Psychopharmacology最新文献

Rationale: One of the leading prognosticators of whether an adolescent or young adult will use drugs is whether the person's peers use drugs. Preclinical studies report that cocaine intake increases in the presence of a social partner that is also self-administering cocaine, but it is not known whether this effect extends across reinforcers.

Objectives: The purpose of this study was to examine the role of the reinforcing stimulus in the effects of social contact on cocaine self-administration.

Methods: Male and female Long-Evans rats were implanted with intravenous catheters and trained to self-administer cocaine or a semi-solid palatable food (i.e., vanilla icing) on a fixed ratio (FR1) schedule of reinforcement. All tests were conducted in custom-built operant conditioning chambers that allowed two rats to simultaneously self-administer either cocaine or food while maintaining complete visual, auditory, and olfactory contact with a social partner.

Results: In rats self-administering cocaine, cocaine intake was significantly greater when a partner was also self-administering cocaine relative to when a partner was self-administering food or when a partner was responding under extinction (i.e., no cocaine or food was available). In rats self-administering food, food intake was significantly inhibited when a partner was self-administering cocaine. Econometric analyses revealed that the behavioral mechanisms responsible for the influence of social contact differed across reinforcing stimuli.

Conclusions: These data indicate that social learning processes influencing drug use depend on the reinforcer maintaining the behavior of both the individual and the individual's social partner.

Background: Major Depressive Disorder (MDD) is a common and debilitating condition. Current treatments fail to provide adequate relief in roughly one-third of individuals, resulting in treatment-resistant depression (TRD). Ketamine has emerged as a promising intervention for TRD, offering rapid and sustained antidepressant effects. However, benefits often require maintenance dosing, and long-term outcomes remain unclear. This has promoted interest in adjunctive approaches such as ketamine-assisted psychotherapy (KAP), which combines ketamine with structured psychological support.

Methods: A comprehensive literature search was conducted via the OVID platform using Embase, Medline, Global Health, and APA PsycInfo. Keyword clusters related to "Ketamine," "Diagnosis," and "Psychotherapy" yielded 768 results. Screening followed PRISMA guidelines, resulting in 11 studies meeting inclusion criteria.

Results: The selected studies clustered into two thematic categories: structured, protocol-based interventions and individualized, experiential approaches. Across all studies, KAP was associated with reductions in depressive symptoms, with some improvements sustained up to six months. However, among the three studies with control groups, no significant differences were found between KAP and control conditions. Methodological heterogeneity-including variability in treatment protocols, outcome measures, and study designs-limits the ability to draw firm conclusions or identify mechanisms driving KAP's effects.

Conclusion: KAP shows promise as a treatment for TRD, potentially offering meaningful and sustained symptom relief. However, limited evidence and methodological variability underscore the need for more rigorous research-particularly randomized controlled trials-to better understand its efficacy and mechanisms.

Rationale: Human self-report data and rodent models indicate cocaine can induce negative affect, which may impact future cocaine use severity. Despite this, understanding of the neurobiology driving cocaine avoidance is limited. Within the striatum, the opioid peptides enkephalin and dynorphin are associated with cocaine reward and aversion, respectively. Additionally, striatal dynorphin signaling resulting from stress or cocaine withdrawal acts as a negative reinforcer to increase cocaine seeking.

Objectives: We validated the use of the cocaine self-administration runway in mice to measure the development of cocaine avoidance and tested whether mice with higher relative striatal dynorphin-to-enkephalin expression are resistant to developing cocaine avoidance.

Methods: Cocaine avoidance in the self-administration runway was measured compared to positive (food) and neutral (saline) controls. We tested two inbred mouse strains, C57BL/6J and DBA/2J, known to have opposite striatal dynorphin/enkephalin milieus, and in mice lacking enkephalin selectively from striatal medium spiny neurons (D2-PenkKO).

Results: Both inbred strains developed cocaine avoidance, though they expressed it differently. Across training, DBA/2J mice increased their latency to self-administer cocaine, and C57BL/6J increased the number of retreats away from the cocaine-paired goal box. D2-PenkKOs developed similar cocaine avoidance compared to littermate controls.

