Showing papers in "Psychopharmacology in 2019"
TL;DR: MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD and supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.
Abstract: Background
Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.
206 citations
TL;DR: Data show that psychotropic medications differentially influence the composition of gut microbiota in vivo and that fluoxetine and escitalopram have specific antimicrobial activity in vitro, suggesting that the two factors are not causally linked.
Abstract: Growing evidence supports a role for the microbiota in regulating gut-brain interactions and, thus, psychiatric disorders Despite substantial scientific efforts to delineate the mechanism of action of psychotropic medications at a central nervous system (CNS) level, there remains a critical lack of understanding on how these drugs might affect the microbiota and gut physiology We investigated the antimicrobial activity of psychotropics against two bacterial strain residents in the human gut, Lactobacillus rhamnosus and Escherichia coli In addition, we examined the impact of chronic treatment with these drugs on microbiota and intestinal parameters in the rat In vitro fluoxetine and escitalopram showed differential antimicrobial effects Lithium, valproate and aripiprazole administration significantly increased microbial species richness and diversity, while the other treatments were not significantly different from controls At the genus level, several species belonging to Clostridium, Peptoclostridium, Intestinibacter and Christenellaceae were increased following treatment with lithium, valproate and aripiprazole when compared to the control group Animals treated with escitalopram, venlafaxine, fluoxetine and aripiprazole exhibited an increased permeability in the ileum These data show that psychotropic medications differentially influence the composition of gut microbiota in vivo and that fluoxetine and escitalopram have specific antimicrobial activity in vitro Interestingly, drugs that significantly altered gut microbial composition did not increase intestinal permeability, suggesting that the two factors are not causally linked Overall, unravelling the impact of psychotropics on gastrointestinal and microbiota measures offers the potential to provide critical insight into the mechanism of action and side effects of these medications
160 citations
TL;DR: The theory is extended to help explain sex differences in depression prevalence and research demonstrating that ovarian hormone fluctuations modulate women’s susceptibility to stress, brain structure and function, and inflammatory activity and reactivity helps explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years.
Abstract: Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.
140 citations
TL;DR: Cannabis containing equivalent concentrations of CBD and THC appears no less impairing than THC-dominant cannabis, and in some circumstances, CBD may actually exacerbate THC-induced impairment.
Abstract: The main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), can impair driving performance. Cannabidiol (CBD), a non-intoxicating cannabis component, is thought to mitigate certain adverse effects of THC. It is possible then that cannabis containing equivalent CBD and THC will differentially affect driving and cognition relative to THC-dominant cannabis. The present study investigated and compared the effects of THC-dominant and THC/CBD equivalent cannabis on simulated driving and cognitive performance. In a randomized, double-blind, within-subjects crossover design, healthy volunteers (n = 14) with a history of light cannabis use attended three outpatient experimental test sessions in which simulated driving and cognitive performance were assessed at two timepoints (20–60 min and 200–240 min) following vaporization of 125 mg THC-dominant (11% THC; < 1% CBD), THC/CBD equivalent (11% THC, 11% CBD), or placebo (< 1% THC/CBD) cannabis. Both active cannabis types increased lane weaving during a car-following task but had little effect on other driving performance measures. Active cannabis types impaired performance on the Digit Symbol Substitution Task (DSST), Divided Attention Task (DAT) and Paced Auditory Serial Addition Task (PASAT) with impairment on the latter two tasks worse with THC/CBD equivalent cannabis. Subjective drug effects (e.g., “stoned”) and confidence in driving ability did not vary with CBD content. Peak plasma THC concentrations were higher following THC/CBD equivalent cannabis relative to THC-dominant cannabis, suggesting a possible pharmacokinetic interaction. Cannabis containing equivalent concentrations of CBD and THC appears no less impairing than THC-dominant cannabis, and in some circumstances, CBD may actually exacerbate THC-induced impairment.
126 citations
TL;DR: This review will take into consideration different classes of psychotropics including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines.
