Psychopharmacology最新文献

Rationale: The sense of smell plays a key role in guiding motivated behavior, and olfactory function is impaired in clinical populations with dysfunctional approach-avoidance behavior, including major depressive and alcohol use disorder (AUD). However, whether olfactory impairments are also observed in individuals with substance use disorders (SUDs) other than AUD is currently unknown.

Objectives: This study aimed to evaluate the relationship between olfactory function and SUDs.

Methods: We tested olfaction in 40 individuals with substance use disorders (SUDs) other than AUD using the Sniffin' Sticks odor identification and olfactory threshold tests, versus 112 controls. Group differences were assessed with linear regression models, with diagnosis (SUD vs. controls) as a predictor, controlling for age, sex and smoking.

Results: Across a diverse range of substances used, individuals with SUDs had significantly lower identification scores than those in the control group. In contrast, olfactory thresholds did not differ significantly by diagnosis overall. However, exploratory analyses showed that men with SUDs had lower olfactory threshold scores (i.e., higher thresholds) than men in the control group, a difference that was absent in women.

Conclusions: These results suggest that olfactory function is impaired in individuals with SUDs relative to controls. There are several plausible pathways by which differences in olfaction could be related to differences in hedonic processing, but longitudinal studies are needed to clarify the timing of olfactory impairment relative to substance use or SUD symptomatology.

Rationale: Tobacco companies reported that electronic cigarette products were developed to reduce the adverse health effects of conventional cigarettes; however, impairments of lung, brain, and kidney are reported in subjects exposed to electronic cigarettes. Both types contain nicotine in varying amounts, raising concerns about nicotine's toxicity in the body. Studies suggest that modulating glutamate transporters with beta-lactam, ceftriaxone, can reduce nicotine intake.

Objectives: We here tested the pharmacological effects of ceftriaxone and MC-100093 as a novel synthetic beta-lactam, which doesn't have antibiotic action, in mouse model of nicotine self-administration.

Methods: Male C57BL/6 mice were exposed to nicotine-self administration for five weeks, and the effects of ceftriaxone and MC-100,093 on nicotine intake were determined in week 5. Brains were collected for determination of changes in glutamatergic system and neuroinflammatory cytokines levels. Blinded in silico study was conducted to determine the binding properties of ceftriaxone and MC-100093 to glutamate transporter 1 (GLT-1).

Results: The results revealed that MC-100093 and ceftriaxone reduced nicotine self-administration. Both compounds attenuated nicotine-induced downregulation of glutamate transporters such as GLT-1 and cystine/glutamate antiporter (xCT), and this effect was associated with attenuation of nicotine-induced increase in glutamate content in the nucleus accumbens. Furthermore, MC-100093 and ceftriaxone attenuated nicotine-increased in TNF-α and IL-6, which indicate that both compounds have a neuroprotective effect. Additionally, the in-silico docking study predicted that both MC-100093 and ceftriaxone exhibited acceptable binding properties into GLT-1.

Conclusion: Together, these data report potential therapeutic effects of MC-100093 targeting glutamate transporters for treating substance use disorders, particularly tobacco-use disorder.

The chronic unpredictable mild stress (CUMS) paradigm is a well-known preclinical model used to investigate the pathophysiology of stress-induced neuropsychiatric disorders. This review integrates recent findings to elucidate how chronic stress initiates a multifaceted cascade involving neuroendocrine dysregulation, metabolic dysfunction, immune activation and synaptic impairment. Persistent stimulation of hypothalamic-pituitary adrenal (HPA) axis results in hypercortisolaemia, insulin resistance and compromised neuroplasticity through dysregulated BDNF-TrkB signalling, oxidative stress and activation of inflammatory pathways. Compelling evidence highlights both the Gut brain axis (GBA) and epigenetic alterations as central to stress-induced neuropathology. Stress-mediated microbial dysbiosis and intestinal barrier disruption amplify central inflammation through altered tryptophan metabolism and immune neurotransmitter signalling. Simultaneously, epigenetic modification including DNA methylation, histone remodelling and microRNAs encodes transcriptional changes that results in behavioural and cognitive deficits. While, CUMS model offers strong face and predictive validity but its translational relevance is constrained by protocol validity and limited modelling of psychological stressors. Nonetheless, it remains instrumental for evaluating pharmacological and non-pharmacological interventions targeting inflammatory, neurotrophic and metabolic pathways. Future refinement should incorporate biomarker discovery and gene-environment interaction paradigms. In synthesizing these diverse mechanistic insights, this review underscores the value of the CUMS model in identifying system-level therapeutic targets and advancing translational research in stress-related brain disorder.

Rationale: Cannabis is one of the most widely used psychoactive drugs in the United States, yet its long-term effects on brain function remain poorly understood. Prior resting-state functional connectivity (rsFC) studies have yielded inconsistent findings, likely due to variability in cannabis use thresholds, a predominant focus on younger populations, and region-of-interest (ROI)-based approaches limited to a small number of a priori brain regions.

