Neuropsychopharmacology最新文献

Despite the rise in electronic cigarette use in recent years, the neurobiological effects of daily e-cigarette use versus smoking cigarettes in young adults remains unknown. This study aimed to investigate the impact of regular, exclusive e-cigarette use on grey matter morphometry in young adults, age 18-25. Structural MRI data were collected from 3 distinct groups of participants (n = 78): daily, exclusive e-cigarette users; tobacco cigarette users; and non-using controls, to assess grey matter volume (GMV) differences. Voxel-based morphometry revealed significant GMV reductions in tobacco cigarette users in the left fusiform gyrus (FG), left and right inferior temporal gyrus (IFG), right middle temporal gyri, and right middle cingulate gyrus (MCG), compared to controls, as well as the anterior cingulate cortex (ACC), compared to both e-cigarette users and controls, even after adjusting for nicotine exposure history. Partial correlation analyses revealed that in tobacco cigarette users, GMV in the FG, ITG, MTG, and MCG displayed a strong, negative association with exposure history but not with nicotine dependence. GMV of the ACC was not associated with duration of use or nicotine dependence score, suggesting distinct relationships between ACC volume and smoking status and FG/ITG/MTG/MCG volume and smoking status. This indicates a distinct difference between regular tobacco cigarette and e-cigarette use, perhaps a relatively safer profile of e-cigarette use on GMV. These findings suggest that factors beyond nicotine, such as other toxicants in tobacco cigarette smoke, may contribute to the observed brain atrophy, or imply potential pre-existing vulnerabilities that might predispose individuals to take up smoking.

While Cannabis use disorder (CUD) is twice as prevalent in males, females transition more quickly from heavy use to CUD and experience more severe withdrawal. These clinically relevant sex differences contrast the lack of knowledge about the underlying brain mechanisms. This study investigated the relationship between CUD and resting-state functional brain connectivity (RSFC), assessing potential sex differences herein. RSFC of the Salience Network (SN), Basal Ganglia Network (BGN), Executive Control Network (ECN), and Default Mode Network (DMN) was compared between 152 individuals (76 males) with CUD and 114 matched controls (47 males). Within the CUD group, relationships between RSFC and heaviness of cannabis use, age of onset, and CUD symptom severity, along with their associations with sex, were investigated. CUD and control groups showed similar RSFC across all networks, regardless of sex. In the CUD group, heavier cannabis use correlated with higher RSFC across all networks and earlier age of onset was related to higher RSFC in the anterior SN, BGN, left ECN, and dorsal DMN. These associations were similar for males and females. CUD severity was related to higher RSFC in the anterior SN, which was moderated by sex, with a positive association seen only in males. In conclusion, CUD may not necessarily be associated with altered RSFC. Individual use characteristics such age of onset and severity of use may determine the potential impact of cannabis use on RSFC in a largely similar way in males and females.

Stress is a recognized risk factor for Parkinson's disease (PD), but the mechanisms by which stress exacerbates PD symptoms through the serotonergic system are not fully understood. This study investigates the role of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) in mediating stress-induced motor deficits and PD progression. Acute and chronic stress were induced in mice using an elevated platform (EP) and combined with MPTP administration to model early-stage PD. Acute EP stress caused transient motor deficits and significant activation of DRN^5-HT neurons projecting to substantia nigra compacta (SNc) dopaminergic (DA) neurons. Manipulating the DRN-SNc pathway with optogenetics and chemogenetics confirmed its critical role in stress-induced motor deficits. Activation of the SNc 5-HT2C receptor with an agonist replicated these deficits, while receptor inhibition prevented them, underscoring its importance. Chronic EP stress worsened MPTP-induced deficits and caused significant SNc^DA neurons loss, suggesting it accelerates PD progression. Prolonged chemogenetic inhibition of the DRN-SNc circuit mitigated chronic stress effects in MPTP-treated mice. These findings highlight the crucial role of the DRN-SNc serotonergic circuit and 5-HT2C receptors in stress-related motor deficits, suggesting potential targets for therapies aimed at treating both stress-related motor disorders and Parkinson's disease.

