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Rationale: Methamphetamine addiction is a persistent and intractable pathological learning and memory, whereas no approved therapeutics is available. However, few attentions have been paid to how associative learning participates in the formation of intractable memory related to drug addiction OBJECTIVES AND METHODS: To investigate the role of associative learning in methamphetamine addiction and the underlying neurobiological mechanism, methamphetamine self-administration, oral sucrose self-administration, chemogenetic neuromanipulation, and fiber photometry in mice were performed in this study., Results: We reported that associative learning increased methamphetamine-induced self-administration, but not oral sucrose self-administration. In addition, the enhancement of methamphetamine-induced self-administration was independent of more methamphetamine consumption, and remained with higher drug-taking and motivation in the absence of visual cues, suggesting the direct effects of the associative learning that enhanced methamphetamine-induced self-administration. Moreover, chemogenetic inactivation of the secondary visual cortex (V2) reduced the enhancement of the drug-taking induced by associative learning but did not alter sucrose-taking. Further fiber photometry of V2 neurons demonstrated that methamphetamine-associative learning elicits V2 neuron excitation, and sucrose-associative learning elicits V2 neuron inhibition., Conclusions: Therefore, this study reveals the neurobiological mechanism of V2 excitability underlying how associative learning participates in the formation of intractable memory related to drug addiction, and gives evidence to support V2 as a promising target for stimulation therapy for methamphetamine addiction., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Theories of addiction guide scientific progress, funding priorities, and policy development and ultimately shape how people experiencing or recovering from addiction are perceived and treated. Choice theories of addiction are heterogenous, and different models have divergent implications. This breeds confusion among laypeople, scientists, practitioners, and policymakers and reduces the utility of robust findings that have the potential to reduce the global burden of addiction-associated harms., Objective: Here we differentiate classes of choice models and articulate a novel framing for a class of addiction models, called contextual models, which share as a first principle the influence of the environment and other contextual factors on behavior within discrete choice contexts., Results: These models do not assume that all choice behaviors are voluntary, but instead that both proximal and distal characteristics of the choice environment-and particularly the benefits and costs of both drug use and non-drug alternatives-can influence behavior in ways that are outside of the awareness of the individual. From this perspective, addiction is neither the individual's moral failing nor an internal uncontrollable urge but rather is the result of environmental contingencies that reinforce the behavior., Conclusions: Contextual models have implications for guiding research, practice, and policy, including identification of novel target mechanisms while also improving existing interventions., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Synthetic cannabinoid receptor agonists (SCRAs) may be used as an alternative to natural cannabis; however, they may carry a greater risk of problematic use and withdrawal. This study aimed to characterise the withdrawal symptom profile of SCRAs and compare their profile of effect with high-potency herbal cannabis. Global Drug Survey data (2015 and 2016) were used to access a clinically relevant sample of people reporting use of SCRAs >10 times in the past 12-months, a previous SCRA quit attempt, and lifetime use of high-potency herbal cannabis. Participants completed an 11-item SCRA withdrawal symptom checklist and compared SCRAs and high-potency herbal cannabis on their onset and duration of effects, speed of the development of tolerance, severity of withdrawal, and difficulty with dose titration. Participants (n = 284) reported experiencing a mean of 4.4 (95% CI: 4.1, 4.8) withdrawal symptoms after not using SCRAs for >1 day; most frequently reported were sleep issues (59.2%), irritability (55.6%), and low mood (54.2%). Withdrawal symptoms were significantly associated with frequency (>51 vs. 11-50 times per year: IRR = 1.43, 95% CI: 1.16, 1.77, p = 0.005) and quantity (grams per session: IRR = 1.13, 95% CI: 1.05, 1.22, p = 0.001) of SCRA use. Compared to high-potency herbal cannabis, SCRAs were rated as having a faster onset and shorter duration of effects, faster development of tolerance, and more severe withdrawal (p's < 0.001). In conclusion, SCRA withdrawal symptoms are more likely to occur after greater SCRA exposure. The effects of SCRA indicate a more severe withdrawal syndrome and a greater risk of problematic use than natural cannabis., (© 2021. The Author(s).)

