Trevor Sharp

Currently there is major research interest in the therapeutic potential of serotonergic psychedelic drugs across a range of neuropsychiatric disorders ^1-3 . Such drugs exert psychedelic and neuroplastic effects, both likely linked to therapeutic outcomes, via agonist action at the 5-HT _2A receptor ^4-7 . This receptor is assumed to generate downstream intracellular signalling via an interaction with either G _q protein coupling and formation of the second messenger inositol trisphosphate (IP ₃ ), or through triggering the effector β-arrestin2. Central to the IP ₃ pathway is mobilisation of Ca ²⁺ stored in the endoplasmic reticulum (ER). Here, we report the unexpected discovery that the 5-HT _2A receptor also signals via an additional second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), which mobilises Ca ²⁺ release from lysosomal stores. This effect was revealed through measurement of changes in cellular NAADP levels, pharmacological inhibition of NAADP and direct biosensor measurement of lysosomal Ca ²⁺ release and was produced not only by 5-HT but also by a range of psychedelic drugs in a receptor-specific manner. Moreover, genetic ablation of the NAADP pathway reduced markers of both hallucinogenic and neuroplastic effects of psychedelic drug administration in mouse models. These findings reveal the involvement of a novel, therapeutically relevant signalling pathway in psychedelic drug action.

A major subpopulation of 5‐hydroxytryptamine (5‐HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) allowing the co‐release of glutamate. Previous evidence has implicated VGLUT3 in 5‐HT neurons in mechanisms of anxiety and reward. Here we examined mice with a genetic loss of VGLUT3 targeted to 5‐HT neurons (VGLUT3 cKO ^5‐HT ) and littermate controls in a battery of behavioural tests, including paradigms assessing levels of anxiety and learning with appetitive rewards. Compared to littermate controls, VGLUT3 cKO ^5‐HT mice displayed no evidence of altered anxiety‐like behaviour in the elevated plus maze, light/dark box, marble burying and social interaction tests. However, VGLUT3 cKO ^5‐HT mice showed reduced preference for low (but not high) sucrose‐containing solution and reduced correct responses in an appetitively motivated spatial reference memory task. Similarly, in an appetitively motivated operant task, VGLUT3 cKO ^5‐HT mice displayed evidence of reduced responding to cues associated with reward. These effects appeared specific in that VGLUT3 cKO ^5‐HT mice did not differ from controls in terms of home cage food consumption, performance in a spatial novelty preference test, as well as contextual and cued fear memory tests. These findings support a role for VGLUT3 in 5‐HT neurons in some aspects of learning, here in association with learning for reward, although not anxiety‐like behaviour.

Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult‐to‐treat conditions, that extend beyond neuropsychiatric disorders, provided the impetus for this themed issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical trials, and insight into the regulatory processes that determine clinical approval. In this editorial, we introduce these aspects and provide an overview of current controversies and challenges in the field, as well as highlighting the exciting potential that these drugs offer. LINKED ARTICLES: This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.14/issuetoc

Serotonin’s role in motivated behaviour remains unresolved due to a lack of causal, spatially precise, and translatable methods. Here, we introduce ultrasound-mediated neuromodulator delivery to achieve focal, non-invasive access to the primate brain by transiently opening the blood–brain barrier, enabling systemically administered serotonin to reach a targeted cortical region. We delivered serotonin to the perigenual anterior cingulate cortex (pgACC) of awake, behaving macaques and combined this with computational modelling and multimodal imaging, including resting-state fMRI and single-voxel MRS. Elevating pgACC serotonin reduced occupancy of high-motivation states by weakening the energizing influence of rich reward environments, while leaving sensitivity to immediate offer value intact. This was accompanied by altered frontal functional connectivity, reduced local glutamatergic metabolite signal, and changes in pupil-linked physiology. Repeated delivery was well tolerated, and histology confirmed increased serotonergic signal at the target. These findings establish a translatable approach for focal neuropharmacological manipulation and identify pgACC serotonin as a regulator of context-dependent motivation.