The pharmacologically active (R,S)-ketamine (ketamine) metabolite (2 R,6 R)-hydroxynorketamine (HNK) maintains ketamine's preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop an in vitro hippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that enhanced N-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours after in vivo dosing. We used this model to reveal novel mechanisms engaged in HNK's temporally-sensitive antidepressant-relevant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK's rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and our incubation model may aid in revealing novel pharmacological targets.

Neuropathic pain, which has become a major public health concern, is frequently accompanied by the deterioration of affective behavior and cognitive function. However, the brain circuitry underlying these changes is poorly understood. Therefore, we aimed to identify in a mouse model the converging circuit that influences the sensory, affective, and cognitive consequences of neuropathic pain. The lateral habenula (LHb) and ventral tegmental area (VTA) have been confirmed to play critical roles in the regulation of pain, cognition, and depression. Given the essential role of the LHb in depression and cognition, we attempted to clarify how neural circuitry involving the LHb integrates pain-related information. Our data confirmed that the VTA receives projections from the LHb, but our results suggest that inhibition of this direct pathway has no effect on the behavior of mice with chronic neuropathic pain. The rostromedial tegmental nucleus (RMTg), a GABAergic structure believed to underlie the transient inhibition of DAergic neurons in the VTA, received glutamatergic inputs from the LHb and projected strongly to the VTA. Furthermore, our data suggest that a projection from LHb glutamatergic neurons to RMTg GABAergic neurons in the VTA, constituting an indirect LHb^Glu → RMTg^GABA → VTA^DA pathway, participates in peripheral nerve injury-induced nociceptive hypersensitivity, depressive-like behavior, and cognitive dysfunction. Ex vivo extracellular recordings of LHb neurons showed that the proportion of burst-firing cells in the LHb was significantly increased in indirect projections rather than in direct projections. This may explain the functional discrepancies between direct and indirect projections of the LHb to the VTA. Collectively, our study identifies a pivotal role of the LHb^Glu → RMTg^GABA → VTA^DA pathway in processing pain. This pathway may offer new therapeutic targets to treat neuropathic pain and its associated depressive-like and cognitive impairments.

Individual differences in brain intrinsic functional connectivity (FC) and reactivity to nicotine cues are linked to variability in clinical outcomes in nicotine dependence. However, the relative contributions and potential interdependencies of these brain imaging-derived phenotypes in the context of craving and nicotine dependence are unclear. Moreover, it is unknown whether these relationships differ in individuals who smoke versus vape nicotine. To investigate these questions, eighty-six individuals who use nicotine daily (n = 67 smoking, n = 19 vaping) completed either a smoking or vaping cue-reactivity task and a resting-state scan during functional magnetic resonance imaging (fMRI). Validating the efficacy of the smoking and vaping tasks, both cohorts displayed robust reactivity to nicotine versus neutral cues in the default mode network (DMN) and the anterior insula (AI), a primary node of the salience network (SN), which did not habituate over time. In the smoking and vaping groups, lower prefrontal reactivity to nicotine versus neutral cues and greater resting-state FC between nodes of the SN and DMN were associated with higher cue-induced craving. Moreover, we found that the former partially mediated the latter, suggesting a mechanism in which high resting SN-DMN connectivity increases craving susceptibility partly via a constraining effect on regulatory prefrontal reactivity to cues. These relationships were not impacted by group, suggesting that links between brain function and craving are similar regardless of smoking or vaping nicotine.

