclusion: These preliminary findings show that 5-HT neurotransmission may be impaired in schizophrenia when in comorbidity with metabolic disturbances, but this impairment is dependent on the physiological function of the MLT system. [ABSTRACT FROM AUTHOR]

Introduction: Alcohol use disorder (AUD) is a major problem that causes significant health and social problem. Pharmacological treatments for AUD are limited in their effectiveness, and new drugs are required (ref). Recently, the potential use of psychedelics as novel therapies in treating mental diseases has come to the forefront in psychiatry. For instance, lysergic acid diethylamide (LSD) is a psychedelic acting as partial agonist of 5-HT2A receptors and exerts its mechanism of action through the modulation of the dopaminergic system in the ventral tegmental area (VTA). For instance, VTA plays a pivotal role in mediating the neurophysiology of AUD. Indeed, chronic alcohol consumption produces a disruption on the dopaminergic (DA) neurotransmission in the VTA. However, the mechanism of action and pre-clinical data about the effectiveness of psychedelic-based therapies for AUD remain limited. Aims and Objectives: This translational study aims at determining whether the LSD can reduce alcohol consumption in an animal model of AUD as well as its ability to restore the impaired VTA DA neurotransmission induced by the AUD. To do so, we employed a mouse model of self-ethanol administration with a paradigm DID (Drinking in the dark) to mimic binge-like drinking in humans and we performed behavioral paradigms and in vivo single-unit extracellular recordings. Method: C57BL6/J 8-week-old male mice underwent 6 cycles of DID. In each cycle, the water bottles were removed from all cages and replaced with bottles containing 20% ethanol solution for 2 hours per day, for 4 consecutive days in one experimental group (AUD mice). In another group of mice (control, CTL) the water bottles were not replaced with ethanol. After 6 cycles of DID, mice received a single intraperitoneal injection of vehicle or LSD (150 mcg/kg, a dose that has been demonstrated to exert antidepressant effects. The day after the injections, animals were assessed for the alcohol consumption with the 40 days two-bottle choice test. Twenty-four hours from the last drinking session in the two- bottle choice test, locomotion was assessed by using the open field test (OFT) and the rotarod test. Finally, in vivo single unit extracellular recordings of VTA DA neurons were performed. Results: AUD mice did not show difference in locomotion in the OFT, compared to CTL (p=0.012). However, AUD mice displayed decreased latency to fall (p<0.01) in the rotarod test. These effects were coupled to an increased DA VTA firing rate activity (p<0.05) and reduced intra-burst frequency (p<0.001) compared to CTL mice. LSD significantly reduced the alcohol intake (p<0.05) and normalized the locomotor impairments in the AUD mice (p<0.001). Moreover, LSD did not revert the enhanced DA VTA firing rate activity but it increased the intra-burst frequency (p<0.001) which was reduced by the chronic alcohol consumption. Discussion and Conclusion: This work show that single administration of LSD reduces alcohol consumption and reverts locomotor impairment. Moreover, LSD partially restores the VTA DA deficits induced by chronic alcohol consumption. Overall, this study will broaden our understanding of the potential therapeutic effects of psychedelics in treating AUD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Psychedelics elicit prosocial, antidepressant and anxiolytic effects via neuroplasticity, neurotransmission and neuro‐immunomodulatory mechanisms. Whether psychedelics affect the brain endocannabinoid system and its extended version, the endocannabinoidome (eCBome) or the gut microbiome, remains unknown. Experimental Approach: Adult C57BL/6N male mice were administered lysergic acid diethylamide (LSD) or saline for 7 days. Sociability was assessed in the direct social interaction and three chambers tests. Prefrontal cortex and hippocampal endocannabinoids, endocannabinoid‐like mediators and metabolites were quantified via high‐pressure liquid chromatography with tandem mass spectrometry (HPLC‐MS/MS). Neurotransmitter levels were assessed via HPLC‐UV/fluorescence. Gut microbiome changes were investigated by 16S ribosomal DNA sequencing. Key Results: LSD increased social preference and novelty and decreased hippocampal levels of the N‐acylethanolamines N‐linoleoylethanolamine (LEA), anandamide (N‐arachidonoylethanolamine) and N‐docosahexaenoylethanolamine (DHEA); the monoacylglycerol 1/2‐docosahexaenoylglycerol (1/2‐DHG); the prostaglandins D2 (PGD2) and F2α (PGF2α); thromboxane 2 and kynurenine. Prefrontal eCBome mediator and metabolite levels were less affected by the treatment. LSD decreased Shannon alpha diversity of the gut microbiota, prevented the decrease in the Firmicutes:Bacteroidetes ratio observed in saline‐treated mice and altered the relative abundance of the bacterial taxa Bifidobacterium, Ileibacterium, Dubosiella and Rikenellaceae RC9. Conclusions and Implications: The prosocial effects elicited by repeated LSD administration are accompanied by alterations of hippocampal eCBome and kynurenine levels, and the composition of the gut microbiota. Modulation of the hippocampal eCBome and kynurenine pathway might represent a mechanism by which psychedelic compounds elicit prosocial effects and affect the gut microbiome. [ABSTRACT FROM AUTHOR]

Melatonin, through its G protein‐coupled receptor (GPCR) (MTNR1B gene) MT2, is implicated in analgesia, but the relationship between MT2 receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured [SNI]), the selective melatonin MT2 agonist UCM924 reversed the allodynia (a pain response to a non‐noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the nonselective opioid antagonist naloxone and the selective MOR antagonist D‐Phe‐Cys‐Tyr‐D‐Trp‐Orn‐Thr‐Pen‐Thr‐NH2 (CTOP) blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral‐ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pronociceptive ON‐cells, and the enhancement of the firing of the antinociceptive OFF‐cells, induced by the microinjection of the MT2 agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT2 receptors are expressed in both excitatory (CaMKIIα+) and inhibitory (GAD65+) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons coexpressed MOR and MT2 receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT2 receptor agonism requires MORs to exert its antiallodynic effects, mostly through an interneuronal circuit involving MOR and MT2 receptors. [ABSTRACT FROM AUTHOR]