Neuropsychopharmacology [JOURNAL]
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200 papers
Adjunctive D-cycloserine to intermittent theta-burst transcranial magnetic stimulation in fibromyalgia: a randomized placebo-controlled trial.
DeMayo MM, Sharifi V, Chen L … +4 more , Zamponi GW, Trang T, Harris AD, McGirr A
Neuropsychopharmacology · 2026 May · PMID 42162266 · Publisher ↗
Fibromyalgia is a chronic condition with a substantial unmet treatment need. Repetitive Transcranial Magnetic Stimulation (rTMS) has shown promise in decreasing fibromyalgia symptom severity. Emerging data suggest that a...
Fibromyalgia is a chronic condition with a substantial unmet treatment need. Repetitive Transcranial Magnetic Stimulation (rTMS) has shown promise in decreasing fibromyalgia symptom severity. Emerging data suggest that adjunctive administration of the N-methyl-D-aspartate receptor partial agonist, D-Cycloserine, with rTMS can significantly improve clinical outcomes for other rTMS indications. Accordingly, this trial investigated adjunctive D-Cycloserine to intermittent Theta-Burst Stimulation (iTBS) of the dorsolateral prefrontal cortex (DLPFC) in adults with fibromyalgia. All participants received 20 daily (Monday-Friday) active iTBS treatments (600 pulses per session) delivered to the left DLPFC at 80% resting motor threshold, with double-blind, random assignment to adjunctive D-Cycloserine (100 mg) or placebo, taken prior to each iTBS session. The primary outcome was change on the Fibromyalgia Impact Questionnaire - Revised (FIQR) from baseline to treatment end. Secondary outcomes included self-report and clinician-rated measures of fibromyalgia-associated symptoms and quantitative sensory testing. Following a planned interim analysis, the trial was terminated for futility at n = 47 participants. There was a very large overall treatment effect on the FIQR (Cohen's d = 1.41, 95% CI: 0.82-2.00) with no significant between-group difference. There was, however, a greater decrease in depressive symptoms in the iTBS+D-Cycloserine group compared to the iTBS+Placebo group. In conclusion, iTBS+/-D-Cycloserine was associated with a large improvement in fibromyalgia symptom severity, while iTBS+D-Cycloserine was superior to iTBS+Placebo only for improvements in depressive symptoms. The large effect of iTBS on fibromyalgia symptoms may have masked specific effects of adjunctive D-Cycloserine. Trial Registration: NCT05395494.
Carprofen and buprenorphine delivery using micropipette-guided drug administration (MDA) in mice.
Krzyzaniak O, Steiner S, Nilsson FAM … +5 more , Dietrich M, Kämpfen L, Johansen P, Jirkof P, Meyer U
Neuropsychopharmacology · 2026 May · PMID 42162265 · Publisher ↗
Refined, non-invasive analgesic delivery methods are essential for improving animal welfare and ethical standards in laboratory rodent research. Here, we evaluated whether the micropipette-guided drug administration (MDA...
Refined, non-invasive analgesic delivery methods are essential for improving animal welfare and ethical standards in laboratory rodent research. Here, we evaluated whether the micropipette-guided drug administration (MDA) method, which promotes voluntary consumption using a sweetened condensed milk vehicle, achieves therapeutically relevant plasma and brain concentrations of two widely used analgesics, carprofen and buprenorphine, in male and female C57BL/6 N and BALB/c mice. Carprofen administered via MDA at 5, 15, and 30 mg/kg produced dose-response relationships and plasma exposure comparable to those observed following conventional subcutaneous (SC) injection of the same doses, with plasma concentrations exceeding the recommended therapeutic threshold ( ~ 25 μg/mL) in a dose-dependent manner. In contrast, the administration route substantially influenced plasma and brain concentrations of buprenorphine, which was administered at higher doses for MDA (0.5, 1.0, and 2.0 mg/kg) than for SC injection (0.05, 0.1, and 0.2 mg/kg) to compensate for presystemic first-pass metabolism. Specifically, SC injections of buprenorphine produced higher plasma concentrations early after administration, whereas MDA caused a dose-dependent delay in peak plasma levels and led to higher plasma concentrations of the major metabolite, buprenorphine-3-glucuronide. Although plasma concentrations of buprenorphine did not reach the recommended therapeutic threshold (1 ng/mL) for either administration route, brain concentrations exceeded proposed efficacy thresholds (3-5 ng/g) at 8 h post-treatment across all MDA buprenorphine doses. Together, our findings demonstrate that MDA provides an effective alternative to parenteral injection for analgesic treatment, while underscoring the importance of evaluating central drug exposure in addition to plasma concentrations.
Good vibrations: Sternal vibration enhances white matter density and interoceptive awareness.
