Neuropharmacology[JOURNAL]
Sun
200 papers
Thyrotropin-releasing hormone and dopaminergic systems interact in the ventral tegmental area to regulate food intake in rats.
Srivastava A, Waghade A, Sahoo D … +5 more , Divyajyoti S, Patil A, Chattopadhyay A, Kokare D, Singru P
Neuropharmacology · 2026 Jul · PMID 42392529 · Publisher ↗
Dopamine neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (Acb) modulate food intake and play a critical role in energy balance. Although a range of signaling agents are known to control th...
Dopamine neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (Acb) modulate food intake and play a critical role in energy balance. Although a range of signaling agents are known to control the activity of VTA and regulate food intake, the underlying microcircuitry is poorly understood. Since VTA expresses thyrotropin-releasing hormone (TRH) receptors, we try to dissect the role of TRH-dopamine (DA) interaction within the VTA in controlling food intake in adult, male Sprague-Dawley rats. TRH-ir axons were seen throughout VTA-subdivisions, inclusive of interfascicular (IF), rostral and caudal linear, paranigral (PN), and parabrachial pigmented nuclei. Among these, the IF and PN showed particularly dense TRH-innervation. The TRH-fiber density in the VTA was significantly increased in fasted rats, while refeeding abolished the response. Double-immunofluorescence showed that VTA-neurons were contacted by TRH-fiber terminals. Intra-VTA TRH microinjection in fasted rats significantly reduced food intake at 2h post-injection and increased DA/DA-metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) turnover in Acb. Ex vivo treatment of midbrain slices from fasted rats with TRH significantly augmented tyrosine hydroxylase-immunoreactivity in VTA. While the retrograde tracer iontophoresced into the VTA retrogradely labelled TRH-neurons in the dorsal raphe nucleus (DRN), hypothalamic TRH-ergic populations showed no labeling. Further, Trh-mRNA levels in DRN-containing tissues were significantly elevated during fasting compared with fed controls and returned to baseline following refeeding. Electrically stimulating DRN during fasting significantly reduced TRH-ir but increased TH-ir in the VTA. We suggest that TRH, probably received from DRN, may directly target the VTA→Acb DAergic pathway to suppress food intake.
TRPC5 as a modulator of TRPV1 signalling in pathological pain states.
Müller C, Geisslinger G, Sisignano M
Neuropharmacology · 2026 Jul · PMID 42385945 · Publisher ↗
Neuropathic pain is a major health problem and occurs after lesions and damage of the somatosensory nervous system. Clinically it remains poorly treatable despite extensive research efforts. Members of the transient rece...
Neuropathic pain is a major health problem and occurs after lesions and damage of the somatosensory nervous system. Clinically it remains poorly treatable despite extensive research efforts. Members of the transient receptor potential (TRP) superfamily, including TRPC5 and TRPV1, are key regulators of sensory perception and neuronal excitability. While TRPV1 is well known for its role in physiological and pathophysiological nociception, TRPC5 has been recently identified as a potential target in different pathological pain conditions. Here, we investigated the interaction between TRPC5 and TRPV1 in dorsal root ganglia (DRG) peripheral neurons from mice and in heterologous expression systems. Performing qPCR, we observed significantly upregulated TRPC5 mRNA expression in dorsal root ganglia following induction of oxaliplatin-induced peripheral neuropathic pain (OIPN), but not in inflammatory or diabetic neuropathic pain models. Calcium imaging experiments showed that that Lysophosphatidylcholines (LPCs) and Hydroxyeicosatetraenoicacids (HETEs) act as endogenous TRPC5 modulators. Pharmacological inhibition of TRPC5 by HC070 reduced TRPV1 mediated calcium responses in transfected HEK293 cells and primary sensory neurons from DRGs without effecting TRPM8-or TRPA1-induced calcium responses. Moreover, HC070 prevented protein kinase C (PKC)- and A (PKA)-dependent sensitization of TRPV1 induced by bradykinin and 8-Bromo-cAMP. Finally, FLIM-FRET experiments confirmed a close physical interaction between TRPC5 and TRPV1. Overall, our findings suggest TRPC5 as a modulatory partner of TRPV1 and highlight its role in nociceptive signalling under pathological circumstances. Because of this TRPC5 inhibition may be an indirect and promising strategy for reducing TRPV1 exacerbated activity in pathological pain states.
