Neuropsychopharmacology
· 2026 Jun · PMID 42277363
·
Publisher ↗
Assigning valence to stimuli supports survival by promoting approach of stimuli associated with beneficial outcomes and avoidance of those associated with noxious outcomes, a process dysregulated in many psychiatric diso...Assigning valence to stimuli supports survival by promoting approach of stimuli associated with beneficial outcomes and avoidance of those associated with noxious outcomes, a process dysregulated in many psychiatric disorders. The nucleus accumbens (NAc) uses valence information to guide appropriate behavioral responses. NAc medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors have long been thought to play opponent roles in valence processing, although this has been challenged by recent work. To test this, we used fiber photometry Ca imaging to record from D1 and D2 MSNs in the NAc medial shell during a mixed-valence conditioning procedure in which distinct cues were paired with either foot-shock (CS), food reward (CS), or no outcome (CS). We find that the reinforced cues elicit bidirectional responses in both D1 and D2 MSNs, with CS increasing activity and CS decreasing activity, although only in female mice, suggesting that both cell types may encode the valence of conditioned stimuli in a sex-biased manner. By contrast, unconditioned stimuli (i.e. foot-shock, chocolate milk) increase activity in both D1 and D2 MSNs, with responses scaling to stimulus magnitude regardless of valence or sex, suggesting salience encoding. Additionally, unsignaled outcomes elicit greater responses than signaled outcomes in D2, but not D1 MSNs, suggesting that D2 MSN activity is sensitive to prediction error. Overall, our findings confirm limited functional opposition between NAc D1 and D2 MSNs in valence processing, and highlight the importance of considering sex and examining appetitive and aversive processing together.
Almeida-Correa S, Wesemann FS, Diez S
… +7 more, Maynard MJ, Yebra Garcia L, Voehringer P, Ferger B, Becker M, Wotjak CT, du Hoffmann J
Neuropsychopharmacology
· 2026 Jun · PMID 42270782
·
Publisher ↗
Motivational deficits and anhedonia are core features of psychiatric disorders such as depression, schizophrenia and addiction, yet current treatments rarely improve these symptoms. Progress towards targeted therapeutics...Motivational deficits and anhedonia are core features of psychiatric disorders such as depression, schizophrenia and addiction, yet current treatments rarely improve these symptoms. Progress towards targeted therapeutics requires preclinical tasks that reliably capture pharmacological modulation of relevant neural circuits. Here, we developed a modified effort-related choice task (mERC) that integrates high effort demands, extended intertrial intervals and choice, to enable robust bidirectional sensitivity to systemic pharmacology. Unlike standard paradigms, mERC detects both impairing and enhancing effects of dopamine modulators within a single task and reveals drug-sensitive anticipatory responses during intertrial intervals-a behavioral feature linked to interval timing and motivational vigor. Using neurochemical and photometric analyses, we show that mERC performance is associated with behavioral signatures consistent with dopaminergic signaling across different timescales and is potentially constrained by a bounded dynamic range beyond which behavioral modulation is lost. Species differences in drug efficacy map onto baseline dopamine tone and depletion dynamics, underscoring the interactions between task structure and neurochemical state. Together, these findings establish mERC as a stable and sensitive preclinical assay for enhancing our understanding of effort-based decision-making and for screening novel therapeutics targeting motivational dysfunction.
Shannon T, Najeeb M, Yi YJ
… +2 more, Shen Y, Gu B
Neuropsychopharmacology
· 2026 Jun · PMID 42265437
·
Publisher ↗
The off-label use of cannabidiol (CBD) has outpaced investigation. We assessed the effects of CBD in Angelman syndrome model mice lacking the Ube3a gene and found that chronic injection of CBD increased rapid-eye movemen...The off-label use of cannabidiol (CBD) has outpaced investigation. We assessed the effects of CBD in Angelman syndrome model mice lacking the Ube3a gene and found that chronic injection of CBD increased rapid-eye movement sleep during the dark cycle, restored "Siesta", improved sleep homeostasis, and reduced spontaneous seizures following flurothyl kindling.