Kondas A, McDermott TJ, Ahluwalia V … +10 more , Siegle GJ, Guelfo A, Fulton TM, Elbasheir A, Karkare MC, Ely TD, Johnston A, Krawczak R, Krafty RT, Fani N
Neuropsychopharmacology · 2026 Jul · PMID 42143134 · Full text
Vibration-based therapies are understudied but promising methods for alleviating psychiatric symptoms, particularly when paired with behavioral practices. The potential neuroplastic changes associated with a novel neuros...
Vibration-based therapies are understudied but promising methods for alleviating psychiatric symptoms, particularly when paired with behavioral practices. The potential neuroplastic changes associated with a novel neurostimulation method, sternal vibration, and associations with clinical change remain unknown. We examined effects of sternal vibration paired with mindfulness meditation on change in white matter microstructure and dissociation using neurite orientation dispersion and density imaging (NODDI) in trauma-exposed adults with elevated dissociative symptoms. A total of 116 trauma-exposed adults with elevated dissociation completed MRI before/after eight mindfulness meditation sessions. Approximately half (n = 60) received sternal vibration augmentation whereas n = 56 had no augmentation. Self-reported dissociation was measured at each session with the Scale of Bodily Connectedness. Significant time-by-intervention type interactions showed vibration-specific improvements in body awareness (p = 0.032; η = 0.139) and increased neurite density index (NDI) in a region within the corticospinal tract (CST), the left cerebral peduncle (CP, p < 0.01, η = 0.102). This finding replicated in tractography analyses showing increased NDI in left (p = 0.007; η = 0.066) and right CST (p = 0.004; η = 0.075). Decreased body dissociation was associated with increased CP NDI in those who received vibration (p = 0.011, η = 0.058); no associations between clinical and white matter change were observed with non-vibration interventions. Findings indicate that brief sternal vibration in the context of mindfulness meditation enhanced body awareness and neurite density in a tract of relevance to somatosensory integration, with white matter changes corresponding with enhanced interoceptive awareness. Findings reveal the promise of sternal vibration as a low-cost, non-invasive neurostimulation method for enhancing interoception via neuroplastic alterations, with applications for various psychiatric populations.
Simvastatin rescues cognitive impairment in an Aβ-induced model of Alzheimer's disease through the HDAC2-BDNF signaling pathway.
Cai C, Chong YS, Liang H … +5 more , Hu Y, Hu Q, Chen J, Sajikumar S, Liu F
Neuropsychopharmacology · 2026 May · PMID 42141074 · Publisher ↗
Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerab...
Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ. Aβ administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.
Acute fentanyl induces opposing directions of changes in tonic and phasic dopamine release patterns and impairs Pavlovian task performance.
Culver OP, Thigpen RE, Jhou TC
Neuropsychopharmacology · 2026 May · PMID 42135424 · Publisher ↗
Mu opioid receptor (MOR) agonists are recognized to disinhibit tonic dopamine (DA) in the ventral striatum (VS), contributing to opioid addiction and euphoria. However, MOR agonists can also inhibit non-drug reward-seeki...
Mu opioid receptor (MOR) agonists are recognized to disinhibit tonic dopamine (DA) in the ventral striatum (VS), contributing to opioid addiction and euphoria. However, MOR agonists can also inhibit non-drug reward-seeking, a phenomenon not readily explained by tonic DA disinhibition. We hypothesized that this effect could be due in part to disruption of phasic DA responses to conditioned stimuli (CS) which critically shape and maintain behaviors to obtain rewards. Because MOR effects on CS-evoked phasic DA are largely unexamined, we used fiber photometry in water-deprived male and female mice to examine acute fentanyl's effects on CS-evoked DA responses to two distinct auditory CS predicting either a liquid sucrose unconditioned stimulus (US), or non-reward. Behaviorally, we observed that acute fentanyl (0.1 or 0.2 mg/kg subcutaneous) increased generalized locomotion while dose-dependently reducing CS-driven anticipatory nose poke entries into the reward port during water deprived states. In parallel with these behavioral changes, acute fentanyl at either dose increased tonic DA while reducing phasic DA responses to the reward CS. In contrast to fentanyl's effects, during water-sated states we observed decreased DA responses to both the reward CS and US. Overall, our findings suggest that MOR agonists reduce cue-driven motivational behavior for non-drug rewards, and influence tonic and reward cue-evoked DA in opposite directions, but in a manner different from the effects of satiation.
PET imaging of FAAH in chronic Cannabis users: longitudinal assessment during short-term abstinence.
Poluga C, Dheda SS, Boachie N … +13 more , McCluskey T, Narciso L, Zilberman M, Côté C, Huestis MA, Tyndale RF, Kloiber S, Kolla NJ, Rusjan PM, Le Foll B, Warsh JJ, George TP, Boileau I
Neuropsychopharmacology · 2026 May · PMID 42106478 · Publisher ↗
Cannabis withdrawal in cannabis use disorder (CUD) increase the risk of relapse and lacks effective treatments. The endocannabinoid enzyme fatty acid amide hydrolase (FAAH) may influence cannabis use and withdrawal, but...