Abstract: The human gut contains trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. Psychotropic medications act on the central nervous system (CNS) and are used in the treatment of various psychiatric disorders. There is increasing emphasis on the bidirectional interaction between drugs and the gut microbiome. An expanding body of evidence supports the notion that microbes can metabolise drugs and vice versa drugs can modify the gut microbiota composition. In this review, we will first give a comprehensive introduction about this bidirectional interaction, then we will take into consideration different classes of psychotropics including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for the future of psychopharmacology pipelines that will routinely need to consider the host microbiome during drug discovery and development.
98 citations
TL;DR: Fear memory processes and their mechanisms are described and the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD are discussed.
Abstract: Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD.
97 citations
TL;DR: These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy of microdosing psychedelics, and have the exciting potential to shape future psychedelic research.
Abstract: Microdosing psychedelics—the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin—is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses. This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity. In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity. Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = − 0.92) and negative emotionality (p = 0.009, r = − 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls. These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.
89 citations
TL;DR: A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers, which warrant exploratory research into therapeutic applications of 5- MeO- DMT.
Abstract: Background
5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited.
85 citations
TL;DR: It is examined how changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders but may in fact play a role in mediating behavioral response to drugs of abuse.
Abstract: Pathological substance use disorders represent a major public health crisis with limited effective treatment options. While much work has been done to understand the neuronal signaling networks and intracellular signaling cascades associated with prolonged drug use, these studies have yielded few successful treatment options for substance use disorders. In recent years, there has been a growing interest to explore interactions between the peripheral immune system, the gut microbiome, and the CNS. In this review, we will present a summary of existing evidence, suggesting a potential role for gut dysbiosis in the pathogenesis of substance use disorders. Clinical evidence of gut dysbiosis in human subjects with substance use disorder and preclinical evidence of gut dysbiosis in animal models of drug addiction are discussed in detail. Additionally, we examine how changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders but may in fact play a role in mediating behavioral response to drugs of abuse. While much work still needs to be done, understanding the interplay of gut microbiome in substance use disorders may offer a promising avenue for future therapeutic development.
82 citations
TL;DR: Resting-state fMRI scans were acquired from 39 1-year-old human infants and results provide exciting new insights into the gut-brain axis during early human development and should stimulate further studies into whether microbiome-associated changes in brain circuitry influence later risk for psychopathology.
Abstract: Recently, there has been a surge of interest in the possibility that microbial communities inhabiting the human gut could affect cognitive development and increase risk for mental illness via the “microbiome-gut-brain axis.” Infancy likely represents a critical period for the establishment of these relationships, as it is the most dynamic stage of postnatal brain development and a key period in the maturation of the microbiome. Indeed, recent reports indicate that characteristics of the infant gut microbiome are associated with both temperament and cognitive performance. The neural circuits underlying these relationships have not yet been delineated. To address this gap, resting-state fMRI scans were acquired from 39 1-year-old human infants who had provided fecal samples for identification and relative quantification of bacterial taxa. Measures of alpha diversity were generated and tested for associations with measures of functional connectivity. Primary analyses focused on the amygdala as manipulation of the gut microbiota in animal models alters the structure and neurochemistry of this brain region. Secondary analyses explored functional connectivity of nine canonical resting-state functional networks. Alpha diversity was significantly associated with functional connectivity between the amygdala and thalamus and between the anterior cingulate cortex and anterior insula. These regions play an important role in processing/responding to threat. Alpha diversity was also associated with functional connectivity between the supplementary motor area (SMA, representing the sensorimotor network) and the inferior parietal lobule (IPL). Importantly, SMA-IPL connectivity also related to cognitive outcomes at 2 years of age, suggesting a potential pathway linking gut microbiome diversity and cognitive outcomes during infancy. These results provide exciting new insights into the gut-brain axis during early human development and should stimulate further studies into whether microbiome-associated changes in brain circuitry influence later risk for psychopathology.
82 citations
TL;DR: These results suggest that microdose LSD produces temporal dilation of suprasecond intervals in the absence of subjective alterations of consciousness, and this effect is most pronounced in the 10 μg dose condition.