Westlund Schreiner M, Manuele SJ, Washburn JJ
… +4 more, Shankman S, Cullen KR, Wang L, Jenkins LM
Neuropsychopharmacology
· 2026 Jun · PMID 42260114
·
Publisher ↗
Non-suicidal self-injury (NSSI) typically begins in adolescence and is associated with higher impulsivity and compromised white matter microstructure in the brain. Identifying early predictors of NSSI is a high priority....Non-suicidal self-injury (NSSI) typically begins in adolescence and is associated with higher impulsivity and compromised white matter microstructure in the brain. Identifying early predictors of NSSI is a high priority. We used data from the Adolescent Brain Cognitive Development Study to examine whether baseline white matter, specifically generalized fractional anisotropy (GFA), and different facets of impulsivity were prospectively associated with NSSI onset two years later (Y). We also examined interactions with sex. We identified 209 youth aged 8-11 years who reported NSSI at Y, but not at baseline (incident NSSI; iNSSI) and 209 controls matched by demographic and clinical characteristics. We conducted a Least Absolute Shrinkage and Selection Operator (LASSO) regularization, which yielded an AUC of .60, to narrow down predictors for logistic regression. Significant main effects indicated that lower GFA of the left parolfactory section of the cingulum (OR = 0.63) and higher negative urgency (OR = 1.54) were prospectively associated with Y NSSI. Sex interactions indicated that the relations between Y NSSI and lower GFA of the left parolfactory section of the cingulum (OR = 1.75) and higher negative urgency (OR = 0.60) were driven by males. Higher sensation seeking (OR = 1.36) and lack of perseverance (OR = 1.46) were more strongly associated with Y NSSI among females than males. Future work is needed to better understand the course of development of white matter microstructure and impulsivity as it relates to NSSI.
Chen Y, Cheng X, Cao Y
… +3 more, Xiao T, Chubykin AA, Kimbrough A
Neuropsychopharmacology
· 2026 Jun · PMID 42249078
·
Publisher ↗
Opioid addiction is characterized by compulsive drug seeking and use, accompanied by pain and heightened pain sensitivity (hyperalgesia) during withdrawal, yet the underlying neural mechanisms remain incompletely underst...Opioid addiction is characterized by compulsive drug seeking and use, accompanied by pain and heightened pain sensitivity (hyperalgesia) during withdrawal, yet the underlying neural mechanisms remain incompletely understood, especially for fentanyl. Using whole-brain Fos mapping and network analysis, we found that the periaqueductal gray is a central hub brain region engaged during fentanyl withdrawal, suggesting a prominent role for this region in withdrawal-associated neural signaling and warranting further examination. The ventrolateral periaqueductal gray (vlPAG) is a key site for nociceptive processing and shows robust neuronal responses during opioid withdrawal, but the role of its GABAergic neurons in fentanyl withdrawal has not been defined, and their contribution to the self-administration of drugs has not been investigated. We combined behavioral, molecular, electrophysiological, and chemogenetic approaches to examine the role of GABAergic vlPAG neurons during fentanyl withdrawal, and their contribution to withdrawal-induced hyperalgesia and fentanyl intake. During withdrawal from fentanyl, we observed increased Fos expression in GABAergic vlPAG neurons and enhanced inhibitory synaptic transmission revealed by channelrhodopsin-assisted circuit mapping, indicating increased GABAergic neuronal activity and inhibitory synaptic activity due to fentanyl use and withdrawal. Chemogenetic inhibition of GABAergic vlPAG neurons alleviated withdrawal-induced hyperalgesia. Male control mice exhibited overall escalating fentanyl self-administration across the final four intravenous self-administration sessions, whereas this escalation was not observed in males whose GABAergic vlPAG neurons were inhibited. Female mice did not exhibit a comparable effect. Together, these findings demonstrate that GABAergic vlPAG neurons are recruited during fentanyl withdrawal and contribute to withdrawal-associated nociceptive hypersensitivity. In addition, modulation of this population affects fentanyl self-administration in a sex-dependent manner. Targeting inhibitory signaling within the vlPAG may represent a strategy to alleviate withdrawal-associated hyperalgesia and limit fentanyl use.