Cannabis withdrawal in cannabis use disorder (CUD) increase the risk of relapse and lacks effective treatments. The endocannabinoid enzyme fatty acid amide hydrolase (FAAH) may influence cannabis use and withdrawal, but the relationship between FAAH levels and withdrawal symptoms remains unclear. This study aims to investigate changes in FAAH levels during short-term abstinence from cannabis and their relationship with withdrawal symptoms. FAAH levels were measured in whole-brain regions of interest using positron emission tomography (PET) with the FAAH-specific probe [C]CURB. An irreversible two-tissue compartment model determined [C]CURB binding. Participants with CUD were scanned once after overnight abstinence (T1) and ~3-7 days after monitored last use (T2). FAAH polymorphism (rs324420) was determined from blood samples, and mood, cognition, withdrawal symptoms, and craving were assessed. In a sample of 14 participants (N = 17 prior to attrition) who completed both scans, FAAH binding in whole-brain increased between T1 and T2 (n = 14; %ΔFAAH = 10%; p = 0.003), with the largest change in the ventral striatum (11%, p = 0.026). Increases in FAAH (%ΔFAAH whole-brain) were significantly associated with longer cannabis abstinence, greater baseline depression severity, and tendency to act without thinking (p < 0.001). Short-term cannabis abstinence is associated with increases in brain FAAH levels. These changes are linked to traits and symptoms associated with relapse vulnerability, including negative mood and impulsivity. These preliminary findings suggest that FAAH may play a key role in the neurobiological response to short-term abstinence and could represent a potential target for interventions.
Sex-specific role of microglia in Δ-tetrahydrocannabinol-induced disruption of fear memory reconsolidation.
Raymundi AM, Cardoso NC, Lourenço GC … +9 more , Queiroz R, Dolzan MD, Vitali L, Meyer E, Lisboa SF, Guimarães FS, Pinna G, Bertoglio LJ, Stern CAJ
Neuropsychopharmacology · 2026 May · PMID 42106477 · Publisher ↗
In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive co...
In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis, is typically linked to cannabinoid type-1 receptor (CB1) signaling. THC also engages peroxisome proliferator-activated receptor gamma (PPARγ), and both CB1 and PPARγ modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC's impact on fear memory reconsolidation may extend beyond classical cannabinoid signaling. We hypothesize that THC disrupts contextual fear memory reconsolidation via microglial recruitment in the dorsal hippocampus (DH) through a sex-specific engagement of CB1 and PPARγ. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002 mg/kg, i.p.) or vehicle administration immediately after memory retrieval. Microglial involvement was assessed using immunofluorescence and pharmacological and chemogenetic inhibition in DH. The role of CB1 and PPARγ receptors was assessed via intra-DH selective antagonist infusion. THC impaired reconsolidation in males and females. In males, fear memory retrieval increased microglial engagement in the DH CA1 subfield, which THC further enhanced. Pharmacological and chemogenetic inhibition of microglia, as well as selective CB1 and PPARγ antagonism, blocked THC's effects in males. In females, THC-induced reconsolidation blockade was cycle-dependent, occurring at estrus and diestrus but not at proestrus, and was mediated exclusively through CB1 activation. These findings identified sex-specific neuroimmune pathways mediating THC's reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.
Prenatal serotonin reuptake inhibitor exposure and maternal depression symptoms are associated with altered fetal brain and placental development.
Wu Y, Andescavage N, Wisner KL … +4 more , Kapse K, Murnick J, Ngwa JS, Limperopoulos C
Neuropsychopharmacology · 2026 May · PMID 42106476 · Publisher ↗
Maternal mental health is associated with fetal neurodevelopment. Identifying effective treatments for maternal psychiatric conditions is a public health priority. SRIs (SSRIs and SNRIs) are commonly prescribed for prena...
