Psychopharmacology最新文献

Rationale: Current treatment options for PTSD have unreliable efficacy, with many individuals unable to achieve complete remission. Cannabis and cannabinoids that act through the endogenous cannabinoid (endocannabinoid) system to help promote trauma recovery by means of enhanced extinction learning are potential therapeutic, pharmacological candidates. Using a preclinical model of translationally-relevant cannabis administration in rodents, we examined the impact of cannabis exposure on aversive memory.

Objectives: Our study investigated the effects of acute cannabis exposure prior to (1) fear conditioning and (2) fear extinction, as well as (3) chronic cannabis exposure prior to fear conditioning, on the behavioural representations of fear memory dynamics in a Pavlovian auditory conditioning paradigm.

Methods: Male and female Sprague Dawley rats were acutely or chronically exposed to THC-dominant cannabis extract or vehicle vapor as described above. We then assessed both passive (freezing) and active (darting) fear behaviours during conditioning, extinction, retrieval, and spontaneous recovery.

Results: Acute cannabis exposure prior to conditioning had no immediate effects on fear acquisition, but impaired fear recall in females 24 h later and prevented spontaneous recovery of conditioned fear following a two-week retrieval test in both male and female rats. Acute cannabis exposure prior to extinction training impaired extinction in females while enhancing extinction acquisition in males. Finally, chronic THC exposure prior to fear conditioning initially potentiated fear responses, predominately in females, but produced no differences in spontaneous recovery in a two-week retrieval test.

Conclusions: Cannabis exposure has complex dynamics on fear memory, however, acute cannabis exposure prior to fear learning appears to result in destabilization of the fear memory long term, which could have potential implications for PTSD.

Rationale: Both topiramate and naltrexone have been shown to affect neural alcohol cue reactivity in alcohol use disorder (AUD). However, their comparative effects on alcohol cue reactivity are unknown. Moreover, while naltrexone has been found to normalize hyperactive localized network connectivity implicated in AUD, no studies have examined the effect of topiramate on intrinsic functional connectivity or compared functional connectivity between these two widely used medications.

Objective: This study compared topiramate versus naltrexone on alcohol cue-elicited brain activation and intrinsic functional connectivity in patients with alcohol use disorder.

Methods: Forty-seven participants with alcohol use disorder received daily topiramate (titrating the dose up to 200 mg/day n = 21) or naltrexone (50 mg/day, n = 26) for at least 6 weeks. Using functional magnetic resonance imaging (fMRI), we examined intrinsic functional connectivity during rest and alcohol cue-elicited neural activation during a visual alcohol cue reactivity task 120 min following treatment administration. Functional connectivity and alcohol cue reactivity and percentage of heavy drinking days (% HDD) associations were assessed.

Results: No differences in either intrinsic functional connectivity or alcohol cue-elicited neural activity were seen between topiramate and naltrexone-treated groups. Overall, participants showed increased alcohol cue-elicited activation in three clusters spanning occipital regions involved in visual recognition of stimuli, and hypoactivation to both alcohol and control cues in three clusters involved in salience attribution and processing of emotional valence of external stimuli. No differences between topiramate versus naltrexone were observed for either functional measure or associations with post-scan % HDD.

Conclusions: Topiramate and naltrexone enacted comparable alcohol cue reactivity and intrinsic functional connectivity patterns. Some overall responses of increased brain activation to alcohol cues in visual processing regions coupled with reduced activation to alcohol and control cues were evidenced for both treatments. These activation patterns were in regions expected to show attenuation of brain activity resulting from treatment. Topiramate and naltrexone may thus enact functional effects through similar modulation of functional neural activity in individuals with AUD.

Trial registration: ClinicalTrials.gov, NCT03479086 https://www.

Clinicaltrials: gov/study/NCT03479086 .

Rationale: Psilocybin shows promise for treating neuropsychiatric disorders. However, insight into its acute effects on cognition is lacking. Given the significant role of executive functions in daily life and treatment efficacy, it is crucial to evaluate how psilocybin influences these cognitive domains.

Objectives: This meta-analysis aims to quantify the acute effects of psilocybin on executive functions and attention, while examining how dosage, timing of administration, cognitive domain, and task characteristics moderate these effects.

Methods: A systematic review and multilevel meta-analysis were conducted on empirical studies assessing psilocybin's acute effects on working memory, conflict monitoring, response inhibition, cognitive flexibility, and attention. Effect sizes for reaction time (RT) and accuracy (ACC) were calculated, exploring the effects of timing (on-peak defined as 90-180 min post-administration), dosage, cognitive function categories, and task sensitivity to executive functions as potential moderators.

Results: Thirteen studies (42 effect sizes) were included. In the acute phase, psilocybin increased RTs (Hedges' g = 1.13, 95% CI [0.57, 1.7]) and did not affect ACC (Hedges' g = -0.45, 95% CI [-0.93, 0.034]). Effects on RT were dose dependent. Significant between-study heterogeneity was found for both RT and ACC. Task sensitivity to executive functions moderated RT effects. Publication bias was evident, but the overall effect remained significant after adjustment for this.