Lin H, Luo X, Hussain S
… +4 more, Santiago N, Sathiyamoorthy A, Strauch J, Li X
Neuropsychopharmacology
· 2026 Jun · PMID 42249077
·
Publisher ↗
A major obstacle in oxycodone addiction treatment is relapse during abstinence. In rats, oxycodone seeking intensifies during abstinence, and orbitofrontal cortex (OFC) is critical for this incubation. Here we studied th...A major obstacle in oxycodone addiction treatment is relapse during abstinence. In rats, oxycodone seeking intensifies during abstinence, and orbitofrontal cortex (OFC) is critical for this incubation. Here we studied the role of submedius thalamus (Sub) and its reciprocal connections with OFC in this incubation in male rats. First, using the pharmacological inactivation approach, we examined the causal role of Sub in incubation of oxycodone craving. Next, combining fluorescence-conjugated cholera toxin subunit b (a retrograde tracer) with Fos (a neuronal activity marker), we assessed whether the activation of Sub and OFC connections was associated with incubated oxycodone seeking on abstinence day 15. Using an anatomical disconnection procedure, we then examined the causal role of interactions between Sub and OFC in incubated oxycodone seeking. We also tested the effect of unilateral Sub inactivation on incubated oxycodone seeking, and contralateral disconnection of Sub and OFC on non-incubated oxycodone seeking on abstinence day 1. We found that bilateral Sub inactivation decreased oxycodone seeking on abstinence day 15 but not on day 1, and incubated oxycodone seeking was associated with activation of both Sub→OFC and OFC→Sub projections. Further, both contralateral and ipsilateral disconnection of Sub and OFC decreased incubated oxycodone seeking. Unilateral Sub inactivation had no effect on the total responding during oxycodone seeking but impacted within-session responses. Lastly, contralateral disconnection of Sub and OFC had no effect on non-incubated oxycodone seeking. Together, these results demonstrated a novel role of Sub and its interactions with OFC in incubation of oxycodone craving.
Thomas SA, Gonsalves MA, LeBlanc G
… +8 more, Lorenc E, Metrik J, Frank M, Ryan S, Olenik E, Brick L, Spirito A, Gilman J
Neuropsychopharmacology
· 2026 Jun · PMID 42230967
·
Publisher ↗
Approximately 10-20% of U.S. adolescents report past-year cannabis use (CU). Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adol...Approximately 10-20% of U.S. adolescents report past-year cannabis use (CU). Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adolescents due to methodological limitations. However, neurophysiology contributing to dopamine can be noninvasively indexed via subcortical tissue iron measured with magnetic resonance imaging (MRI). We examined adolescent CU quantity, frequency, and problems in relation to tissue iron in regions with high dopamine activity, hypothesizing that greater CU would be linked to less tissue iron. Adolescents (n = 81; 64.2% female) aged 14-17 reporting either fewer than 5 lifetime cannabis episodes (n = 47) or more than 11 episodes (n = 34), with limited alcohol and nicotine use and no other illicit substance use, completed substance use assessments and an MRI. We calculated the inverse of the normalized T2* measurement (1/nT2*; lower values indicate less tissue iron) from resting-state functional scans by assessing relative T2* decay. 1/nT2* was estimated using subcortical masks for hypothesized regions. Lower 1/nT2* signal was associated with increased daily concentrate hits (b = -0.01, p < 0.001), cannabis hours high (b = -0.01, p = 0.016), CU frequency (b = -0.01, p = 0.01), and cannabis use disorder (CUD) severity (b = -0.01, p = 0.003). Post-hoc analyses highlighted the VTA as a key region. Results align with reduced dopamine-related neurophysiology associated with CU in adult and animal samples, and have implications for understanding adolescent CUD development. Measuring 1/nT2* offers an innovative, non-invasive method to index neurobiological alterations in adolescent CU.