Loss of mGlu receptors from PV inhibitory neurons attenuates sex differences in ethanol and sucrose seeking.
Fabian CB, Jordan ND, Falciani GR … +4 more , Soleo L, Nelson LH, Lasek AW, Joffe ME
Neuropharmacology · 2026 Jul · PMID 42385944 · Publisher ↗
Binge drinking continues to pose major societal and health challenges. Understanding the molecular mechanisms that drive problematic alcohol use is critical for developing novel therapeutics. Parvalbumin-expressing inter...
Binge drinking continues to pose major societal and health challenges. Understanding the molecular mechanisms that drive problematic alcohol use is critical for developing novel therapeutics. Parvalbumin-expressing interneurons (PV-INs), a key subpopulation of interneurons within the prefrontal cortex (PFC) and other brain areas, have been implicated in a variety of alcohol-seeking behaviors. Recent work has identified the metabotropic glutamate 5 (mGlu) receptor as a critical sex-specific regulator of PV-IN activity. Genetic deletion of mGlu from PV-INs alters PFC-dependent cognitive behaviors and sex-specifically decreases volitional ethanol intake, but its role in motivated drinking remains unknown. Here, we use operant self-administration to examine how disruption of mGlu in PV-INs alters motivated drinking. Under a fixed ratio schedule, PV-mGlu mice show impairments in the acquisition of ethanol self-administration. By contrast, PV-mGlu mice readily acquire sucrose self-administration, suggesting a specific deficit to ethanol reinforcement. With sucrose administration, we found that males produced more active nosepokes and consumed more sucrose than females, an effect attenuated in male PV-mGlu mice. Using a fading procedure, mice were gradually transitioned to respond for 20% ethanol. Following the fade, male wildtypes maintained elevated responding relative to females and to male PV-mGlu mice. Progressive ratio and quinine adulteration suggest that these sex- and genotype-dependent effects reflect differences in motivation rather than altered taste sensitivity. Finally, we found that PV-mGlu mice displayed reduced expression of perineuronal nets and PV protein, with a greater disruption in males than females. Together, these data highlight mGlu receptors and PV-INs as critical regulators of motivated drinking.
PM289, a synthetic CB2 in vitro receptor agonist, modulates morphine-induced antinociceptive effect and withdrawal syndrome in an animal model of osteoarthritic pain.
Garcia MM, Paniagua N, Morales P … +7 more , Rodríguez-Rivera C, Sánchez-Robles EM, Pascual D, Herradón E, Goicoechea C, Jagerovic N, Girón R
Neuropharmacology · 2026 Jul · PMID 42385943 · Publisher ↗
Osteoarthritis is a common condition, and the associated pain is a leading cause of disability. One main challenge in its management stems from the complexity of the disease and the limited efficacy of current analgesic...
Osteoarthritis is a common condition, and the associated pain is a leading cause of disability. One main challenge in its management stems from the complexity of the disease and the limited efficacy of current analgesic treatments. Although evidence-based clinical guidelines provide valuable recommendations, they often prove inadequate. Opioids, while effective, are not considered first-line therapies due to adverse effects, particularly with long-term use. A promising strategy for chronic pain involves the coadministration of opioid and cannabinoid receptor agonists. This study investigates the efficacy of combining morphine with PM289, a novel and selective CB2 in vitro receptor agonist, in a rat model of knee osteoarthritis-associated pain, including both sexes. Effects on tactile allodynia, movement-evoked pain, analgesic tolerance, locomotor impairment, conditioned reward and anxiety-like behaviours, and naloxone-precipitated withdrawal symptoms were assessed. Additionally, protein levels of μ-opioid receptor and clusterin-a recognised biomarker of substance abuse-were analysed. PM289 alone produced sustained anti-allodynic and antinociceptive effects without inducing tolerance. When coadministered with morphine, it enhanced analgesia and attenuated opioid withdrawal symptoms, particularly in females. However, it did not reduce morphine-induced conditioned reward in this group. Chronic treatment also increased plasma clusterin levels in both sexes, with enhanced expression in the nucleus accumbens of males. These findings support the potential of PM289 as an adjuvant to chronic opioid therapy, highlighting the importance of sex-specific considerations in its efficacy and safety profile.