Conclusions: Mice develop avoidance to self-administer cocaine in the runway across a range of strains. Pre-existing strain differences in the striatal dynorphin/enkephalin milieu, however, do not appear to alter the development of cocaine avoidance, and striatal enkephalin is not necessary for the development of cocaine avoidance. This suggests higher relative striatal dynorphin does not facilitate cocaine seeking by mitigating cocaine avoidance.

Rationale: Alcohol craving is an antecedent and consequence of drinking. However, there is little research regarding cyclic relations between alcohol-induced craving and drinking behavior occurring during naturalistic drinking episodes.

Objectives: This study tested a theoretical model wherein early-episode craving predicts continued drinking and heightened reinforcing subjective effects, which then are associated with increases in craving and subsequent drinking thereafter.

Methods: Young adults (N = 131) completed 21 days of ecological momentary assessment, including event-contingent reports completed after first drink, followed by assessments 60-minutes and 120-minutes later. Participants self-reported consumption quantity, alcohol craving, and subjective stimulation/relaxation.

Results: Craving during the drink initiation assessment predicted increased consumption over the next 60-minutes, which predicted increased stimulation and decreased relaxation at the 60-minute assessment. Increased stimulation (and decreased relaxation) were then associated with increased craving at the 60-minute assessment, which in turn predicted increased consumption between 60-minute and 120-minute assessments. Thus, early-episode craving predicted increased consumption 60-minutes later, which was then associated with subsequent craving and consumption another 60-minutes later indirectly via increased stimulation and decreased relaxation during the 60-minute assessment. Residual relations between craving and consumption remained. Sensitivity analyses demonstrated that cyclic indirect effects beginning with early-episode craving were only present during binge drinking episodes, and models were unchanged when accounting for early-episode subjective effects. Further, cyclic indirect effects operated through craving but not subjective effects when specified as contemporaneously correlated mediators.

Conclusions: Relations between craving and naturalistic drinking appear to be cyclic processes in young adults, with subjective reinforcement potentially serving a mechanistic role in relations.

Rationale: Opioid withdrawal is a serious obstacle to self-initiated abstinence, and previous experiences of opioid withdrawal may exacerbate the severity of subsequent incidences.

Methods: To study the impact of repeated opioid withdrawal episodes, we compared male and female mice after one or five cycles of fentanyl exposure and withdrawal. We selectively expressed hemagglutinin-tagged ribosomes (RiboTag) in microglia of transgenic mice to immunoprecipitate and sequence RNA actively undergoing translation (the "translatome") from striatal microglia during fentanyl withdrawal. Key changes were confirmed by RTqPCR of RiboTag RNA.

Results: Repeated bouts of fentanyl treatment and withdrawal impacted striatal microglia much more than a single cycle of fentanyl followed by withdrawal. Multiple withdrawal cycles reduced ramification of microglial processes, suggesting a more reactive cell state, and induced more severe behavioral withdrawal signs in mice. Five cycles of fentanyl exposure and withdrawal increased the expression of gene networks associated with innate immunity signaling. Indeed, 100% of the genes associated with the "microglia core sensome", were upregulated after five cycles of withdrawal.

Conclusions: Together these results suggest that mouse striatal microglia initiate a proinflammatory response following five, but not one, opioid exposure and withdrawal experiences and suggest that drug therapies targeting microglial innate immune responses may mitigate the severe withdrawal associated with repeated opioid tolerance and withdrawal.

Rationale/objectives: Major Depressive Disorder is a common and disabling psychiatric illness whose pharmacological treatment options have historically been characterized by relatively low response rates. "Treatment-resistant depression" has emerged to describe patients whose depressive symptoms fail to respond to multiple courses of oral antidepressant medications. In 2019, the FDA approved intranasal esketamine as augmentation to an oral antidepressant in patients with treatment-resistant depression (TRD). While intranasal esketamine's efficacy was demonstrated in Janssen pharmaceutical's drug development program, publications on its real-world use have shown varying degrees of effectiveness. We aim to assess intranasal esketamine's effectiveness in a real-world clinical setting in Hartford, Connecticut, and are among the first to do so in an American sample using the Montgomery-Asberg Depression Rating Scale (MADRS), the same outcome measure used in the clinical trials where efficacy was established.