Braden K, Trinagel A, Acevedo E
… +6 more, Massó-Quiñones LN, Bernstein AE, Arguello M, Evans-Strong A, Dunn SS, Castro DC
Neuropsychopharmacology
· 2026 Jun · PMID 42225850
·
Publisher ↗
The endogenous opioid system is a powerful modulator of motivation and affect. The dorsal raphe nucleus (DRN) in the midbrain has been established as an important site of opioid action and is an integral hub in behaviora...The endogenous opioid system is a powerful modulator of motivation and affect. The dorsal raphe nucleus (DRN) in the midbrain has been established as an important site of opioid action and is an integral hub in behavioral modulation. To investigate the functional significance of DRN opioid signaling in aversive and appetitive behaviors we disrupted preproenkephalin (Penk) in DRN using CRISPR-Cas9 technology in Penk-Cre mice. We found that CRISPR mediated knockdown of enkephalin peptide in the DRN (DRN) enhanced inflammation-induced mechanical sensitivity and odor avoidance. Additionally, loss of DRN diminished sucrose preference and engagement with a novel social stimulus. To further characterize the opioid system within the DRN, we performed Hiplex in situ hybridization of 12 genes in the same tissue. This revealed that DRN is largely separate from DRN serotonin cells and is instead distributed on glutamatergic and GABAergic cells. However, subtype-specific knockdown of DRN from glutamatergic and GABAergic cells was insufficient to replicate the behavioral effects of general DRN knockdown. This suggests that these neurons represent a novel population that mediate motivated behaviors distinctly from canonical DRN mechanisms.
Kumaragamage C, Jiang L, Angarita GA
… +10 more, de Graaf RA, Guidone E, Coppoli A, Behar KL, Gulanski BI, Pittman B, Weinzimer SA, Rothman DL, Krystal JH, Mason GF
Neuropsychopharmacology
· 2026 May · PMID 42218273
·
Publisher ↗
Alcohol consumption elevates circulating acetate. Prior studies showed that acute alcohol reduces brain glucose uptake and increases brain acetate oxidation. Previously we showed that heavy drinkers have elevated capacit...Alcohol consumption elevates circulating acetate. Prior studies showed that acute alcohol reduces brain glucose uptake and increases brain acetate oxidation. Previously we showed that heavy drinkers have elevated capacity to oxidize brain acetate. Here we repeat the study, adding individuals with alcohol use disorder (AUD). Four groups were enrolled. The analysis data set included Light Drinkers (LD, n = 13, female = 5), at-risk Heavy Drinkers (HD, n = 15, female = 7), AUD patients in long-term recovery (≥6 months; AUD, n = 6, female = 1), and a separate group of AUD treatment-seekers (AUD, n = 12, female = 1) underwent medically supervised detoxification, scanned at ~1 week abstinence (n = 9) and 1 month (n = 10). Seven AUD participants successfully completed scans at both time points. We infused participants with [2-C]acetate during magnetic resonance spectroscopy (MRS) of C-glutamate (Glu) and C-glutamine (Gln) in the brain, to measure the cerebral metabolic rate for acetate (CMR) and the neuronal tricarboxylic acid cycle relative to glutamate-glutamine neurotransmitter cycling (V/V; Energy Per Cycle: EPC). There was a group effect for CMR (p = 0.007) primarily owing to lower CMR in AUD at 1 week. Furthermore, higher CMR was observed among HD compared to LD participants, as previously reported. CMR was similar between the AUD and HD groups. In a separate within-subject comparison among AUD participants, CMR increased after 1 month to levels similar to those of LD. EPC was similar among the groups, representing normal glutamate-glutamine cycling versus energetics. In summary, abstinence reversed the lower acetate oxidation in early AUD, showing that just a few weeks of recovery can normalize this metabolic abnormality.