Abstract: Previous research demonstrating that lysergic acid diethylamide (LSD) produces alterations in time perception has implications for its impact on conscious states and a range of psychological functions that necessitate precise interval timing. However, interpretation of this research is hindered by methodological limitations and an inability to dissociate direct neurochemical effects on interval timing from indirect effects attributable to altered states of consciousness. We conducted a randomised, double-blind, placebo-controlled study contrasting oral administration of placebo with three microdoses of LSD (5, 10, and 20 μg) in older adults. Subjective drug effects were regularly recorded and interval timing was assessed using a temporal reproduction task spanning subsecond and suprasecond intervals. LSD conditions were not associated with any robust changes in self-report indices of perception, mentation, or concentration. LSD reliably produced over-reproduction of temporal intervals of 2000 ms and longer with these effects most pronounced in the 10 μg dose condition. Hierarchical regression analyses indicated that LSD-mediated over-reproduction was independent of marginal differences in self-reported drug effects across conditions. These results suggest that microdose LSD produces temporal dilation of suprasecond intervals in the absence of subjective alterations of consciousness.
TL;DR: Evidence is reviewed that the microbiota-gut-brain axis is key to the physiopathology of several neuropsychiatric disorders involving those where dopaminergic neurotransmission is compromised, and appears as a key player when it comes to proposing novel strategies to the treatment of these psychiatric conditions.
Abstract: Increasing evidence shows changes in gut microbiota composition in association with psychiatric disorders, including anxiety and depression. Moreover, it has been reported that perturbations in gut microbe diversity and richness influence serotonergic, GABAergic, noradrenergic, and dopaminergic neurotransmission. Among these, dopamine is regarded as a main regulator of cognitive functions such as decision making, attention, memory, motivation, and reward. In this work, we will highlight findings that link alterations in intestinal microbiota and dopaminergic neurotransmission, with a particular emphasis on the mesocorticolimbic circuit, which is involved in reward to natural reinforcers, as well as abuse substances. For this, we reviewed evidence from studies carried out on germ-free animals, or in rodents subjected to intestinal dysbiosis using antibiotics, and also through the use of probiotics. All this evidence strongly supports that the microbiota-gut-brain axis is key to the physiopathology of several neuropsychiatric disorders involving those where dopaminergic neurotransmission is compromised. In addition, the gut microbiota appears as a key player when it comes to proposing novel strategies to the treatment of these psychiatric conditions.
TL;DR: The present review shows that extinction in instrumental learning has much in common with other examples of retroactive interference in instrumentallearning (e.g., omission learning, punishment, second-outcome learning, discrimination reversal learning, and differential reinforcement of alternative behavior).
Abstract: This article reviews recent research on the extinction of instrumental (or operant) conditioning from the perspective that it is an example of a general retroactive interference process. Previous discussions of interference have focused primarily on findings from Pavlovian conditioning. The present review shows that extinction in instrumental learning has much in common with other examples of retroactive interference in instrumental learning (e.g., omission learning, punishment, second-outcome learning, discrimination reversal learning, and differential reinforcement of alternative behavior). In each, the original learning can be largely retained after conflicting information is learned, and behavior is cued or controlled by the current context. The review also suggests that a variety of stimuli can play the role of context, including room and apparatus cues, temporal cues, drug state, deprivation state, stress state, and recent reinforcers, discrete cues, or behaviors. In instrumental learning situations, the context can control behavior through its direct association with the reinforcer or punisher, through its hierarchical relation with response-outcome associations, or its direct association (inhibitory or excitatory) with the response. In simple instrumental extinction and habit learning, the latter mechanism may play an especially important role.
TL;DR: Results suggest that progressive fear attenuation mediated by repetitive exposure is accompanied by sustained neuronal activation and not reverted to a pre-conditioning brain state, and contribute to the identification of brain areas as targets for therapeutic approaches against traumatic memories.