Purinergic-cytokine signaling as a regulatory axis in neuroimmune development.
Silva JB, Viero FT, Higa GSV … +10 more , Turrini N, Marques LB, Carlos GO, Silva ABS, Kihara AH, Takada SH, Britto LRG, de Pasquale R, Kim E, Ulrich H
Neuropharmacology · 2026 Jun · PMID 42379470 · Publisher ↗
Neurodevelopment is a biological process through which the nervous system grows, organizes, and matures. This process is guided by genetic programs and shaped by environmental influences. During neurodevelopment, microgl...
Neurodevelopment is a biological process through which the nervous system grows, organizes, and matures. This process is guided by genetic programs and shaped by environmental influences. During neurodevelopment, microglia and astrocytes secrete neurotrophic factors and signaling molecules. These orchestrate neuroimmune interactions essential for healthy brain development. The activity of these cells is modulated by both intrinsic and environmental cues, including neuronal activity, synaptic communication, circulating small molecules and hormones, and peripheral immune cells that infiltrate the brain parenchyma. Within this framework, this review provides information on the physiological role of cytokines in driving key neurodevelopmental processes, along with evidence for purinergic coordination of cytokine signaling. Purinergic signaling operates through a limited repertoire of extracellular molecules, with outcomes determined by tightly regulated receptor expression and enzymatic degradation, which complicates precise fine-tuning. In contrast, cytokine signaling is largely defined by cytokine identity and receptor-specific downstream pathways, which enables greater specificity. The crosstalk between purines and cytokines is tightly regulated, forming a central signaling axis within neuroimmune communication. In this context, purinergic-cytokine signaling coordinates critical neurodevelopmental processes. These include progenitor proliferation, migratory trajectories, neurite growth, differentiation, and synaptic refinement.
Acupuncture improves depressive symptoms and prefrontal cortical function in mild to moderate depressive disorder: A randomized sham-controlled trial and fNIRS study.
Yang B, Wang T, Zhu F … +7 more , Liu Y, Li Z, Luo L, Yin L, Mao S, Wu J, Miao R
Neuropharmacology · 2026 Jun · PMID 42379469 · Publisher ↗
BACKGROUND: Depressive disorder is a common mental illness associated with substantial functional impairment. Although pharmacotherapy is widely used, its effectiveness is often limited by adverse effects and poor adhere...
BACKGROUND: Depressive disorder is a common mental illness associated with substantial functional impairment. Although pharmacotherapy is widely used, its effectiveness is often limited by adverse effects and poor adherence. Acupuncture has been increasingly applied as a complementary treatment for depression, and its neurobiological characteristics remain unclear. OBJECTIVE: This randomized, sham-controlled trial aimed to evaluate the clinical efficacy of acupuncture for mild to moderate depressive disorder and to investigate its effects on prefrontal cortical function using functional near-infrared spectroscopy (fNIRS). METHODS: Patients with mild to moderate depressive disorder were randomly assigned to a real acupuncture (RA) group or a sham acupuncture (SA) group and received standardized treatment for 8 weeks. Clinical outcomes were assessed using the Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Short Form-36 Health Survey (SF-36), and a traditional Chinese medicine syndrome score. A subset of participants underwent fNIRS assessment during resting-state and task-based conditions to evaluate prefrontal cortical activation and functional connectivity. RESULTS: Compared with baseline, the RA group showed significant reductions in SDS and SAS scores and significant improvements in SF-36 emotional domains, with effects emerging at Week 4 and persisting up to 12 weeks after treatment. Improvements were greater and more stable in the RA group than in the SA group. fNIRS analyses revealed enhanced activation in dorsolateral and medial prefrontal regions and strengthened prefrontal functional connectivity following acupuncture, whereas neural changes in the SA group were limited. CONCLUSION: Acupuncture is effective for improving depressive and anxiety symptoms and quality of life in patients with mild to moderate depressive disorder. Modulation of prefrontal cortical activation and connectivity may underlie its antidepressant effects.