Lee JH, Lee SH, Yang J
… +6 more, Kim H, Pitt MA, Park HJ, Joh HK, Konova AB, Ahn WY
Neuropsychopharmacology
· 2026 May · PMID 42215735
·
Publisher ↗
Addiction involves rapidly fluctuating affective and value-based decision-making processes that undermine cessation efforts, yet capturing these dynamics at clinically meaningful timescales remains challenging. Standard...Addiction involves rapidly fluctuating affective and value-based decision-making processes that undermine cessation efforts, yet capturing these dynamics at clinically meaningful timescales remains challenging. Standard cognitive decision-making tasks are time-intensive and require many trials to achieve reliable parameter estimates, limiting their use longitudinally and in real-world settings. Here, we developed a rapid, smartphone-based framework that integrates ecological momentary assessment (EMA) with adaptive design optimization (ADO), a Bayesian method that enables reliable estimation of computational decision-making parameters from as few as 20-30 trials per task. We tested this framework in N = 79 individuals undergoing a 5-6-week smoking cessation program, who completed daily ADO-based delay discounting and risk/ambiguity tasks alongside EMA surveys assessing smoking behavior, craving, stress, mood, anxiety, and medication adherence. At the day-to-day level, elevated craving, depressive symptoms, and ambiguity tolerance predicted increased smoking the following day, whereas lower discounting rates and reduced craving and stress predicted cessation success at treatment completion. For the latter, models using data from the first week achieved meaningful predictive performance (mean AUC = 0.76), approaching the upper-bound performance observed in models incorporating both task and survey data from the full study period (mean AUC = 0.83). Together, these findings demonstrate that rapid, low-burden, ADO-based delivery of decision-making tasks via EMA can capture clinically relevant, dynamic vulnerability states during smoking cessation treatment. This methodology offers a promising approach for identifying cognitive markers that may facilitate or inhibit cessation success and informing personalized, time-sensitive intervention strategies for nicotine addiction and related psychiatric disorders.
Akula N, Liu S, Shah S
… +4 more, Peddada TN, Sung H, Raznahan A, McMahon FJ
Neuropsychopharmacology
· 2026 May · PMID 42203964
·
Publisher ↗
Allele-specific expression (ASE), where genetic variants exert dynamic control over gene expression, is not well studied in major psychiatric disorders. Here, we used transcriptome analysis in postmortem brain to identif...Allele-specific expression (ASE), where genetic variants exert dynamic control over gene expression, is not well studied in major psychiatric disorders. Here, we used transcriptome analysis in postmortem brain to identify genes with ASE, quantify differences in ASE in Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD), and explore regional relationships between differential ASE (dASE) and cortical thickness. Genome-wide analysis of ASE was performed by comparing RNA-sequencing read ratios of parental alleles in subgenual anterior cingulate cortex (sgACC) from 185 individuals with SCZ, BD, MDD, or no psychiatric disorder. ASE was detected by read-back phasing using phASER. dASE between cases and controls was performed using ASEP, a mixed model that accounts for sample information and correlation among SNPs. Heritability enrichment was calculated using linkage disequilibrium score regression. The Allen human brain atlas was used to map regional expression of dASE genes, which were compared with regional neuroanatomical changes reported in psychiatric patients. Of all 11,234 genes considered, 27% showed ASE at FDR < 0.05. Partitioned heritability analysis showed that ASE SNPs accounted for 13-16% of the heritability of MDD, BD and SCZ (enrichment p < 0.001). ASE SNPs significantly (p < 0.001) overlapped with GWAS variants in SCZ (odds ratio (OR) = 3.15), BD (OR = 2) and MDD (OR = 1.52). At FDR < 0.05, 1871 genes showed dASE in one or more diagnostic groups. These genes were enriched for regions with neuropsychiatric copy number variants (CNVs) and for several brain-relevant functional categories, especially those related to synapses. Expression of genes with dASE was increased in brain regions previously reported to show cortical thinning in patients with psychiatric disorders. This is the first study to explore the role of ASE in 3 major adult psychiatric disorders. We show that ASE is widespread in sgACC, that ASE SNPs contribute disproportionately to psychiatric disease heritability, dASE genes cluster in genomic regions with known neuropsychiatric CNVs and are most highly expressed in brain regions reported to show cortical thinning in psychiatric patients. Taken together, these findings highlight the importance of ASE in psychiatric disease risk and suggest that dysregulation of gene expression contributes to thinning of the cerebral cortex associated with psychiatric disorders.
Madangopal R, Drake OR, Pham DQ
… +8 more, Lennon VA, Weber SJ, Lee J, Sobukunola A, Holmes AR, Nurudeen O, Shaham Y, Hope BT
Neuropsychopharmacology
· 2026 Jul · PMID 42191863
·
Full text
Relapse to opioid use during abstinence is often triggered by drug-associated cues but the persistence of this effect during prolonged abstinence is unknown. Using a rat model, we found that relapse provoked by heroin-pr...Relapse to opioid use during abstinence is often triggered by drug-associated cues but the persistence of this effect during prolonged abstinence is unknown. Using a rat model, we found that relapse provoked by heroin-predictive discriminative stimuli persisted for over one year of abstinence, suggesting enduring, potentially lifelong opioid relapse vulnerability.