Conclusions: Our meta-analysis shows that psilocybin impairs executive functions and results in a slowing down of RT. We discuss potential neurochemical mechanisms underlying the observed effects as well as implications for the safe use of psilocybin in clinical and experimental contexts.

Rationale and objectives: In vivo receptor interactions vary as a function of behavioral endpoint, with key differences between reflexive and non-reflexive measures that assess the motivational aspects of pain and pain relief. There have been no assessments of D₁ dopamine agonist / mu opioid receptor (MOR) agonist interactions in non-reflexive behavioral measures of pain. We examined the hypothesis that D₁/MOR mixtures show enhanced effectiveness in blocking pain depressed behaviors while showing decreased side effects such as sedation and drug reward.

Methods: SKF82958 and methadone were used as selective/high efficacy D₁ and mu agonists, respectively. An FR10 operant schedule was utilized in the presence and absence of a lactic acid inflammatory pain-like manipulation, to measure antinociceptive and operant-rate-suppressing effects, respectively. Rewarding properties of the drug combinations were determined using a conditioned place preference procedure.

Results: Methadone alone, but not SKF82958 alone, produced dose-dependent restoration of pain-depressed responding. Both SKF82958 and methadone produced dose-dependent response rate suppression. Three fixed proportion mixtures, based on the relative potencies of the drugs in the rate suppression assay, produced dose-dependent antinociception and sedation. Isobolographic analysis indicated that the 0.17:1 mixture produced supra-additive antinociception and additive sedation. The 0.055:1 mixture produced additive antinociception with sub-additive sedation, and the 0.018:1 mixture had the highest therapeutic index (TI) relative to other mixtures and drugs alone. The antinociceptive doses and component doses for the 0.018:1 mixture did not produce conditioned place preference.

Conclusions: These results suggest that D₁-selective dopamine agonists may have utility as candidate opioid-sparing analgesics.

Rationale: To examine the acute effects of ayahuasca use and their relationship to sub-acute changes in affect and mindfulness in a non-clinical sample, addressing the need for a better understanding of ayahuasca's immediate and short-term impacts as interest in its use grows.

Objectives: Using prospective ecological assessment, this study investigates how ayahuasca used at a 4-day retreat affects positive/negative affect and mindfulness skills in daily living compared to pre-retreat. Additionally, we explore acute psychedelic experiences during the ayahuasca retreat, assessed retrospectively 1-2 days post-retreat, as potential mechanisms for theorized effects in daily living post-retreat.

Methods: Thirty-six participants reported positive/negative affect and mindfulness skills three times daily for 5 days before and after the retreat. Baseline assessments included lifetime psychedelic experience, and post-retreat assessments covered acute ayahuasca experiences. Mixed-effect linear models were used to analyze the data.

Results: Post-retreat, we observed reduced negative affect, increased positive affect, and enhanced mindfulness skills in daily living. Ayahuasca-induced acute experiences, such as time/space transcendence, emotional breakthrough and challenging experiences predicted greater subacute positive affect. Notably, none of these experiences were linked to subacute improvements in negative affect or mindfulness. No participants showed clinically significant adverse responses post-retreat, and only 5.5% exhibited some degree of potentially clinically significant deterioration in affect.

Conclusions: Ayahuasca use may lead to improvement in mood and mindfulness skills, and key acute psychedelic experiences induced by ayahuasca may be important to some of these salutary effects, positive affect in particular.

Rationale: One of the most debilitating drawbacks of cisplatin chemotherapy is neurotoxicity which elicits memory impairment and cognitive dysfunction (chemobrain). This is primarily triggered by oxidative stress and inflammation. Captopril, an angiotensin-converting enzyme inhibitor, has been reported as a neuroprotective agent owing to its antioxidant and anti-inflammatory effects.

Objective: We examined the possible neuroprotective effect of captopril against cisplatin-induced neurological and behavioral abnormalities in rats.

Methods: Chemobrain was induced in rats by cisplatin (5 mg/kg, i.p.) on the 7th and 14th days of the study while captopril was administered orally (25 mg/kg) daily for three weeks. The effects of captopril were assessed by performing behavioral tests, histological examination, and evaluation of oxidative stress and inflammatory markers.

Results: Cisplatin caused learning/memory dysfunction assessed by passive avoidance and Y-maze tests, decline in locomotion, and rotarod motor balance loss which were further verified by neurodegeneration observed in histological examination. Also, cisplatin aggravated oxidative stress by elevating lipid peroxidation (MDA) levels and diminishing catalase activity. Moreover, cisplatin upregulated the neuroinflammatory markers (TNF, IL-6, GFAP, and NF-κB). Captopril successfully ameliorated cisplatin damage on the levels of neurobehavioral and histopathological changes. Mechanistically, captopril significantly diminished MDA production and preserved catalase antioxidant activity. Captopril also counteracted neuroinflammation through inhibiting NF-κB and its downstream proinflammatory cytokines besides repressing astrocyte activity by reducing GFAP expression.