Objective: Impulsivity is a transdiagnostic risk factor for numerous health morbidities and is strongly associated with early relapse and poor treatment outcomes in addictions and mood‐disorders. Lithium carbonate can be helpful in moderating the impulsive behaviors associated with mania, possibly mediated by reduced myo ‐inositol activity following inhibition of the enzyme inositol monophosphatase (IMPase). We tested the hypothesis that impulsivity—as motor disinhibition, decisions without adequate information, and stronger preferences for small immediate rewards over larger later rewards—can be moderated by the IMPase inhibitor ebselen in healthy adult volunteers. Methods: One hundred and thirty healthy adults completed a between‐subjects, double‐blind, placebo‐controlled protocol. Over 2 days, participants received a previously validated dose of 1800 mg of ebselen or placebo before completing tests of impulsivity and decision‐making. Results: There were no substantive changes in any measure of impulsivity following treatment with ebselen compared with placebo. Neither was there any convincing evidence of stronger treatment effects in high‐trait impulsive participants compared with low‐trait participants. Conclusion: These results fail to replicate findings that ebselen administration moderates validated measures of impulsivity in healthy adults, at least at doses shown to reduce myo ‐inositol within the medial prefrontal cortex and produce changes in emotional processing and reward‐based learning.

Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult to treat conditions that extend beyond neuropsychiatric disorders provided the impetus for this Themed Issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical trials, and insight into the regulatory processes that determine clinical approval. In this Editorial we introduce these aspects and provide an overview of current controversies and challenges in the field, as well as highlighting the exciting potential that these drugs offer.

Psychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of vigilance. Here, we performed chronic electrophysiological recordings from the neocortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We report an acute induction of a dissociated state, characterised by prominent slow oscillations in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was initially markedly suppressed, but was overcompensated in the subsequent 48 hours, while administration of 5-MeO-DMT immediately after sleep deprivation attenuated the subsequent rebound of sleep slow-wave activity. We argue that the occurrence of a dissociated state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics — from dream-like hallucinations to reopening of the critical period for plasticity.

Background and Purpose: Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5‐HT _2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5‐HT _2A receptor ligand bias or signalling efficacy. Here, we investigated 5‐HT _2A receptor signalling properties of selected psychedelic and non‐psychedelic drugs. Experimental Approach: G _q ‐coupled (Ca ²⁺ and IP ₁ ) and β‐arrestin2 signalling effects of six psychedelic drugs (psilocin, 5‐MeO‐DMT, LSD, mescaline, 25B‐NBOMe and DOI) and three non‐psychedelic drugs (lisuride, TBG and IHCH‐7079) were characterised using SH‐SY5Y cells expressing human 5‐HT _2A receptors. Ligand bias and signalling efficacy were measured using concentration–responses curves, compared with 5‐HT. The generality of findings was tested using rat C6 cells which express endogenous 5‐HT _2A receptors. Key Results: In SH‐SY5Y cells, all psychedelic drugs were partial agonists at both 5‐HT _2A receptor signalling pathways and none showed significant ligand bias. In comparison, the non‐psychedelic drugs were not distinguishable from psychedelic drugs in terms of ligand bias properties but exhibited the lowest 5‐HT _2A receptor signalling efficacy of all drugs tested. The latter result was confirmed in C6 cells. Conclusion and Implications: In summary, all psychedelic drugs tested were unbiased, partial 5‐HT _2A receptor agonists. Importantly, the non‐psychedelic drugs lisuride, TBG and IHCH‐7079 were discriminated from psychedelic drugs, not through ligand bias but rather by low efficacy. Therefore, low 5‐HT _2A receptor signalling efficacy may explain why some 5‐HT _2A receptor agonists are not psychedelic, although a larger panel of drugs should be tested to confirm this idea. LINKED ARTICLES: This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.14/issuetoc

Serotonin plays a prominent role in neurodevelopment, regulating processes from cell division to synaptic connectivity. Clinical studies suggest that alterations in serotonin signalling such as genetic polymorphisms or antidepressant exposure during pregnancy are risk factors for neurodevelopmental disorders. However, an understanding of how dysfunctional neuromodulation alters systems level activity over neocortical development is lacking. Here, we use a longitudinal imaging approach to investigate how genetics, pharmacology, and aversive experience disrupt state-dependent serotonin signalling with pathological consequences for sensory processing. We find that all three factors lead to increased neocortical serotonin levels during the initial postnatal period. Genetic deletion of the serotonin transporter or antidepressant dosing results in a switch from hypo- to hyper-cortical activity that arises as a consequence of altered cortical GABAergic microcircuitry. However, the trajectories of these manipulations differ with postnatal exposure to antidepressants having effects on adult sensory encoding. The latter is not seen in the genetic model despite a similar early phenotype, and a distinct influence of maternal genotype on the development of supragranular layers. These results reveal the dynamics and critical nature of serotonin signalling during perinatal life; pharmacological targeting of which can have profound life-long consequences for cognitive development of the offspring.