Shadani S, McCoy K, Ong L
… +4 more, Greaves E, Conn K, Andrews ZB, Foldi CJ
Neuropsychopharmacology
· 2026 May · PMID 42185639
·
Publisher ↗
With the resurgence of psychedelic research and growing evidence of their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their...With the resurgence of psychedelic research and growing evidence of their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5 mg/kg) in C57BL/6 J mice across multiple aspects of social behaviour. Psilocybin acutely enhanced huddling and induced hypothermia selectively in female mice and post-acutely (4 h) enhanced novelty-seeking and grooming in females, with no comparable effects in males. By 24 h, psilocybin-treated males showed reduced grooming and rearing alongside increased sociability directed toward a cage-mate. This was accompanied by blunted novelty-evoked nucleus accumbens dopamine responses that persisted to 7 days post-administration. At 7 days, psilocybin shifted female social preference toward familiarity over novelty, associated with prolonged nucleus accumbens dopamine release during familiar conspecific interactions, while males exhibited increased grooming, opposing the effect observed at 24 h. Both 5-HT1AR and 5-HT2AR contributed to psilocybin's behavioural effects in sex-specific ways. These findings reveal temporally dynamic, sex-differentiated patterns of social behaviour and dopaminergic modulation following psilocybin, underscoring the importance of sex-informed approaches in preclinical research and clinical application of psychedelic compounds.
Jang M, Lee KH, Shin J
… +5 more, Lee J, Yoo JH, Chun J, Ahn J, Kim JW
Neuropsychopharmacology
· 2026 May · PMID 42168587
·
Publisher ↗
Adolescent depression differs from adult depression in neurobiology and treatment response. Although resting-state functional connectivity (rsFC) of the default mode network (DMN) has been linked to treatment response in...Adolescent depression differs from adult depression in neurobiology and treatment response. Although resting-state functional connectivity (rsFC) of the default mode network (DMN) has been linked to treatment response in adults, its value as a biomarker in adolescents remains unclear. This study investigated whether baseline DMN rsFC predicts response to selective serotonin reuptake inhibitor (SSRI) treatment in adolescents with major depressive disorder (MDD). Seventy medication-naïve adolescents with MDD (ages 12-17 years) underwent baseline resting-state functional magnetic resonance imaging and an 8-week open-label escitalopram trial. Depressive symptoms were measured using the Children's Depression Rating Scale-Revised (CDRS-R). Seed-based DMN rsFC analyses used the ventromedial prefrontal cortex (vMPFC), dorsomedial prefrontal cortex (dMPFC), and posterior cingulate cortex (PCC) as seeds. Voxel-wise regressions assessed associations between baseline rsFC and treatment response, defined as the change in CDRS-R score from baseline to week 8. Our results showed that greater baseline DMN rsFC consistently predicted SSRI treatment response in adolescents with MDD. Stronger vMPFC-postcentral gyrus, vMPFC-insula, dMPFC-supramarginal, and PCC-supramarginal gyrus rsFCs at baseline were significantly associated with greater treatment response, as reflected by greater reductions in CDRS-R score following escitalopram treatment (r = -0.498 to -0.603, all p < 0.001). However, rsFCs within the DMN did not predict SSRI treatment response (all p > 0.05). These findings suggest that baseline rsFC between DMN hubs and regions in the sensorimotor and frontoparietal networks may serve as a biomarker of SSRI treatment response in adolescents with depression. This could support individualized treatment strategies within precision psychiatry for youth with MDD.