Abstract: The experience of strong traumata leads to the formation of enduring fear memories that may degenerate into post-traumatic stress disorder. One of the most successful treatments for this condition consists of extinction training during which the repeated exposure to trauma-inducing stimuli in a safe environment results in an attenuation of the fearful component of trauma-related memories. While numerous studies have investigated the neural substrates of recent (e.g., 1-day-old) fear memory attenuation, much less is known about the neural networks mediating the attenuation of remote (e.g., 30-day-old) fear memories. Since extinction training becomes less effective when applied long after the original encoding of the traumatic memory, this represents an important gap in memory research. Here, we aimed to generate a comprehensive map of brain activation upon effective remote fear memory attenuation in the mouse. We developed an efficient extinction training paradigm for 1-month-old contextual fear memory attenuation and performed cFos immunohistochemistry and network connectivity analyses on a set of cortical, amygdalar, thalamic, and hippocampal regions. Remote fear memory attenuation induced cFos in the prelimbic cortex, the basolateral amygdala, the nucleus reuniens of the thalamus, and the ventral fields of the hippocampal CA1 and CA3. All these structures were equally recruited by remote fear memory recall, but not by the recall of a familiar neutral context. These results suggest that progressive fear attenuation mediated by repetitive exposure is accompanied by sustained neuronal activation and not reverted to a pre-conditioning brain state. These findings contribute to the identification of brain areas as targets for therapeutic approaches against traumatic memories.
TL;DR: This article reviews models of impaired extinction built around experimentally induced brain region and neural circuit disruptions, spontaneously-arising and laboratory-induced genetic modifications, or exposure to environmental insults, including stress, drugs of abuse, and unhealthy diet.
Abstract: The measurement of Pavlovian forms of fear extinction offers a relatively simple behavioral preparation that is nonetheless tractable, from a translational perspective, as an approach to study mechanisms of exposure therapy and biological underpinnings of anxiety and trauma-related disorders such as post-traumatic stress disorder (PTSD). Deficient fear extinction is considered a robust clinical endophenotype for these disorders and, as such, has particular significance in the current “age of RDoC (research domain criteria).” Various rodent models of impaired extinction have thus been generated with the objective of approximating this clinical, relapse prone aberrant extinction learning. These models have helped to reveal neurobiological correlates of extinction circuitry failure, gene variants, and other mechanisms underlying deficient fear extinction. In addition, they are increasingly serving as tools to investigate ways to therapeutically overcome poor extinction to support long-term retention of extinction memory and thus protection against various forms of fear relapse; modeled in the laboratory by measuring spontaneous recovery, reinstatement and renewal of fear. In the current article, we review models of impaired extinction built around (1) experimentally induced brain region and neural circuit disruptions (2) spontaneously-arising and laboratory-induced genetic modifications, or (3) exposure to environmental insults, including stress, drugs of abuse, and unhealthy diet. Collectively, these models have been instrumental in advancing in our understanding of extinction failure and underlying susceptibilities at the neural, genetic, molecular, and neurochemical levels; generating renewed interest in developing novel, targeted and effective therapeutic treatments for anxiety and trauma-related disorders.
TL;DR: The observation that females are more susceptible to incentive-sensitization when intermittently exposed to cocaine may provide a mechanism for the more rapid development of problematic drug use in females reported in clinical studies.
Abstract: Intermittent Access (IntA) cocaine self-administration, which models intermittent patterns of cocaine use in humans during the transition to addiction, is especially effective in producing incentive-sensitization and other addiction-like behavior in male rats. However, female rats show more robust psychomotor sensitization than males, and following initial use, women develop problematic patterns of drug use more readily than men. We hypothesized, therefore, that female rats might be more susceptible to the incentive-sensitization produced by IntA experience. To assess changes in motivation for cocaine, using a behavioral economic indicator of cocaine demand (“elasticity” of demand curves), and other addiction-like behavior, as a function of IntA cocaine self-administration experience in male and female rats. IntA experience produced a progressive increase in motivation for cocaine in both males and females, as indicated by a decrease in the elasticity of cocaine demand curves, and this persisted undiminished following 14 days of abstinence. However, IntA produced a more rapid and greater increase in motivation for cocaine (incentive-sensitization) in females than males. Females also consumed more cocaine than males, although this did not predict changes in motivation. On the other hand, there were no sex differences in the preferred level of cocaine consumption when cost was low (Q0), nor in cocaine- or cue-induced reinstatement of drug-seeking behavior. The observation that females are more susceptible to incentive-sensitization when intermittently exposed to cocaine may provide a mechanism for the more rapid development of problematic drug use in females (“telescoping effect”) reported in clinical studies.