Rationale: There has been increasing attention on cannabis use for medical purposes, but there is currently a lack of data on its epidemiology., Objectives: To examine the epidemiology of self-reported cannabis use for medical purposes by (1) estimating its prevalence, (2) comparing gender and age differences, and (3) investigating what reasons they were used to manage., Methods: Participants included 27,169 respondents (aged 16-65) who completed Wave 1 of The International Cannabis Policy Study (ICPS) conducted across Canada and the USA in 2018 via online surveys. Cannabis policy conditions were "US legal-recreational" (legal for both recreational and medical uses), "US legal-medical only", "US illegal", and "Canada-medical only"., Results: The overall prevalence of self-reported ever cannabis use for medical purposes was 27%, with similar rates by sex and the highest prevalence in young adults. Prevalence was higher in US legal-recreational states (34%) than US illegal states (23%), US legal-medical only states (25%), and Canada (25%). The most common physical health reasons include use to manage pain (53%), sleep (46%), headaches/migraines (35%), appetite (22%), and nausea/vomiting (21%). For mental health reasons, the most common were for anxiety (52%), depression (40%), and PTSD/trauma (17%). There were 11% who reported using cannabis for managing other drug or alcohol use and 4% for psychosis., Conclusions: A substantial proportion of the North American population self-reported cannabis use for medical purposes for a variety of medical reasons, including those living in jurisdictions without legal markets. Further research is needed to understand the safety and efficacy of these forms of medical cannabis use., (© 2022. The Author(s).)

Rationale: Methylphenidate (MPH) and mixed D,L-amphetamine salts (MASs; Adderall) were previously found to have unreliable effects on judgment and decision processes., Objective: We predicted that MPH and MASs have a specific effect of reducing heuristic responses, which should lead to increased performance on the cognitive reflection test (CRT). The CRT is considered to be a testbed for heuristic versus deliberative response modes., Methods: We recruited a sample of 15,361 individuals using the Prolific Academic crowdsourcing platform. From this initial pool, our final sample consisted of 294 participants (125 MPH users and 169 MASs users) who conformed to the study criteria and completed the experimental tasks. Tasks were performed on days where participants were either medicated or not, allowing to assess the effect of medication status., Results: There was a strong positive effect of taking MPH on CRT scores (Cohen's d = 0.40) which was not qualified by frequency of MPH usage, ADHD symptoms, and demographic factors. There was also a somewhat weaker effect for MASs (Cohen's d = 0.07). No effects of MPH and MASs were recorded for risk-taking and numeracy., Conclusions: The results indicate that MPH enhances decision-making in tasks where heuristic responses typically bias it., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Isobutyryl-carfentanyl is the most recently discovered fentanyl analogue with a chemical structure that is similar to that of carfentanyl. Its analogue, carfentanyl, is regarded as one of the most lethal drugs in the world, with a potency of 10,000 times that of morphine. Therefore, isobutyryl-carfentanyl may possess a comparably high potency and its harmful effects cannot be ignored., Objectives: This study was designed to assess the analgesic effect of isobutyryl-carfentanyl and the potential risks associated with its misuse., Methods: In this study, we assessed the acute toxicity of isobutyryl-carfentanyl by up-and-down-procedure, the analgesic efficacy by hot-plate test, the abuse potential by conditioned place preference (CPP), drug self-administration, and drug discrimination tests, and compared it with fentanyl and carfentanyl., Results: The estimated median lethal dose (LD 50 ) of isobutyryl-carfentanyl administered were 175 mg/kg (intragastric administration, IG), 15.84 mg/kg (intraperitoneal injection, IP), 15.84 mg/kg (subcutaneous injection, SC), and 1.6 mg/kg (intravenous injection, IV), respectively. The 50% maximal analgesic effect (ED 50 ) of isobutyryl-carfentanyl was determined to be 0.00319 mg/kg, with an analgesic potency 14 times that of fentanyl and 0.82 times that of carfentanyl. Isobutyryl-carfentanyl exhibited a significant positional preference at a minimum dose of 0.1 mg/kg, while fentanyl exhibited a significant positional preference at a minimum dose of 0.3 mg/kg. In the heroin (0.05 mg/kg/infusion) self-administration substitution experiment, isobutyryl-carfentanyl showed significant self-administration behaviour at doses of 0.0005-0.001 mg/kg/infusion, with the maximum number of infusions observed at a dose of 0.001 mg/kg. In the heroin (1 mg/kg) drug discrimination experiment, fentanyl (0.005-0.02 mg/kg), carfentanyl (0.0005-0.002 mg/kg), and isobutyryl-carfentanyl (0.001-0.005 mg/kg) were tested in the dose-effect curves. The results showed that all three drugs exhibit dose-dependent increase in the number of drug-associated nose pokes responses and reduction in the rate of nose pokes. The subjective effect potency of isobutyryl-carfentanyl was found to be 4.4 times that of fentanyl and 0.5 times that of carfentanyl., Conclusions: In summary, isobutyryl-carfentanyl has high acute toxicity and analgesic effect, with strong psychological dependence approximately 5 times that of fentanyl and 0.5 times that of carfentanyl, and has extremely high abuse potency., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors in rodents. On the other hand, lithium, as one of the oldest drugs used in neuropsychiatric disorders, is still one of the best drugs for the treatment and control of bipolar disorder. In this study, we aimed to investigate the