A staged zebrafish-mouse screening strategy for antiseizure compound prioritization.
Christie CF, Bendell E, Renaud L … +10 more , Williamson T, Li X, Himes RA, Prosser LC, Edwards SF, Metcalf CS, West PJ, Wilcox KS, James Chou C, Chan SSL
Neuropharmacology · 2026 Jun · PMID 42349747 · Publisher ↗
Epilepsy affects more than 50 million people worldwide, and the identification of new antiseizure medications (ASMs) with adequate blood-brain barrier (BBB) penetration remains a major challenge. The pentylenetetrazol (P...
Epilepsy affects more than 50 million people worldwide, and the identification of new antiseizure medications (ASMs) with adequate blood-brain barrier (BBB) penetration remains a major challenge. The pentylenetetrazol (PTZ)-induced zebrafish model is widely used for early ASM screening, but most studies use larvae at 7 days post-fertilization (dpf) or earlier, before later stages of BBB maturation are fully assessed. Here, we evaluated whether staged testing in 7-, 14-, and 21-dpf zebrafish could improve prioritization of CNS-active compounds before mammalian testing. Thirty-one Vitamin K (VK) analogs were screened in 7-dpf zebrafish using PTZ-induced seizure-like hyperlocomotor activity as a phenotypic endpoint. Seventeen compounds significantly reduced PTZ-induced hyperlocomotor activity at 7 dpf. Based on quantitative selection criteria, three compounds were advanced to dose-response studies in older zebrafish, and two compounds retained activity at 14 and 21 dpf. These compounds were then evaluated in the mouse 6 Hz seizure model. Both compounds showed protection at 32 mA, whereas only compound 3d remained active in the higher-intensity 44 mA model. Brain-to-plasma analysis confirmed CNS exposure for 3d and 3l, with ratios of 2.64 and 0.853, respectively. These findings support later-stage zebrafish screening as a practical phenotypic prioritization step for selecting CNS-active compounds for mammalian seizure models, while highlighting the need for direct mammalian validation and further PK/PD characterization.
DNMT3a-mediated GluN2B desilencing in the anterior cingulate cortex underlies chemotherapy-induced neuropathic pain.
Liu X, Chen H, Wei J … +10 more , Song Q, Wang H, Yao R, Zeng Y, Liu X, Ou-Yang G, Wan B, Nie H, Mao Q, Liang L
Neuropharmacology · 2026 Jun · PMID 42341912 · Publisher ↗
Chemotherapy-induced neuropathic pain (CINP) involves chemotherapy toxicity to cortical tissues. DNA methylation, a key epigenetic mechanism for gene regulation, has been implicated in neuropathic pain pathogenesis. The...