TL;DR: A systematic review of the evidence up to date on the kynurenine pathway role in linking depression and cancer, as well as the potential antidepressant efficacy of novel immunotherapies for cancer, is provided.
Abstract: Depression is a common comorbidity in cancer cases, but this is not only due to the emotional distress of having a life-threatening disease. A common biological mechanism, involving a dysregulated immune system, seems to underpin this comorbidity. In particular, the activation of the kynurenine pathway of tryptophan degradation due to inflammation may play a key role in the development and persistence of both diseases. As a consequence, targeting enzymes involved in this pathway offers a unique opportunity to develop new strategies to treat cancer and depression at once. In this work, we provide a systematic review of the evidence up to date on the kynurenine pathway role in linking depression and cancer and on clinical implications of this evidence. In particular, complications due to chemotherapy are discussed, as well as the potential antidepressant efficacy of novel immunotherapies for cancer.
TL;DR: Whether SGAs drive dysbiosis, whether gut microbiota alterations affect body weight and metabolic outcomes, and the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies are investigated.
Abstract: Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin. We investigated whether SGAs drive dysbiosis, assessed whether gut microbiota alterations affect body weight and metabolic outcomes, and looked for the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies. A systematic literature search (PubMed/Medline/Embase/ClinicalTrials.gov/PsychInfo) was conducted from database inception until 03 July 2018 for studies that reported the microbiome and weight alterations in SGA-treated subjects. Seven articles reporting studies in mice (experiments = 8) and rats (experiments = 3) were included. Olanzapine was used in five and risperidone in six experiments. Only three articles (experiments = 4) in humans fit our criteria of using risperidone and mixed SGAs. The results confirmed microbiome alterations directly (rodent experiments = 5, human experiments = 4) or indirectly (rodent experiments = 4) with predominantly increased Firmicutes abundance relative to Bacteroidetes, as well as weight gain in rodents (experiments = 8) and humans (experiments = 4). Additionally, olanzapine administration was found to induce both metabolic alterations (adiposity, lipogenesis, plasma free fatty acid, and acetate levels increase) (experiments = 3) and inflammation (experiments = 2) in rodents, whereas risperidone suppressed the resting metabolic rate in rodents (experiments = 5) and elevated fasting blood glucose, triglycerides, LDL, hs-CRP, antioxidant superoxide dismutase, and HOMA-IR in humans (experiment = 1). One rodent study suggested a gender-dependent effect of dysbiosis on body weight. Antipsychotic treatment-related microbiome alterations potentially result in body weight gain and metabolic disturbances. Inflammation and resting metabolic rate suppression seem to play crucial roles in the development of metabolic disorders.
TL;DR: Computational modelling is used to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D1/3 antagonist amisulpride affected these responses.
Abstract: Collection of data obtained for this study was originally funded by GlaxoSmithKline. J.W.K. is supported by a Gates Cambridge Scholarship and this analysis is supported by a Wellcome Trust Senior Investigator Grant 104631/Z/14/Z to T.W.R. RNC’s research is supported by the UK Medical Research Council (MC_PC_17213). This research was supported in part by the UK National Health Service (NHS) National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre; the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. This research was supported in part by a Medical Research Council Clinical Research Infrastructure award (MR/M009041/1).
TL;DR: Children who had received antibiotics in the first 6 months of life had significantly lower overall cognitive and verbal comprehension abilities, increased risk of problems with metacognition, executive function, impulsivity, hyperactivity, attention-deficit hyperactivity disorder, anxiety and emotional problems.
Abstract: Antibiotics are commonly prescribed for infants. In addition to increasing concern about antibiotic resistance, there is a concern about the potential negative impact of antibiotics on the gut microbiota and health and development outcomes. The aim of this study was to investigate the association between early life antibiotic exposure and later neurocognitive outcomes. Participants were infants born to mothers enrolled in the probiotics study. The initial study was designed to evaluate the effect of two different probiotics on allergy outcomes in childhood. Antibiotic exposure was based on parent report and categorised according to the following timing of the first exposure: 0–6 months, 6–12 months, 12–24 months or not at all. At 11 years of age, children’s neurocognitive outcomes were assessed using psychologist-administered, parent-report and self-report measures. The relationship between the timing of antibiotic exposure and neurocognitive outcomes was examined using regression models. Of the 474 participants initially enrolled, 342 (72%) children had a neurocognitive assessment at 11 years of age. After adjustment for mode of delivery, probiotic treatment group assignment, income and breastfeeding, children who had received antibiotics in the first 6 months of life had significantly lower overall cognitive and verbal comprehension abilities, increased risk of problems with metacognition, executive function, impulsivity, hyperactivity, attention-deficit hyperactivity disorder, anxiety and emotional problems. These results provide further evidence that early exposure to antibiotics may be associated with detrimental neurodevelopmental outcomes.