role of chronic short-term REM SD in the induction of manic-like behaviors in female rats., Methods: The rats were exposed to REM SD for 14 days (6 hours/day). Lithium was intraperitoneally injected at the doses of 10, 50, and 100 mg/kg., Results: REM SD induced hyperactivity and OCD-like behavior, and decreased anxiety, depressive-like behavior, and pain subthreshold. REM SD also impaired passive avoidance memory and decreased hippocampal brain-derived neurotrophic factor (BDNF) expression level. Lithium at the doses of 50 and 100 mg/kg partly and completely abolished these effects, respectively. However, lithium (100 mg/kg) increased BDNF expression level in control and sham REM SD rats with no significant changes in behavior., Conclusions: Chronic short-term REM SD may induce a mania-like model and lead to OCD-like behavior and irritability. In the present study, we demonstrated a putative rodent model of mania induced by chronic REM SD in female rats. We suggest that future studies should examine behavioral and mood changes following chronic REM SD in both sexes. Furthermore, the relationship between manic-like behaviors and chronic REM SD should be investigated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Depressed individuals demonstrate debilitating symptoms, including depressed mood, anhedonia, and effort-related deficits. Effort-related decision-making can be measured through providing subjects with a choice between high effort/reward and low effort/reward options, which is a dopamine (DA)-dependent behavior. While previous research has shown sex differences in depression rates, this has not been examined within operant-based effort-related decision-making tasks nor has DA been shown to underlie this behavior in female rats., Objectives: The current study investigated sex differences in an effort-related decision-making task prior to and following administration of the DA D2 receptor antagonist haloperidol (HAL)., Methods: Adult rats were food restricted or fed freely and trained in an effort-related progressive ratio choice task. After stable responding, HAL was administered acutely (0.05-0.2 mg/kg) prior to testing., Results: Results indicate a significant effect of sex on training variables, with males having a greater number of lever presses, higher ratios, and longer active lever times. Pretreatment with HAL significantly reduced the same measures in both sexes for the high-valued reward, while increasing chow consumption in the food restricted males. Food restricted rats showed a greater number of total lever presses and achieved higher ratios; however, the effect in male food restricted rats was greatest., Conclusions: These data suggest that, although there are sex differences in training, HAL decreases behavior across sexes, demonstrating that the D2 mechanism is similar in both sexes. These findings provide a better understanding of motivational dysfunction in both sexes and potential treatment targets for depression.

Nowadays, high morbidity and mortality of cardiovascular diseases (CVDs) and high comorbidity rate of neuropsychiatric disorders contribute to global burden of health and economics. Consequently, a discipline concerning abnormal connections between the brain and the heart and the resulting disease states, known as psychocardiology, has garnered interest among researchers. However, identifying a common pathway that physicians can modulate remains a challenge. Gut microbiota, a constituent part of the human intestinal ecosystem, is likely involved in mutual mechanism CVDs and neuropsychiatric disorder share, which could be a potential target of interventions in psychocardiology. This review aimed to discuss complex interactions from the perspectives of microbial and intestinal dysfunction, behavioral factors, and pathophysiological changes and to present possible approaches to regulating gut microbiota, both of which are future directions in psychocardiology., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Schizophrenia and autism spectrum disorder have long been associated with elevated levels of various small phenolic molecules (SPMs). In turn, the gut microbiota (GMB) has been implicated in the kinetics of many of these analytes. Unfortunately, research into the possible relevance of GMB-mediated SPMs to neuropsychiatry continues to be limited by heterogeneous study design, numerous sources of variance and technical challenges. Some SPMs have multiple structural isomers and most have conjugates. Without specialized approaches, SPMs can be incorrectly assigned or inaccurately quantified. In addition, SPM levels can be affected by dietary polyphenol or protein consumption and by various medications and diseases. Nonetheless, heterotypical excretion of various SPMs in association with schizophrenia or autism continues to be reported in independent samples. Recent studies in human cerebrospinal fluid demonstrate the presence of many SPMs A large number of these are bioactive in experimental models. Whether such mechanisms are relevant to the human brain in health or disease is not known. Systematic metabolomic and microbiome studies of well-characterized populations, an appreciation of multiple confounds, and implementation of standardized approaches across platforms and sites are needed to delineate the potential utility of the phenolic interactome in neuropsychiatry.

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by reviewing aberrant 5-HT 1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT 1A receptor agonist properties-and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform activity, suggesting a similarity to electroconvulsive therapy. It is also noted that "reactivations," the sudden re-experiencing of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms in research settings and among naturalistic users are warranted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)