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Smausz, Rebecca; Neill, Joanna; Gigg, John
doi: 10.1177/02698811221092508pmid: 35638159
Psilocybin is a naturally occurring psychedelic compound with profound perception-, emotion- and cognition-altering properties and great potential for treating brain disorders. However, the neural mechanisms mediating its effects require in-depth investigation as there is still much to learn about how psychedelic drugs produce their profound and long-lasting effects. In this review, we outline the current understanding of the neurophysiology of psilocybin’s psychoactive properties, highlighting the need for additional preclinical studies to determine its effect on neural network dynamics. We first describe how psilocybin’s effect on brain regions associated with the default-mode network (DMN), particularly the prefrontal cortex and hippocampus, likely plays a key role in mediating its consciousness-altering properties. We then outline the specific receptor and cell types involved and discuss contradictory evidence from neuroimaging studies regarding psilocybin’s net effect on activity within these regions. We go on to argue that in vivo electrophysiology is ideally suited to provide a more holistic, neural network analysis approach to understand psilocybin’s mode of action. Thus, we integrate information about the neural bases for oscillatory activity generation with the accumulating evidence about psychedelic drug effects on neural synchrony within DMN-associated areas. This approach will help to generate important questions for future preclinical and clinical studies. Answers to these questions are vital for determining the neural mechanisms mediating psilocybin’s psychotherapeutic potential, which promises to improve outcomes for patients with severe depression and other difficulty to treat conditions.
Collins, Helen M; Pinacho, Raquel; Ozdemir, Dersu; Bannerman, David M; Sharp, Trevor
doi: 10.1177/02698811221093032pmid: 35607713
Background:Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals.Aim:Here, the effect of SSRI discontinuation on anxiety-like behaviour was systematically investigated in mice.Methods:Experiments were based on a three-arm experimental design comprising saline, continued SSRI and discontinued SSRI. Mice were assessed 2 days after SSRI discontinuation over a 5-day period using the elevated plus maze (EPM) and other anxiety tests.Results:An exploratory experiment found cessation of paroxetine (12 days) was associated with decreased open-arm exploration and reduced total distance travelled, in male but not female mice. Follow-up studies confirmed a discontinuation effect on the EPM in male mice after paroxetine (12 days) and also citalopram (12 days). Mice receiving continued paroxetine (but not citalopram) also showed decreased open-arm exploration but this was dissociable from the effects of discontinuation. The discontinuation response to paroxetine did not strengthen after 28 days of treatment but was absent after 7 days of treatment. A discontinuation response was not discernible in other anxiety and fear-learning tests applied 3–5 days after treatment cessation. Finally, discontinuation effects on the EPM were typically associated with decreased locomotion on the test. However, separate locomotor testing implicated anxiety-provoked behavioural inhibition rather than a general reduction in motor activity.Conclusion:Overall, this study provides evidence for a short-lasting behavioural discontinuation response to cessation of SSRI treatment in mice.
Russo, Adrian M; Payet, Jennyfer M; Kent, Stephen; Lesku, John A; Lowry, Christopher A; Hale, Matthew W
doi: 10.1177/02698811221089039pmid: 35475390
Background:The BALB/c mouse has been proposed as a model of human psychiatric disorders characterised by elevated anxiety and altered sociability. Juvenile BALB/c mice show decreased social exploratory behaviour, increased anxiety, and reduced brain serotonin synthesis compared to other strains including C57BL/6J mice.Aim:To determine whether supplementation of brain serotonin synthesis alters social behaviour and activation of serotonergic neurons across subregions of the dorsal raphe nucleus (DR) in BALB/c mice.Methods:Juvenile male BALB/c mice were assigned to one of four treatment conditions: vehicle/vehicle, carbidopa (25 mg/kg)/vehicle, vehicle/5-HTP (10 mg/kg), carbidopa (25 mg/kg)/5-HTP (10 mg/kg). Social behaviour was measured using the three-chamber social approach test, followed by immunohistochemical staining for TPH2 and c-Fos to measure activation of serotonergic neurons across subregions of the DR.Results:Mice treated with carbidopa/5-HTP spent more time in the social cage zone and covered more distance in the social approach test compared to other treatment groups. There was no difference between treatment groups in the activation of serotonergic neurons across subregions of the DR. However, the DRD was associated with increased social approach behaviour in carbidopa/5-HTP treated animals.Conclusions:Supplementation of serotonin synthesis can increase social approach behaviour in juvenile BALB/c mice. An increase in locomotor behaviour was also observed suggesting that increasing central serotonin synthesis may have led to a reduction in state anxiety, manifesting in increased exploratory behaviour. As no effect on serotonergic activation within the DR was found, alternative mechanisms are likely important for the effects of 5-HTP on social behaviour.