TL;DR: RSV suppressed the production of inflammatory cytokines by enhancing Sirt1 levels and counteracted estrogen deficiency-induced psychobehavioral changes via inhibition of inflammatory processes in the hippocampus in ovariectomized mice.
Abstract: Resveratrol (RSV) has been indicated to exhibit beneficial effects on depression and anxiety treatment by suppression of inflammatory processes. Depression triggered by deficiency of estrogen and anxiety-like behaviors are associated with inflammation. The role of RSV in ovariectomized mice is unclear. We examine whether the RSV, a Sirt1 activator, alleviates ovariectomy-induced anxiety- and depression-like behaviors through the inhibition of inflammatory processes. Female C57BL/6J mice (6–8 weeks of age, 17–20 g) were ovariectomized and treated with RSV at a dose of 20 mg/kg for 2 weeks. Depression- and anxiety-like behaviors were compared with vehicle-injected control animals. Immunohistochemistry and qPCR were used to detect inflammation in the hippocampal region. Ovariectomized mice were observed to suffer from anxiety- and depression-like behaviors. These effects were attenuated by treatment with RSV. Immunohistochemical staining results showed that RSV could reverse the increase of microglial activation in the hippocampal dentate gyrus. At a molecular level, RSV inhibited the activation of NLRP3 and NF-κB in the hippocampal region caused by deficiency of estrogen. RSV suppressed the production of inflammatory cytokines by enhancing Sirt1 levels. Our findings indicated that RSV-induced Sirt1 activation counteracted estrogen deficiency-induced psychobehavioral changes via inhibition of inflammatory processes in the hippocampus. In anxiety and depression disorders, RSV is supposed to be an effective treatment for postmenopausal changes.
TL;DR: Recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence are summarized to demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model.
Abstract: Results from clinical studies suggest that drug relapse and craving are often provoked by exposure to drug-associated contexts. Since 2002, this phenomenon has been modeled in laboratory animals using the ABA renewal model. In the classical version of this model, rats with a history of drug self-administration in one context (A) undergo extinction in a different context (B) and reinstate (or relapse to) drug seeking after exposure to the original drug-associated context (A). In a more recent version of the model introduced in 2013, the experimental conditions in context A are identical to those used in the classical model, but drug-reinforced responding in context B is suppressed by probabilistic punishment. The punishment-based ABA renewal model is proposed to resemble abstinence in humans, which is often initiated by the desire to avoid the negative consequences of drug use. The goal of our review is to discuss similarities and differences in mechanisms that play a role in suppression of drug seeking in context B and context-induced relapse to drug seeking in context A in the two models. We first describe psychological mechanisms that mediate extinction and punishment of drug-reinforced responding in context B. We then summarize recent findings on brain mechanisms of context-induced relapse of drug seeking after extinction, or punishment-imposed abstinence. These findings demonstrate both similarities and differences in brain mechanisms underlying relapse in the two variations of the ABA renewal model. We conclude by briefly discussing clinical implications of the preclinical studies.
TL;DR: It is proposed that (mal)-adaptive interplay via (dis)-balanced oscillatory communication between the anxiety network and the fear network may determine the strength of fear memories and their resistance to extinction.