Wronski ML, Bahnsen K, Bernardoni F
… +14 more, Seidel M, Doose A, Hellerhoff I, Schimack M, Steinhäuser JL, Lombardo G, Keeler JL, Poitz DM, Ziemssen T, Weidner K, Roessner V, King JA, Pariante CM, Ehrlich S
Neuropsychopharmacology
· 2026 May · PMID 42168586
·
Publisher ↗
Anorexia nervosa (AN) involves limbic dysfunction, yet its neurobiology remains unclear. Examining morphological alterations in subcortical limbic regions across AN's nutritional states and associations with neuroendocri...Anorexia nervosa (AN) involves limbic dysfunction, yet its neurobiology remains unclear. Examining morphological alterations in subcortical limbic regions across AN's nutritional states and associations with neuroendocrine markers may improve understanding. We hypothesized that subcortical limbic volumes would be reduced in AN, normalize partially following short-term weight-restoration, and fully after long-term recovery. We examined whether leptin, ghrelin, neurofilament light (NFL), and brain-derived neurotrophic factor (BDNF) predict subcortical limbic dynamics. We studied 547 female individuals (aged 12-30 years): 168 with acute AN, 113 reassessed after ≈3 months of weight-restoration (>14% BMI increase), 80 long-term weight-recovered individuals, and 299 healthy controls. Ten subcortical limbic structures were segmented with FreeSurfer. Blood concentrations of leptin, ghrelin, NFL, and BDNF were measured. Group comparisons and marker associations were analyzed with mixed-effects models. Mediation was tested via regression-based mediation models. Most subcortical limbic volumes were reduced in AN (mean = -5.3%; Cohen's d-range = 0.24-0.76) but normalized after short-term weight-restoration (longitudinal change: mean = +5.8%; d-range = 0.30-0.56), except residual hypothalamic reductions. Rising leptin mediated weight gain-related volumetric increases in the left inferior tubular hypothalamus (proportion mediated = 52.8%) and left (96.7%) and right (156.8%) nucleus accumbens. Declining ghrelin mediated volumetric increase of the right nucleus accumbens (77.8%). Decreasing NFL following weight-restoration predicted increases in two hypothalamic subunits, the fornix, and right nucleus accumbens (d-range = 0.56-0.98). BDNF was unrelated to limbic dynamics. Subcortical limbic alterations in AN exceed other mental disorders, highlighting neuroplasticity. Neuroendocrine recovery (leptin and ghrelin) may reverse, and reduced axonal damage (NFL) may indicate neurostructural alterations in homeostatic and reward-related regions, with prognostic and therapeutic relevance in AN.
P A Costa G, Sofuoglu M, Compton P
… +3 more, Ranganathan M, Pittman B, De Aquino JP
Neuropsychopharmacology
· 2026 May · PMID 42162267
·
Full text
Even during opioid agonist treatment (OAT) for opioid use disorder (OUD), chronic pain remains common and unrelieved, as opioids impair endogenous pain modulation. Cannabidiol (CBD) may represent a non-opioid adjunct, bu...Even during opioid agonist treatment (OAT) for opioid use disorder (OUD), chronic pain remains common and unrelieved, as opioids impair endogenous pain modulation. Cannabidiol (CBD) may represent a non-opioid adjunct, but its effects among persons with co-occurring OUD and chronic pain receiving OAT are unknown. We conducted a randomized, double-blind, placebo-controlled crossover study evaluating acute oral CBD (400, 800, 1200 mg) effects on pain modulation, craving, and cognition among 23 participants (11 female) with co-occurring OUD and chronic pain receiving methadone (mean dose 85.7; SD: 29.7 mg/day). An opioid withholding model assessed CBD effects during two phases: Pre-OAT (delayed methadone dosing) and Post-OAT (following methadone administration). Primary outcomes included conditioned pain modulation (CPM; descending inhibition) and temporal summation of pain (TSP; ascending facilitation) assessed via quantitative sensory testing. Secondary outcomes included heat pain threshold and tolerance, and exploratory outcomes included cue-induced craving and cognitive performance. Pre-OAT, CBD was associated with a significant linear dose-response for enhanced descending pain inhibition (p = 0.034; d'=0.34 at 800 mg, d'=0.59 at 1200 mg). Post-OAT, CBD 1200 mg was associated with significant reduction of heat pain threshold relative to placebo (d'=-0.63, p = 0.017). CBD showed no significant effects on opioid craving. Cognitive performance was preserved across doses and CBD demonstrated a favorable safety profile. Among persons with co-occurring OUD and chronic pain receiving OAT, CBD demonstrated phase-dependent effects on pain modulation-dose-dependent enhanced descending inhibition Pre-OAT but worsened pain sensitivity Post-OAT at higher doses. These findings highlight OAT timing as a critical consideration for CBD-based pain interventions.