Turan Yücel, Nazlı; Evren, Asaf Evrim; Kandemir, Ümmühan; Can, Özgür Devrim
doi: 10.1177/02698811221095528pmid: 35638175
Background:Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology.Objectives:In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect.Methods:The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies.Results:Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors.Conclusion:This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.
Duarte-Filho, Luiz Antonio Miranda de Souza; Amariz, Isabela Araujo; Nishimura, Rodolfo Hideki Vicente; Massaranduba, Ana Beatriz Rodrigues; Menezes, Pedro Modesto Nascimento; Damasceno, Tauana Araújo; Brys, Ivani; Rolim, Larissa Araújo; Silva, Fabrício Souza; Ribeiro, Luciano Augusto de Araújo
Zhu, Han; Bai, Yuyan; Wang, Gaorui; Su, Yousong; Tao, Yanlin; Wang, Lupeng; Yang, Liu; Wu, Hui; Huang, Fei; Shi, Hailian; Wu, Xiaojun
doi: 10.1177/02698811221089041pmid: 35475391
Elsilä, Lauri V; Harkki, Juliana; Enberg, Emma; Martti, Alvar; Linden, Anni-Maija; Korpi, Esa R
doi: 10.1177/02698811221104641pmid: 35695174
Background:Psychedelics, like lysergic acid diethylamide (LSD), are again being studied as potential therapies for many neuropsychiatric disorders, including addictions. At the same time, the acute effects of psychedelics on rewarding behaviours have been scarcely studied.Aims:The current study aimed to clarify if LSD decreases binge-like ethanol drinking in mice, and whether the observed acute effects on ethanol consumption are generalizable to a natural reinforcer, sucrose, and if the effects resulted from aversive or reward-attenuating effects caused by LSD.Methods:The effects of acute LSD were examined using 2-bottle choice intermittent ethanol (20%) and sucrose drinking (10%), discrete-trial current-intensity threshold method of intracranial self-stimulation and short-term feeding behaviour assay in C57BL/6 male mice.Results:The results showed that acute 0.1 mg/kg, but not 0.05 mg/kg, dose (i.p.) of LSD reduced 2-h intermittent ethanol drinking transiently without any prolonged effects. No effects were seen in intermittent 2-h sucrose drinking. The tested LSD doses had neither effect on the intracranial self-stimulation current-intensity thresholds, nor did LSD affect the threshold-lowering, or rewarding, effects of simultaneous amphetamine treatment. Furthermore, LSD had small, acute diminishing effects on 2-h food and water intake.Conclusions:Based on these results, LSD decreases binge-like ethanol drinking in mice, but only acutely. This effect is not likely to stem from reward-attenuating effects but could be in part due to reduced consummatory behaviour.
Custodio, Raly James Perez; Kim, Mikyung; Sayson, Leandro Val; Ortiz, Darlene Mae; Buctot, Danilo; Lee, Hyun Jun; Cheong, Jae Hoon; Kim, Hee Jin
doi: 10.1177/02698811221089040pmid: 35486444
Background:Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock.Aim:We explored morphine reward and reinforcement using mouse models with Per2 gene modifications (knockout (KO); overexpression (OE)).Methods:Mice were exposed to various behavioral, electroencephalographic, pharmacological, and molecular tests to assess the effects of morphine and identify the underlying mechanisms with a focus on reward and reinforcement and the corresponding involvement of circadian and clock-controlled gene regulation.Results:Per2 deletion enhances morphine-induced analgesia, locomotor sensitization, conditioned place preference (CPP), and self-administration (SA) in mice, whereas its overexpression attenuated these effects. In addition, reduced withdrawal was observed in Per2 KO mice, whereas an augmented withdrawal response was observed in Per2 OE mice. Moreover, naloxone and SCH 23390 blocked morphine CPP in Per2 KO and wild-type (WT) mice. The rewarding (CPP) and reinforcing effects (SA) observed in morphine-conditioned and morphine self-administered Per2 KO and WT mice were accompanied by activated μ-opioid and dopamine D1 receptors and TH in the mesolimbic (VTA/NAcc) system. Furthermore, genetic modifications of Per2 in mice innately altered some clock genes in response to morphine.Conclusion:These findings improve our understanding of the role of Per2 in morphine-induced psychoactive effects. Our data and those obtained in previous studies indicate that targeting Per2 may have applicability in the treatment of substance abuse.