Abstract: The hippocampus plays a central role as a hub for episodic memory and as an integrator of multimodal sensory information in time and space. Thereby, it critically determines contextual setting and specificity of episodic memories. It is also a key site for the control of innate anxiety states and involved in psychiatric diseases with heightened anxiety and generalized fear memory such as post-traumatic stress disorder (PTSD). Expression of both innate "unlearned" anxiety and "learned" fear requires contextual processing and engagement of a brain-wide network including the hippocampus together with the amygdala and medial prefrontal cortex. Strikingly, the hippocampus is also the site of emergence of oscillatory rhythms that coordinate information processing and filtering in this network. Here, we review data on how the hippocampal network oscillations and their coordination with amygdalar and prefrontal oscillations are engaged in innate threat evaluation. We further explore how such innate oscillatory communication might have an impact on contextualization and specificity of "learned" fear. We illustrate the partial overlap of fear and anxiety networks that are built by the hippocampus in conjunction with amygdala and prefrontal cortex. We further propose that (mal)-adaptive interplay via (dis)-balanced oscillatory communication between the anxiety network and the fear network may determine the strength of fear memories and their resistance to extinction.
TL;DR: It is argued that glucocorticoid-based interventions facilitate fear extinction by reducing the retrieval of aversive memories and enhancing the consolidation of extinction memories.
Abstract: Extensive evidence from both animal model and human research indicates that glucocorticoid hormones are crucially involved in modulating memory performance. Glucocorticoids, which are released during stressful or emotionally arousing experiences, enhance the consolidation of new memories, including extinction memory, but reduce the retrieval of previously stored memories. These memory-modulating properties of glucocorticoids have recently received considerable interest for translational purposes because strong aversive memories lie at the core of several fear-related disorders, including post-traumatic stress disorder and phobias. Moreover, exposure-based psychological treatment of these disorders relies on successful fear extinction. In this review, we argue that glucocorticoid-based interventions facilitate fear extinction by reducing the retrieval of aversive memories and enhancing the consolidation of extinction memories. Several clinical trials have already indicated that glucocorticoids might be indeed helpful in the treatment of fear-related disorders.
TL;DR: Common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning are identified in preclinical animal models to explain the co-occurrence of fear and drug-seeking behaviors.
Abstract: Comorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use. The goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse. After extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding. The overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors.
TL;DR: Findings suggest that lactobacilli and inflammation may be differentially associated with mood disorder via brain mechanisms underpinning self-judgement and cognitive empathy, respectively.
Abstract: The gut-brain axis includes bidirectional communication between intestinal microbiota and the central nervous system. Bifidobacterium and Lactobacillus spp. have been implicated in psychological health, such as depression, through various pathways (e.g. inflammation). Research needs a better understanding of direct and indirect effects through examination of psychological factors that make people susceptible to, or offer protection against, depression. This study investigated the relationships between gut microbiota, inflammation and psychological risk and resilience factors for depression. Forty participants (13 m/27 f) recruited from the general population completed self-report questionnaires for depression, self-judgement, over-identification and affective and cognitive empathy. Faecal and blood samples were taken to assay microbiota (Bifidobacterium; Lactobacillus spp.) and pro-inflammatory molecules (C-reactive protein, CRP and interleukin-6, IL-6), respectively. Hierarchical regression analyses (controlling for sex, age and the shared variance of risk and resilience factors) showed that (i) cognitive depression was significantly predicted by negative self-judgement and reduced cognitive empathy; (ii) abundance of Lactobacillus spp. was directly related to positive self-judgement but only indirectly to cognitive depression and lower affective empathy (both through self-judgement); and (iii) CRP was the strongest predictor of reduced cognitive empathy, with suppression effects seen for age (negative) and IL-6 (positive) after controlling for CRP. Findings suggest that lactobacilli and inflammation may be differentially associated with mood disorder via brain mechanisms underpinning self-judgement and cognitive empathy, respectively. Further trials investigating interventions to increase Lactobacillus spp. in depression would benefit from direct measures of self-judgement and affective empathic distress, whilst those that aim to reduce inflammation should investigate cognitive empathy.
TL;DR: The gut microbiome of anorexia nervosa patients was different to healthy controls both prior and following nutritional rehabilitation, though it is noted that these states were associated with lower and higher nutritional intakes, respectively.