Neuroimaging research has yet to elucidate whether reported gray matter volume (GMV) alterations in major depressive disorder (MDD) exist already before the onset of the first episode. Recruitment of presently healthy individuals with a subsequent transition to MDD (converters) is extremely challenging but crucial to gain insights into neurobiological vulnerability. Hence, we compared converters to patients with MDD and sustained healthy controls (HC) to distinguish pre-existing neurobiological markers from those emerging later in the course of depression. Combining two clinical cohorts (n = 1709), voxel-based morphometry was utilized to analyze GMV of n = 45 converters, n = 748 patients with MDD, and n = 916 HC in a region-of-interest approach and exploratory whole-brain. By contrasting the subgroups and considering both remission state and reported recurrence at a 2-year clinical follow-up, we stepwise disentangled effects of (1) vulnerability, (2) the acute depressive state, and (3) an initial vs. a recurrent episode. Analyses revealed higher amygdala GMV in converters relative to HC (p_tfce-FWE = 0.037, d = 0.447) and patients (p_tfce-FWE = 0.005, d = 0.508), remaining significant when compared to remitted patients with imminent recurrence. Lower GMV in the dorsolateral prefrontal cortex (p_tfce-FWE < 0.001, d = 0.188) and insula (p_tfce-FWE = 0.010, d = 0.186) emerged in patients relative to HC but not to converters, driven by patients with acute MDD. By examining one of the largest available converter samples in psychiatric neuroimaging, this study allowed a first determination of neural markers for an impending initial depressive episode. Our findings suggest a temporary vulnerability, which in combination with other common risk factors might facilitate prediction and in turn improve prevention of depression.

Acute intoxication from Δ9-tetrahydrocannabinol (THC, the primary active ingredient of cannabis) can lead to neurocognitive impairment and interference with day-to-day operations, such as driving. Present evaluations of THC-induced impairment in legal settings rely on biological drug tests that solely establish cannabis use, rather than cannabis impairment. The current study evaluated the metabolome in blood collected from occasional and chronic cannabis users (N = 35) at baseline and following treatments with cannabis (300 μg/kg THC) and placebo, with the aim to identify unique metabolic alterations that are associated with acute cannabis intoxication and cannabis use frequency. Blood samples were collected at baseline and repeatedly during 70 min after treatment. Sustained attention performance and ratings of subjective high were taken twice within 40 min after treatment. Metabolomic fingerprints of occasional and chronic cannabis users were distinctly different at baseline, when both groups were not intoxicated. A total of 14 metabolites, mainly related to endocannabinoid and amino acid metabolism, were identified that distinguished chronic from occasional cannabis users and that yielded a discriminant analysis model with an 80% classification rate (95% CI: 61-91%). Distinct metabolomic fingerprints were found for occasional cannabis users who, in contrast to chronic cannabis users, showed attentional impairment and elevated ratings of subjective high during cannabis intoxication. These included increments in organic acids, β-hydroxybutyrate and second messenger ceramides. The current study demonstrates the feasibility of the metabolomics approach to identify metabolic changes that are specific to the neurocognitive state of cannabis intoxication and to the history of cannabis use.

Accumulating evidence indicates that drug addiction may lead to adaptive behavioral changes in offspring, potentially due to epigenetic modifications in parental germline. However, the underlying mechanisms remain inadequately understood. In this study, we show that paternal heroin self-administration (SA) increased heroin-seeking behavior in the F1 generation, when compared with offspring sired by yoke-infused control males, indicating cross-generational impact of paternal voluntary heroin seeking behavior. Notably, the increase of heroin seeking behavior in offspring was replicated by zygotic microinjection of sperm RNAs derived from sperm of heroin-SA-experienced rats. Analysis of non-coding RNAs in spermatozoa revealed coordinated changes in miRNA content between the nucleus accumbens and spermatozoa. We validated that restoration of miR-19b downregulation in sperm RNA from self-administration-experienced rats, in parallel with its overexpression in the nucleus accumbens of F1 offspring sired by heroin-SA-experienced fathers, reversed the increased heroin SA observed in these F1 offspring. Taken together, our findings suggest in rats that paternal heroin self-administration induces epigenetic changes in both brain and sperm miRNA, with miR-19b downregulation playing a critical role in mediating the epigenetic inheritance of increased heroin self-administration behavior in the F1 generation.