Maternal mental health is associated with fetal neurodevelopment. Identifying effective treatments for maternal psychiatric conditions is a public health priority. SRIs (SSRIs and SNRIs) are commonly prescribed for prenatal mental health conditions; however, their impact on fetal brain development remains understudied. In this observational cohort study, we compared fetal brain and placental structures between SRI-exposed and unexposed pregnancies divided by categories of maternal depressive symptom severity from the Edinburgh Postnatal Depression Scale (EPDS). Pregnant women treated with SRIs and controls without mental illness or antidepressant exposure underwent fetal MRI studies between 20-40 weeks' gestation. Fetal brain motion correction and 3D reconstructions were performed using slice-to-volume registration. Fetal brain volumes (cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampi) were quantified using deep learning-based segmentation with manual correction. Cerebral cortical folding measures included local gyrification index, sulcal depth, curvedness, and surface area. Placental volume and microstructure were assessed with T2-weighted and diffusion-weighted MRI, respectively. EPDS scores were categorized as low ( ≤ 4), moderate (5-9), and high ( ≥ 10). A total of 182 pregnant women were included [62 SRI-exposed (59 SSRIs, 3 SNRIs); 120 controls]. Notably, 29% of SRI-exposed women continued to report elevated depression. SRI-exposed fetuses had smaller hippocampal volumes and reduced cortical gyrification, curvedness, and surface area. Subgroup analysis of stratification by EPDS scores revealed that SRI-exposed fetuses had reduced hippocampal volumes compared to unexposed fetuses with low and moderate, but not high, EPDS scores, and reduced cortical curvedness compared to unexposed subgroups. Among unexposed subgroups, fetuses exposed to high maternal EPDS scores had smaller hippocampal volumes compared to those with low scores. Placenta volume and microstructural diffusion were increased in the SRI-exposed compared to the unexposed group. Larger placental volume was associated with larger total fetal brain volume, and higher placental diffusion was associated with larger fetal white matter and cerebellar volumes in the SRI-exposed group. These findings suggest that prenatal SRI exposure may be associated with altered fetal hippocampal volumes, cerebral cortical maturation, and placental volume and microstructural diffusion. The clinical significance and long-term neurodevelopmental consequences of these structural alterations remain unknown and are currently under study.
Examining fronto-limbic brain and sleep mechanisms of antidepressant effects in cognitive-behavioral therapy for insomnia.
Krause AJ, Osorno R, Solomon NL … +16 more , Ahmadi M, Lam P, Magana O, Blozyte-Sakenis E, Harris LN, Babros MC, Izabel SS, Bernert RA, Williams LM, Gross JJ, Ma J, Lazzeroni LC, Yesavage JA, Manber R, Saletin JM, Goldstein-Piekarski AN
Neuropsychopharmacology · 2026 May · PMID 42098309 · Full text
Treating insomnia with Cognitive-Behavioral Therapy for Insomnia (CBT-I) improves depression symptoms, but the underlying mechanisms remain unknown. This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) exa...
Treating insomnia with Cognitive-Behavioral Therapy for Insomnia (CBT-I) improves depression symptoms, but the underlying mechanisms remain unknown. This single-arm mechanistic trial (ClinicalTrials.gov, NCT04424407) examined fronto-limbic and sleep mechanisms of CBT-I's antidepressant response in 48 participants (64% female; age 25-60) with insomnia and depression symptoms. Participants completed functional magnetic resonance imaging (fMRI), polysomnography (PSG), and symptom assessments before and after 6 CBT-I sessions. CBT-I resulted in reduced amygdala reactivity to fearful faces (d = 0.55, p = 0.008). Depression and sleep (objective and self-reported insomnia symptoms also improved. However, fMRI-assessed fronto-limbic changes were not associated with a reduction of depressive symptom severity. Instead, reduced depressive symptoms correlated with reduced self-reported insomnia symptoms (p = 0.001, ηp = 0.19) and increased objective sleep efficiency (p = 0.04, ηp = 0.10). Notably, pre-treatment PSG-assessed sleep efficiency, but not fronto-limbic function nor insomnia symptoms, predicted reduced depressive symptoms (p = 0.007, ηp = 0.16), suggesting that lower objective sleep efficiency prior to treatment may be associated with greater antidepressant benefit from CBT-I.
Traumatic stress recruits an excitatory orbitofrontal-amygdala pathway to drive maladaptive aggression.
Aholt ML, Jacobs JT, Adjei MP … +5 more , Mojahed N, Qasem E, Athul SW, Ellsworth B, Nordman JC
Neuropsychopharmacology · 2026 May · PMID 42091643 · Publisher ↗
Traumatic stress is a reliable predictor of heightened aggression, yet the mechanisms linking stress exposure to aggression remain poorly understood. We previously found that traumatic stress activates the posterior vent...
Traumatic stress is a reliable predictor of heightened aggression, yet the mechanisms linking stress exposure to aggression remain poorly understood. We previously found that traumatic stress activates the posterior ventral segment of the medial amygdala (MeApv) to drive persistent increases in aggressive behavior. However, why traumatic stress would engage an aggression-promoting pathway is unclear. To address this, we mapped the inputs to the MeApv and identified a population of excitatory, but not inhibitory, neurons in Layer 5 of the medial orbitofrontal cortex (mOFC). The OFC is classically viewed as an inhibitory brake on amygdala-driven impulses, yet emerging evidence suggests it can also facilitate context-dependent emotional responses. Notably, traumatic stress is known to disrupt OFC function and its connectivity with the amygdala, implicating this circuit in pathological aggression. Using fiber photometry, we found that traumatic stress selectively activates these MeApv-projecting excitatory mOFC (mOFC) neurons as well as their downstream MeApv outputs. Chemogenetic inhibition of the excitatory mOFC neurons during traumatic stress exposure prevented the subsequent increase in aggression while preserving non-aggressive social behavior. Together, these findings identify an excitatory cortical-amygdala pathway that is necessary for stress-induced aggression and support a model in which traumatic stress recruits, rather than suppresses, OFC output to drive maladaptive behavior.