Conclusion: Our findings revealed that captopril could abrogate cisplatin neurotoxicity via reducing oxidative stress and neuroinflammation thus enhancing cognitive and behavioral performance. This could suggest the repurposing of captopril as a neuroprotective agent, especially in hypertensive cancer patients receiving cisplatin.

Rationale: Rapid adaptation to stressful events is essential for survival and requires acute stress response and stress-coping strategy. However, the molecular mechanisms that govern this coping strategy have yet to be fully discovered.

Objectives: This study aims to investigate the effects of poly ADP-ribosylation (PARylation) on stress-coping strategies following acute stress and to identify the target genes influenced by Parp1-induced histone PARylation.

Methods: Mice were subjected to a forced swim test, a well-established acute stress paradigm, to evaluate cortical PARylation and assess the expression of activity-dependent genes. The pharmacological inhibition of Parp1 was conducted using ABT888 (Veliparib) to determine its effects on stress-coping behavior and related molecular changes.

Results: The forced swim test increased cortical PARylation and upregulated the expression of activity-dependent genes. Systemic inhibition of Parp1 with ABT888 led to impaired stress-coping behavior, evidenced by a reduced immobility response during a subsequent forced swim test done 24 hours later. This impairment was associated with decreased chromatin PARylation and histone H4 acetylation at the Arc promoter and reduced Arc expression observed one hour after Parp1 inhibition.

Conclusion: Our findings indicate that chromatin PARylation at the Arc promoters regulates histone H4 acetylation and Arc gene expression, and a subsequent impact on successful stress-coping behavior in response to acute stress.

Rationale: Chronic stress is one of the leading causes of depression. Yet, knowledge of the pathomechanism of this process still eludes us. Chronic unpredictable mild stress (CUMS) model of depression enables researchers to look for a root cause of the disease in mice by mimicking a stressful human environment.

Objective: Since zinc has already been shown to impact the treatment of depression, in our study we aimed to shed light on the role of the zinc receptor GPR39 in stress-induced depression. We also aimed to highlight the role of GPR39 activation in monoamine-based antidepressant treatment.

Methods: Using large battery of behavioural tests, we provided a detailed description of CUMS-induced phenotype in both - CD-1 and GPR39 knock-out mice.

Results: Our experiments showed that combined treatment with TC-G 1008 (GPR39 agonist) and antidepressants produces stronger antidepressant-like effect of classic antidepressants. We also demonstrated the inter-strain differences in stress response and the greater stress susceptibility of GPR39 knock-out mice. The lack of GPR39 expression also either diminished or completely abolished the response to treatment with different antidepressants combined with TC-G 1008.

Conclusions: The results show that GPR39 KO mice are more susceptible to chronic stress and that they are non-responsive to SSRI treatment. Utilizing various behavioural tests gave us much broader understanding not only of the role of GPR39 in depression treatment, but also of the importance of detailed behavioural description in a proper interpretation of the results. Further research with known selective agonists and antagonists of GPR39 will be necessary to understand the full potential of this receptor as a pharmacological target.

Rationale: Psychedelic-assisted therapy is increasingly applied within mental health treatment.

Objectives: This study focused on factors moderating changes in the acute and long-term effects of an individual psilocybin-assisted program on depression, anxiety, PTSD and personality structures by including demographic factors, subjective experience and degree of mystical type experiences during the dosing, as well as emotional breakthrough and personal growth after the program.

Methods: At baseline, 1 week and 3 months after the psilocybin program participants completed the Generalized Anxiety Disorder Assessment (GAD-7), Patient Health Questionnaire (PHQ-9), PTSD Checklist for DSM-5 (PCL-5) and NEO Five-Factor Inventory-3 (NEO-FFI-3). In addition, after the dosing the Mystical Experiences Questionnaire (MEQ-30), Posttraumatic Growth Inventory (PTGI) and Emotional Breakthrough Inventory (EBI) were administered. Moderation effects were established using linear mixed-model analysis.

Results: A single high dose of psilocybin in combination with therapy was found to lower symptoms of anxiety, depression, PTSD and neuroticism over a period of 3-months. Scores on openness and conscientiousness increased after the treatment only. Participants reported mystical type experiences, emotional breakthrough and personal growth. These subjective experiences together with demographic factors were moderating the observed positive changes.

Conclusions: Findings indicate that individual psilocybin-assisted therapy has the potential for beneficial effects on mood and personality characteristics. Moreover, the study highlights the importance of subjective experiences and demographic factors in moderating this effect. This study adds to the ongoing research on psilocybin-assisted therapy by investigating contributing factors for optimizing this evolving type of therapy.

Rationale: Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior.

Objectives: We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice.

Methods: C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol.

Results: Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC.

Conclusions: CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.