Objectives: We aimed to address these limitations by examining rsFC across the entire brain using an atlas-based, whole-brain, ROI-to-ROI approach in a middle-aged sample (mean age = 41.64 years) of individuals with chronic cannabis use (CCU) and a demographically matched group of controls who did not use cannabis or other illicit substances. Based on the known neuroanatomical distribution of type 1 cannabinoid receptors (CB1Rs), we hypothesized that regions with high CB1R density would be the most affected. However, given our whole-brain approach, we were also sensitive to other regions that may exhibit altered connectivity.

Methods: Using the Automated Anatomical Labeling (AAL) atlas, we computed rsFC matrices across 116 brain regions in 22 adults with CCU and 23 demographically matched controls.

Results: The CCU group showed decreased rsFC (p_FDR< .05) between the right cerebellar Crus II and the left pars triangularis, bilateral pars orbitalis, left superior frontal gyrus, left middle temporal gyrus, and left inferior temporal gyrus compared with the control group. The CCU group also had lower rsFC (p_FDR < .05) between the right cerebellar Crus I and the left pars triangularis compared with controls.

Conclusions: Our findings revealed disrupted rsFC between cerebellar and prefrontal-temporal regions in the CCU group. This study advances the literature by using an atlas-based, whole-brain, ROI-to-ROI approach in a middle-aged sample with sustained cannabis use. Future studies should integrate neuropsychological assessments and task-based paradigms to understand how such alterations in rsFC affect behavioral outcomes.

Rationale: Individuals with methamphetamine use disorder (MUD) can experience significant suffering due to the harmful effects of methamphetamine (METH) on physical and mental health. Although there are no approved medications for MUD, immunotherapies, including monoclonal antibodies (mAb), could serve as treatments for this debilitating condition. Our candidate anti-METH mAb called "devextinetug" features a mouse-derived variable binding region called "7F9" and a humanized constant domain. Our earlier work has shown that devextinetug is effective in altering METH's pharmacological effects. However, it is unknown whether the effectiveness of a chimeric mAb would be altered, or possibly improved, if the variable region were humanized. Moreover, no studies have determined whether onset and offset rates of binding to METH predicts anti-METH effectiveness of mAb candidates.

Objectives: The goals of the present study were to compare the anti-METH effectiveness of a chimeric mAb (called "IS12") that features our parental 7F9 variable region with a panel of mAbs that have fully humanized variable regions, and to determine whether onset and/or offset rates of binding to METH are associated with anti-METH effectiveness.

Methods: We humanized the variable region from ch-mAb7F9 with multiple sequences to produce 48 IgGs. The on and off rates to METH binding were determined for these IgGs and, based on their various onset/offset rats, we chose eight candidate IgGs for further testing (including our parental IS12). All eight IgGs were tested for ligand cross-reactivity and in a METH-elicited locomotor stimulation model in rats.

Results: Cross-reactivity results revealed that IS12 exhibited the greatest affinity to METH, and it also produced the largest reduction in METH-elicited locomotor stimulation compared to the other seven candidates. Furthermore, onset and offset rates of binding to METH did not appear to be associated with reducing METH's in vivo pharmacological effects.

Conclusions: The 7F9 variable region is the most promising to treat MUD.

Rationale: Limited data exist on the potential of nicotine pouches to help smokers quit.

Objectives: To examine nicotine delivery from and user reactions to a popular nicotine pouch.

Methods: Twenty smokers provided data after overnight abstinence, first after smoking a cigarette and then, a week or more later, after using 9 mg nicotine ZYN pouch. Blood samples were collected before and 2, 4, 6, 8, 10 and 30 min (and also 60 min in the pouch condition) after starting product use. Participants also rated their urges to smoke at 5, 10, 15 and 30 minutes, and provided ratings of pouch characteristics at the end of the session.

Results: Pouches delivered nicotine more slowly than cigarettes (Tmax 30 min vs. 6 min, z =-3.93, p < 0.001), though nicotine levels from pouches reached 13 ng/ml within 10 min. Cmax was higher than from cigarettes (27.9 vs. 19.5 ng/ml, t (19) =-2.17, p = 0.043). Both products had the same effect on reducing urges to smoke over 30 min although cigarettes were more effective at 5 min. With pouches, urges to smoke remained low at 60 min. Pouches were rated as delivering more nicotine and being less pleasant than cigarettes; but as effective and as fast in reducing urges to smoke. Three participants who were light smokers experienced nausea and one vomited.

Conclusions: The initial appeal of pouches to smokers is likely to be more limited than the appeal of products that resemble smoking more closely, and ZYN pouches with 9 mg of nicotine may be too strong for light smokers. However, in terms of nicotine delivery and effects on urges to smoke, pouches have good potential to provide effective replacement for smoking.