Methods: In this analysis, a sample of 50 patients were enrolled in an intranasal esketamine treatment program at the Institute of Living (IOL) in Hartford, Connecticut. Information for these patients was obtained through retrospective analysis of the electronic health record. Descriptive statistics were used to analyze symptom severity and outcomes, using the Montgomery-Asberg Depression Rating Scale (MADRS) score at baseline and over 16 weeks of treatment.

Results: Assessment showed that moderate to severe baseline symptoms of depression were reduced to the mild range after 4 weeks and this effect was sustained over 16 weeks of treatment. Adverse effects were transient and generally mild (dissociation and sedation being the most common), with no safety events, and very few discontinuations related to tolerability.

Conclusion: Results of this analysis demonstrate real-world effectiveness of intranasal esketamine as augmentation therapy in treatment resistant depression. The medication was well tolerated, with no safety events, misuse or dependence. While results demonstrating the efficacy of intranasal esketamine in patients with TRD were observed in the clinical trial studies, this analysis shows intranasal esketamine treatment to be safe and effective in a real-world clinical setting.

Rationale: Early life stress (ELS) is associated with an increased risk for alcohol consumption and development of alcohol use disorder (AUD). Inflammation may be a sex-dependent link between ELS and alcohol use; however, there is limited evidence to support such an association in individuals with AUD.

Methods: This secondary analysis utilized cross-sectional mediation to investigate the role of peripheral inflammation in the relationship between ELS and alcohol consumption (i.e., drinks per drinking day (DPDD)) in treatment-seeking individuals with AUD (n = 99; 60 M/39 F). A cross-sectional moderated mediation analysis was conducted to test sex as a moderator in the link between ELS and inflammation for the above relationship. ELS was conceptualized as a dichotomous "no-moderate ELS" vs. "high-ELS" predictor.

Results: High-ELS was associated with higher inflammation (95%CI 0.039,1.558), and higher inflammation was associated with greater DPDD (95%CI 0.024,0.098). A mediation effect emerged where high-ELS influenced greater DPDD through elevated inflammation (ab = 0.044, 95%CI 0.002,0.113). No direct effects between ELS and DPDD emerged (95%CI -0.177,0.108). The interaction between ELS and sex on inflammation was significant for females (95%CI: 0.304,2.719) but not males (95%CI: -0.634,1.270). The mediation relationship between ELS and DPDD through inflammation was significant for females (ab(female) = 0.087, 95%CI: 0.013,0.199) but not males (95%CI: -0.040,0.086).

Conclusions: Findings suggest that ELS is associated with recent alcohol use through peripheral inflammation in treatment-seeking individuals with AUD and indicate that this pathway is sex-dependent. Inflammation may be a treatment target for individuals with AUD who have experienced ELS, especially females.

Clinical trials registration: NCT03594435, registered July 11, 2018.

Rationale: Sleep disturbances are closely associated with cognitive decline and an increased risk of neurodegenerative diseases in humans. This association may be mediated by glymphatic dysfunction, which could ultimately lead to cognitive deterioration.

Objectives: This review aims to provide an overview of current research on the impact of sleep on the functions of the glymphatic system. It analyzes the regulatory roles of the sleep-wake cycle and neurovascular coupling (NVC), along with molecular mechanisms such as astrocytic calcium signaling and aquaporin-4 (AQP4) polarization, intending to identify potential targets for preventing and alleviating cognitive decline and neurodegenerative diseases.

Results: This review summarizes the intrinsic mechanisms by which sleep regulates the metabolic waste clearance capacity of the glymphatic system, highlighting its central role in regulating glymphatic function. Furthermore, it provides a detailed overview of the significant contributions of NVC and astrocytes within this regulatory framework, as well as novel interventions targeting neurodegenerative diseases.

Conclusions: Given that sleep disturbances are a significant factor affecting human cognitive function and neurodegenerative diseases, it is imperative to advance research in this field. Efforts should focus on deepening our understanding of the glymphatic system and its regulatory mechanisms while integrating clinical practice to explore new research directions.