Computational phenotyping of effort-based decision-making in type-2 diabetes on and off semaglutide.
Mehrhof SZ, Fleming H, Nord CL
Neuropsychopharmacology · 2026 May · PMID 42086986 · Publisher ↗
Motivation plays a fundamental role in human behaviour. Dopaminergic pathways have long been implicated in individual differences in motivation. Emerging evidence suggests such neural mechanisms interact with metabolic p...
Motivation plays a fundamental role in human behaviour. Dopaminergic pathways have long been implicated in individual differences in motivation. Emerging evidence suggests such neural mechanisms interact with metabolic processes to coordinate energy expenditure with energy resources, thereby linking motivation with metabolic health. We ask whether a cognitive-computational index of motivation-reliably linked to neuropsychiatric symptoms-is altered in the context of type-2 diabetes and treatment with a GLP-1 agonist (semaglutide). In a pre-registered experiment, we quantified computational effort-based decision-making parameters in participants with diabetes on (N = 58) or off (N = 54) semaglutide treatment, compared to two groups of matched controls without diabetes (N = 58 each). Subjects with type-2 diabetes showed a blunted acceptance bias, a computational parameter describing the bias to accept effort for reward. This effect was not driven by neuropsychiatric comorbidity or antidepressant use. Across all participants, we found that increasing diabetes risk linearly predicted reduced acceptance bias. Participants with diabetes treated with semaglutide did not show restored motivation. Metabolic ill-health is associated with reduced acceptance bias during motivational decision-making. This blunting mirrors-but is largely independent of-neuropsychiatric motivational deficits. This suggests metabolic ill-health is accompanied by a cognitive shift towards energy conservation, potentially contributing to comorbidity between metabolic ill-health and mental illness.
Maternal control during prenatal oxycodone exposure: differential effects of voluntary versus involuntary self-administration on offspring substance use vulnerability in rats.
Aaron CC, Budge KE, Isgate SB … +2 more , Vassoler FM, Byrnes EM
Neuropsychopharmacology · 2026 May · PMID 42082774 · Publisher ↗
Prenatal opioid exposure is a growing clinical concern, yet the impact of maternal control over drug intake on long-term offspring outcomes remains unclear. Here, we utilized a translational rat model to examine how the...
Prenatal opioid exposure is a growing clinical concern, yet the impact of maternal control over drug intake on long-term offspring outcomes remains unclear. Here, we utilized a translational rat model to examine how the mode of oxycodone administration during pregnancy influences substance use vulnerability in adult offspring. Female Sprague-Dawley rats (n = 10-11/group) were assigned to one of three groups: voluntary intravenous self-administration (Oxycodone-Lead), yoked non-contingent oxycodone delivery (Oxycodone-Yoked), or yoked saline control (Saline-Yoked). The dam self-administered oxycodone in 6h sessions for three weeks, 5 days/week, prior to conception and then daily throughout gestation. Offspring were cross-fostered to drug-naïve dams at birth. In adulthood, male and female offspring were evaluated for oxycodone (0.1 mg/kg/infusion) and cocaine (0.5 mg/kg/infusion) intravenous self-administration using fixed ratio (7 sessions FR1; 5 sessions FR5) and progressive ratio schedules (3 sessions), as well as drug-seeking under extinction conditions (1 session). Despite equivalent overall drug exposure, offspring of Oxycodone-Yoked dams exhibited enhanced motivated responding and drug-seeking behaviors. Female Oxycodone-Yoked offspring showed increased intake and motivated responding specifically for oxycodone, while Oxycodone-Yoked offspring of both sexes displayed augmented cocaine seeking and drug-seeking under extinction. Pearson's correlations between maternal intake and offspring behavior were sex- and drug-specific and were only observed in the Oxycodone-Yoked group. These findings indicate that maternal control over drug intake, rather than opioid exposure per se, plays a critical role in shaping neurodevelopmental trajectories underlying substance use vulnerability. This study highlights the importance of considering patterns of maternal opioid use when assessing long-term developmental risks.
Aberrant cortico-striato-limbic functional connectivity to alcohol cues in co-occurring bipolar disorder and alcohol use disorder.
Mellick WH, Tolliver BK, Anton RF … +1 more , Prisciandaro JJ
Neuropsychopharmacology · 2026 Jul · PMID 42069879 · Full text
Reward brain circuitry dysfunction is a hypothesized mechanism of bipolar disorder and alcohol use disorder co-occurrence (BD + AUD) that remains largely untested. This neuroimaging study represents the first investigati...