Kolesnikova, Tatiana O; Galstyan, David S; Demin, Konstantin A; Barabanov, Mikhail A; Pestov, Alexander V; S de Abreu, Murilo; Strekalova, Tatyana; Kalueff, Allan V
doi: 10.1177/02698811221098192pmid: 35713386
Background:Cognitive deficits represent an urgent biomedical problem, and are commonly reduced by nootropic drugs. Animal models, including both rodents and zebrafish, offer a valuable tool for studying cognitive phenotypes and screening novel nootropics. Beta-alanine and its derivatives have recently been proposed to exert nootropic activity.Aims:This study aimed to characterize putative nootropic profile of a novel β-alanine analogue, 1,3-diaminopropane (MB-005), in adult zebrafish.Methods:Nootropic profile of MB-005 was assessed in adult zebrafish in the novel tank and conditioned place aversion (CPA) tests acutely, and in cued-learning plus-maze (PMT) tests chronically.Results/Outcomes:MB-005 did not alter zebrafish anxiety-like behavior or monoamine neurochemistry acutely, improved short-term memory in the CPA test, but impaired cognitive performance in both CPA and PMT tests chronically.Conclusions/Interpretation:This study reveals high sensitivity of zebrafish cognitive phenotypes to MB-005, suggesting it as a potential novel cognitive enhancer acutely, but raises concerns over its cognitive (and, possibly, other) side-effects chronically.
Showing 1 to 10 of 10 Articles
doi: 10.1177/02698811221104050pmid: 35723216
Background:Depression is a psychiatric disorder with limited therapy options. Psychedelics are new antidepressant candidates, being the ayahuasca one of the most promising ones. A synergistic combination of N,N-dimethyltryptamine (DMT) and β-carbolines allows ayahuasca antidepressant properties. Another psychedelic and DMT-containing beverage is the jurema wine used religiously by indigenous people from Northeastern Brazil.Aims:To evaluate the antidepressant-like effect of standardized extract of Mimosa tenuiflora (SEMT), associated or not with harmine (β-carboline), in behavioral models of depression.Methods:The SEMT was submitted to (+) ESI-IT-LC/MS analysis for DMT quantification. To assess the antidepressant-like effect of SEMT, the open field (OFT), tail suspension (TST), and forced swim (FST) tests were performed. To verify the participation of serotonergic systems, the 5-hydroxytryptophan (5-HTP)-induced head twitch test was performed.Results:The content of DMT found in SEMT was 24.74 ± 0.8 mg/g. Yuremamine was also identified. SEMT presented an antidepressant-like effect in mice submitted to the TST and FST, independent from harmine, with no significant alterations on the OFT. The sub-dose interaction between SEMT and ketamine also produced an anti-immobility effect in the TST, with no changes in the OFT. SEMT potentiated the head twitch behavior induced by 5-HTP and ketanserin prevented its antidepressant-like effect in the TST (p < 0.05).Conclusions:SEMT presented a harmine-independent antidepressant-like effect in mice submitted to the TST and FST. This effect occurs possibly via activation of serotonergic systems, particularly the 5-HT2A/2C receptors.
Background:Hyodeoxycholic acid (HDCA) is a natural secondary bile acid with enormous pharmacological effects, such as modulating inflammation in neuron. However, whether HDCA could suppress microglial inflammation has not been elucidated yet.Aims:To determine the anti-microglial inflammatory effect of HDCA in lipopolysaccharide (LPS) models and its mechanisms.Methods:The effect of HDCA was evaluated in LPS-stimulated BV2 microglial cells in vitro and the cortex of LPS-treated mice in vivo. Immunohistochemistry and immunofluorescence were used to visualize the localization of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and ionized calcium-binding adaptor protein-1 (Iba-1), respectively. The mRNA expression of inflammatory cytokines was measured by RT-qPCR. The protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), takeda G-coupled protein receptor 5 (TGR5), and the phosphorylation of protein kinase B (AKT), NF-κB, and inhibitor of NF-κB protein α (IκBα) was examined by Western blot.Results:HDCA inhibited the inflammatory responses in LPS-treated BV2 cells and in the cortex of LPS-treated mice, evidenced by decreased production of inflammatory mediators such as iNOS, COX-2, tumor necrosis factor (TNF-α), interleukin (IL)-6, and IL-1β. Further study demonstrated that HDCA repressed the phosphorylation, nuclear translocation, and transcriptional activity of NF-κB and inhibited the activation of AKT in BV-2 cells induced by LPS. Meanwhile, addition of TGR5 inhibitor, triamterene, abolished the effects of HDCA on TGR5, AKT, and NF-κB.Conclusion:The present study demonstrated that HDCA prevents LPS-induced microglial inflammation in vitro and in vivo, the action of which is via regulating TGR5/AKT/NF-κB signaling pathway.