Abstract: Rapidly accumulating evidence supports the important role of gut microbiome in the regulation of mood, behaviour, appetite, gastrointestinal symptomology, and nutrient metabolism. These are all core features frequently altered in individuals with anorexia nervosa (AN). Current treatment recommendations for AN support the use of high-calorie diets as an essential part of nutritional rehabilitation, commonly achieved by elevating the fat content of the diet. However, in contrast to this approach, there is accumulating evidence suggesting the importance of balanced, high-fibre diets on the gut microbiome. Studies have demonstrated profound differences in the microbial composition of underweight people with AN and those of normal- or overweight individuals. Specific alterations vary widely between studies. It is thus far unclear to what extent the observed differences are brought on by iatrogenic effects of nutritional rehabilitation or the disorder itself. To date, only two studies have investigated the changes in the intestinal microbiota during nutritional rehabilitation and corresponding weight restoration. These studies suggest that the gut microbiome of AN patients was different to healthy controls both prior and following nutritional rehabilitation, though it is noted that these states were associated with lower and higher nutritional intakes, respectively. There is a clear need for further investigation regarding the effects of nutritional rehabilitation on the gut microbiome. Such research would provide insights into the potential role of gut microbiome in modulating the pathophysiology of AN and inform future treatment strategies.
TL;DR: It is argued that intermittent access self-Administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.
Abstract: A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people, bouts of use are thought to be more intermittent. Here, we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out, the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.
TL;DR: Neither cannabis smoke nor THC exposure during adolescence produced robust alterations in adult behavior after a period of abstinence, suggesting that adverse effects associated with adolescent cannabis use might be due to non-cannabinoid concomitants of cannabis use.
Abstract: Cannabis use is common among adolescents and some research suggests that adolescent cannabis use increases the risk for depression, anxiety, and cognitive impairments in adulthood. In human studies, however, confounds may affect the association between cannabis use and the development of brain disorders. These experiments investigated the effects of adolescent exposure to either cannabis smoke or THC on anxiety- and depressive-like behavior and cognitive performance in adulthood in Long-Evans rats. Adolescent rats of both sexes were exposed to either cannabis smoke from postnatal days (P) 29–49 or ascending doses of THC from P35–45. When the rats reached adulthood (P70), anxiety-like behavior was investigated in the large open field and elevated plus maze, depressive-like behavior in the sucrose preference and forced swim tests, and cognitive function in the novel object recognition test. Despite sex differences on some measures in the open field, elevated plus maze, forced swim, and novel object recognition tests, there were no effects of either adolescent cannabis smoke or THC exposure, and only relatively subtle interactions between exposure conditions and sex, such that sex differences on some performance measures were slightly attenuated. Neither cannabis smoke nor THC exposure during adolescence produced robust alterations in adult behavior after a period of abstinence, suggesting that adverse effects associated with adolescent cannabis use might be due to non-cannabinoid concomitants of cannabis use.
TL;DR: The findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-κB-NLRP3 signaling pathway in the brain.
Abstract: Depression is a common but serious mental illness; meanwhile, it is also an inflammatory disorder. Toll-like receptor 4 (TLR4), as the pattern recognition receptor, has been shown to play a vital role in neuroinflammation. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important signaling molecule downstream of TLR4 and can promote the maturation of inflammatory cytokines, such as interleukin-1β (IL-1β). Tetramethylpyrazine (TMP) is a natural compound with neuroprotective effects but with unknown mechanisms on its antidepressant-like effect. In this study, we hypothesized that TMP ameliorates depression may be through the inhibition of the TLR4-NF-κB-NLRP3 signal pathway. Our results have shown that chronic unpredictable mild stress (CUMS) that induced the decreased sucrose preference and increased immobile time was prominently reversed by TMP and fluoxetine. Additionally, we also found that CUMS induced the upregulation of proinflammatory cytokines; TLR4 and NLRP3-associated proteins were significantly suppressed by TMP in the prefrontal cortex and hippocampus. TMP also exhibited potent antioxidant effects and increased the monoamine levels in the serum and brain, such as increasing the activity of SOD and GSH-Px, and reducing the activity of MDA in the serum, and elevating the 5-HT and NE concentration in the serum and brain. Moreover, treatment with Cli-095 (TLR4 inhibitor) also markedly inhibited CUMS-induced depression-like behaviors. Taken together, our findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-κB-NLRP3 signaling pathway in the brain.