Reward brain circuitry dysfunction is a hypothesized mechanism of bipolar disorder and alcohol use disorder co-occurrence (BD + AUD) that remains largely untested. This neuroimaging study represents the first investigation of functional connectivity in BD + AUD. Following a two-by-two factorial design (N = 90), individuals with BD + AUD (n = 22), AUD alone (n = 20), BD alone (n = 23), and healthy control participants (n = 25) were administered a fMRI alcohol-cue reactivity paradigm. Generalized psychophysiological interaction (PPI) modeling (p < 0.001; p-FDR < 0.05) was performed for regions of interest, including the right dorsal anterior insula, inferior frontal gyrus, and bilateral amygdala and dorsal striatum (i.e., caudate body). Extracted beta weights were explored for bivariate associations with key behavioral correlates (AUD age of onset, alcohol craving and dependence severity, abstinence duration, and impulsivity) (p < 0.05). BD + AUD individuals exhibited cue-modulated hyperconnectivity between the left dorsal striatum and right posterior cingulate cortex (p-FDR = 0.045) versus the AUD and BD groups, who both exhibited hypoconnectivity between these regions versus healthy participants. Additionally, there were main effects of AUD and BD (p-FDR ≤ 0.040) on cue-modulated functional connectivity of the right dAI (↓ middle frontal gyrus [MFG]) and left amygdala (↑ right superior temporal gyrus, anterior cingulate cortex, and MFG), respectively. Select functional connectivity data were associated with trait characteristics of AUD in BD + AUD (r ≥±0.50, p ≤ 0.026) but not AUD. A distinct pattern of cortico-striato-limbic functional connectivity and brain-behavior relationships was found to characterize BD + AUD with implications for treatment development. Namely, leveraging neuromodulation techniques that can effectively normalize the identified circuitry disruptions could represent a novel path for treatment advances in BD + AUD.
Sequence termination cues drive automated habit-like strategy via dopamine-mediated processes.
Magnard R, Cheng Y, Zhou J … +4 more , Province H, Thiriet N, Janak PH, Vandaele Y
Neuropsychopharmacology · 2026 May · PMID 42069878 · Publisher ↗
Mesolimbic dopamine (DA) neurons are central to cue-guided reward seeking and action sequence learning. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution rema...
Mesolimbic dopamine (DA) neurons are central to cue-guided reward seeking and action sequence learning. Yet, the mechanisms by which cue-induced DA neural activity drives goal-directed or habitual sequence execution remain unknown. We designed two novel tasks to isolate the effect of sequence-delineating cues on DA-driven behavioral strategies and learning. In the lever insertion fixed-ratio 5 task (LI5), the lever insertion marked sequence initiation. In the lever retraction fixed-ratio 5 task (LR5), the lever retraction served as both sequence termination and reward-predictive cue. We found that sequence initiation and termination cues differentially affect reward expectation during action sequences, with only the termination cue contributing to greater outcome devaluation insensitivity, automaticity and behavioral chunking. Mesolimbic fiber photometry recording revealed that this habit-like behavior was associated with a rapid backpropagation in DA signals from the reward to the immediately preceding cue and with attenuated DA reward prediction error signals, which reflected greater behavioral inflexibility. Finally, in absence of external cues, brief optogenetic stimulation of VTA DA neurons at sequence termination was sufficient to drive automaticity and, to some extent, behavioral chunking. Our results highlight the critical role of cue-evoked DA signals at sequence termination in driving the development of automated, habit-like sequence execution.
Synaptic plasticity in cocaine-seeking ensembles of the nucleus accumbens core.
Flom LT, Hodgins SL, Gutierrez Erives G … +5 more , Russelavage JM, Hyken SM, Zhang Z, Vaaga CE, Bobadilla AC
Neuropsychopharmacology · 2026 May · PMID 42069877 · Publisher ↗
Cue-induced seeking engages neuronal ensembles within the nucleus accumbens core (NAcore), with neuronal ensembles defined here as neurons coactivated during specific behavioral experiences that have been implicated in c...
Cue-induced seeking engages neuronal ensembles within the nucleus accumbens core (NAcore), with neuronal ensembles defined here as neurons coactivated during specific behavioral experiences that have been implicated in cued-reinstatement. Although transient synaptic plasticity has been widely observed in unidentified ensemble and non-ensemble neuronal populations in the NAcore during reinstatement, its expression within behaviorally relevant ensembles remains unclear. Here, we used c-Fos-TRAP2-based tagging to characterize structural and functional synaptic plasticity within ensembles during cocaine-seeking in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural plasticity was measured via spine confocal imaging, and functional changes were evaluated by AMPA/NMDA ratios using whole-cell electrophysiology across reinstatement time points. Ensemble neurons exhibited increased dendritic spine head diameter during cue-induced reinstatement and were functionally potentiated relative to non-ensemble neurons. Spine classification showed reduced mature spines during reinstatement in both ensemble and non-ensemble cells, suggesting morphological remodeling rather than new spine formation. Non-ensemble neurons showed no change in spine head diameter during reinstatement but did exhibit an increased AMPA/NMDA ratio during cued-reinstatement. Paired-pulse ratio analysis suggested that yoked-cocaine exposure decreased presynaptic vesicle release probability, while operant cocaine exposure had no effect. Ensemble neurons showed an elevated AMPA/NMDA ratio following cocaine exposure, regardless of whether intake was yoked or contingent. Together, these findings suggest that ensemble and non-ensemble neurons undergo distinct forms of synaptic plasticity during cue-induced reinstatement. By distinguishing ensemble-specific structural plasticity from non-ensemble functional plasticity, this study refines the current understanding of mechanisms underlying cue-induced relapse. SIGNIFICANCE STATEMENT: In preclinical models of substance use disorder drug seeking is associated with cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic plasticity has been extensively described in non-selective neuronal populations pooling recordings of both ensemble and non-ensemble neurons of the nucleus accumbens core, ensemble-specific plasticity remains unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that structural synaptic plasticity is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify plasticity within the ensemble as a potential target for therapeutic intervention.
Energy-dependent modulation of nucleus accumbens output via K-ATP channel activity.
Astori S, Zanoletti O, Grosse J … +1 more , Sandi C
Neuropsychopharmacology · 2026 Apr · PMID 42062486 · Publisher ↗
Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-...
Mitochondria are central to neuronal bioenergetics, supporting the high metabolic demands required for synaptic signaling and network activity. Yet how neurons adapt their activity to rapid fluctuations in energy supply-and how such adaptations shape behavior-remains poorly understood. We previously showed that acute pharmacological manipulation of mitochondrial complex activity in the nucleus accumbens (NAc) affects motivated behaviors, which led us to hypothesize that medium spiny neurons (MSNs) can rapidly adjust their output in response to bioenergetic levels. To test this hypothesis, we examined how acute mitochondrial inhibition alters MSN function using mouse brain slices. Inhibition of mitochondrial complex I with the selective inhibitor rotenone reduced MSN intrinsic excitability, an effect that was counteracted by intracellular ATP replenishment. We next asked whether ATP-sensitive potassium (K-ATP) channels, canonical regulators of membrane excitability under metabolic stress, contribute to these responses. Histological analyses revealed specific expression of Kir6.2 subunits in both D1- and D2-MSNs, as compared to non-MSNs, and electrophysiological recordings showed that K-ATP channel activation blockade prevented rotenone-induced reductions in MSN excitability. In behavioral assays, complex I inhibition impaired effort-related performance, an effect that was rescued by K-ATP channel blockade. These findings identify K-ATP channels in MSNs as key mediators that sense acute changes in neuronal energy state and translate them into rapid adjustments in NAc excitability and behavior.
Correction: Vitamin A deficiency induces sex-specific reward processing alterations through a dysregulation of the mesolimbic dopamine transmission in mice.
Couty P, Yung S, Dulapt I … +16 more , Berger L, Santoro A, Hardt L, Petitbon A, Ducrocq F, Walle R, Catanese J, Alfos S, Helbling JC, Angelo MF, Sabran C, Borel P, Ferreira G, Bosch-Bouju C, Trifilieff P, Touyarot K
Neuropsychopharmacology · 2026 Jun · PMID 42056608 · Full text
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Lasting effects of early-life oxytocin treatment on LTP and episodic memory in a mouse model of Fragile X syndrome.
Chavez J, Le AA, Lauterborn JC … +4 more , Cox BM, Jia Y, Lynch G, Gall CM
Neuropsychopharmacology · 2026 Apr · PMID 42049944 · Publisher ↗
Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in person...
Deficits in episodic memory are a debilitating feature of Fragile X syndrome (FXS) and other congenital autism spectrum disorders (ASDs). There is evidence that oxytocin (OXT) treatments can improve sociability in persons with ASD and related animal models, encouraging the idea that benefits might extend to cognitive function. We tested this possibility in male FXS model, Fmr1-knockout (KO) mice. Intranasal treatments with OXT or saline were given daily during the second or fifth postnatal week, and effects on social behavior, spatial and episodic memory, and hippocampal synaptic plasticity were assessed in adulthood. Saline-treated Fmr1-KOs exhibited profound deficits in social recognition, object location memory, what-when-where components of episodic memory and long-term potentiation (LTP) in both the CA3-CA1 and lateral perforant path (LPP) systems; NMDAR-mediated components of LPP responses were also impaired. OXT treatments during the second week postnatal normalized all of these functions in Fmr1-KOs assessed in adulthood; this included restoration of initial stages of CA3-CA1 LTP and granule cell NMDAR-mediated currents. In hippocampal slices from naïve adult male Fmr1-KO mice, bath-applied OXT treatment restored LTP in CA1 but not the LPP, indicating pathway-specific effects. Intranasal OXT treatments during the 5 week postnatal did not have enduring effects in either genotype. The present evidence that early OXT treatment corrects a broad range of cognitive and synaptic plasticity deficits in Fmr1-KO mice identifies a clinically plausible strategy for normalizing hippocampal function in ASD and FXS, and highlights the presence of a critical developmental window for effective intervention.
Acute dose-dependent effects of 4-bromo-2,5-dimethoxyphenethylamine (2C-B) compared with 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin in a double-blind, placebo-controlled study in healthy participants.
Arikci D, Borgulya J, Straumann I … +8 more , Vizeli P, Luethi D, Thomann J, Rudin D, Vukalovic I, Eckert A, Liechti ME, Holze F
Neuropsychopharmacology · 2026 Jul · PMID 42049943 · Full text
Based on its in vitro profile and preliminary evidence, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) may have psychoactive properties that are similar to 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, which are i...
Based on its in vitro profile and preliminary evidence, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) may have psychoactive properties that are similar to 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, which are investigated for the treatment of posttraumatic stress disorder and depressive disorders. We compared acute effects of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin in 24 healthy participants (12 women, 12 men) using a double-blind, randomized, placebo-controlled, crossover design. Outcome measures included acute subjective effects, autonomic effects, adverse effects, effects on emotional and cognitive empathy, plasma oxytocin and neurophysin I concentrations, and pharmacokinetics up to 9 h. 2C-B produced dose-dependent subjective effects, with the 30 mg dose exerting comparable "any drug effects" to MDMA but lower "any drug effects" than psilocybin. Only psilocybin induced "bad drug effects" and "anxiety" compared with placebo. The 30 mg dose of 2C-B induced psychedelic-type alterations of state of consciousness and increased emotional empathy similarly to MDMA. The average subjective effect duration of 30 mg 2C-B was 4.9 h and similar to MDMA (4.8 h) and shorter than psilocybin (6.1 h). MDMA produced the highest cardiovascular stimulation, followed by psilocybin and 2C-B. Only MDMA increased plasma oxytocin and neurophysin I concentrations. 2C-B exhibited dose-proportional pharmacokinetics, with a plasma elimination half-life of ~1.3 h. The 30 mg dose of 2C-B induced entactogenic and psychedelic effects similarly to MDMA and psilocybin, respectively. MDMA is more cardiostimulant than psilocybin and 2C-B. At the tested dose-level, psilocybin is more distressing than MDMA and 2C-B. These results may assist with dose-finding for future 2C-B research and provide a direct comparison with standard doses of the prototypical compounds MDMA and psilocybin. Trial registration: ClinicalTrials.gov identifier: NCT05523401.
A frontotemporal dementia-like phenotype in schizophrenia: links to striatal dopamine and iron accumulation.
Chang X, Bryant L, Mena Ortega S … +8 more , Howes O, Sedlacik J, Veronese M, Schroeter ML, Lalousis PA, Koutsouleris N, Vano L, Coutts F
Neuropsychopharmacology · 2026 Apr · PMID 42034849 · Publisher ↗
Some schizophrenia patients share characteristics with behavioral variant frontotemporal dementia (bvFTD) including gray matter volume (GMV) similarities, suggesting overlapping brain mechanisms that may contribute to di...
Some schizophrenia patients share characteristics with behavioral variant frontotemporal dementia (bvFTD) including gray matter volume (GMV) similarities, suggesting overlapping brain mechanisms that may contribute to disease heterogeneity in schizophrenia. However, it is not yet understood whether schizophrenia patients with a bvFTD-like GMV signature also show additional features of bvFTD. Seventy-six patients with schizophrenia (mean age 31.2 years; 71% male) from a previous clinical trial (NCT04038957) underwent structural magnetic resonance imaging (MRI) to measure GMV. Healthy controls (n = 79) were used for age-related dynamic standardisation. Subsets of patients also completed [¹⁸F]-DOPA positron emission tomography (PET; n = 40) for striatal dopamine synthesis, neuromelanin-sensitive MRI (NM-MRI; n = 68) for midbrain dopaminergic integrity, and quantitative susceptibility mapping (QSM; n = 69) for brain iron accumulation. A previously validated machine-learning-based GMV classifier quantified bvFTD-like pattern expression in each schizophrenia patient. Associations with neurochemical, clinical, and medication measures were examined using correlation analyses. Higher bvFTD scores were associated with lower striatal dopamine synthesis capacity (r = -0.343, p = 0.032) and higher striatal QSM values (r = 0.282, p = 0.020), but showed no significant association with QSM or NM-MRI values in the dopaminergic midbrain (p = 0.903 and p = 0.102, respectively). No significant associations were found with negative symptom severity or with medication. Schizophrenia patients expressing a stronger bvFTD-like GMV pattern show lower striatal dopamine synthesis and elevated striatal iron, both hallmark features of bvFTD. This contrasts with the hyperdopaminergic model of schizophrenia and suggests distinct, potentially neurodegenerative mechanisms.
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