Chemotherapy-induced neuropathic pain (CINP) involves chemotherapy toxicity to cortical tissues. DNA methylation, a key epigenetic mechanism for gene regulation, has been implicated in neuropathic pain pathogenesis. The anterior cingulate cortex (ACC) is critical for pain processing, yet its susceptibility to DNA methylation-mediated epigenetic regulation remains unexplored. In a mouse model of paclitaxel (PTX)-induced CINP, we found that PTX downregulated DNA methyltransferase 3a (DNMT3a) in the ACC and induced mechanical and thermal pain hypersensitivity. Overexpression of DNMT3a specifically in ACC pyramidal neurons alleviated these PTX-induced nociceptive behaviors, whereas knockdown of DNMT3a in the ACC alone was sufficient to produce pain hypersensitivity. Western blot analysis revealed that PTX selectively upregulated GluN2B, but not other NMDA (GluN1, GluN2A), AMPA (GluA1, GluA2), or GABA receptor subunits. Mechanistically, pyramidal neuron-specific DNMT3a overexpression in the ACC silenced GluN2B expression in a DNA methylation-dependent manner, consequently suppressing GluN2B-mediated NMDA currents in ACC pyramidal neurons. Furthermore, intra-ACC application of the GluN2B antagonist Ifenprodil reversed pain hypersensitivity induced by either PTX or DNMT3a knockdown. Finally, our results establish DNMT3a-mediated epigenetic desilencing of GluN2B in the ACC as a key mechanism underlying PTX-induced neuropathic pain, identifying both as promising therapeutic targets for CINP.
Resveratrol alleviates neurological disorders and motor dysfunction in 3-NP induced- Huntington's Disease in rats: Role of activating AMPK/SIRT1/ULK1 autophagy pathway.
Fahmy MI, Rizk NI, Eitah HE … +4 more , Arab HH, Alsufyani SE, Arafa EA, Azzam HN
Neuropharmacology · 2026 Jun · PMID 42331250 · Publisher ↗
Huntington's disease (HD) is a genetic neurodegenerative disease characterized by striatum damage, which results in a number of uncontrollable muscle movements alongside intellectual and cognitive impairment. The progres...
Huntington's disease (HD) is a genetic neurodegenerative disease characterized by striatum damage, which results in a number of uncontrollable muscle movements alongside intellectual and cognitive impairment. The progression of HD is accompanied by neuroinflammation, oxidative stress, and neuronal apoptosis. Resveratrol (RESV) is a naturally occurring compound known for its potent antioxidant and anti-inflammatory effects. RESV showed promising neuroprotective effects against Alzheimer's and Parkinson's disease. The current research aims to study the neuroprotective effects of RESV against 3-nitropropionic acid (3-NP)-induced HD. Forty adult male rats were divided equally into four groups as follows: Group 1- normal control group. Group 2- RESV (25 mg/kg/day, p.o) - treated rats. Group 3- rats treated with 3-NP (10 mg/kg/day, i.p). Group 4- rats treated with 3-NP (10 mg/kg/day, i.p) + RESV (25 mg/kg/day, p.o). The results showed that RESV alleviated the behavioral deficits observed in 3-NP treated rats. In addition, the histopathological images showed obvious improvement in RESV-treated rats. RESV activated the AMP-activated protein kinase (AMPK)-related autophagy pathway that resulted in neuroprotection and cell survival. Moreover, RESV showed anti-inflammatory and antioxidant effects by decreasing levels of inflammatory biomarkers including tumor necrosis factor (TNF)-α, nuclear factor kappa (NF-κ)-B, and interleukin (IL)-1β, alongside increasing neuronal antioxidant capacity by stimulating reduced glutathione (GSH), superoxide dismutase (SOD), and preventing lipid peroxidation. In conclusion, our study showed that RESV has a potent neuroprotective effect as evidenced by its ability to significantly alleviate biochemical and behavioral hallmarks of HD.
Repurposing Citicoline for single prolonged stress-induced behavioral and hippocampal molecular abnormalities in male mice: Novel mechanistic attenuation of endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and apoptosis.
Fahmy NG, Kamel NM, Hedya SA … +1 more , Abd El-Latif AM
Neuropharmacology · 2026 Jun · PMID 42320748 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited effective pharmacological options. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have emerged as pivotal patholo...
Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited effective pharmacological options. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have emerged as pivotal pathological mechanisms in PTSD pathophysiology, yet therapies targeting these pathways remain largely unexplored. Citicoline, recognized for its neuroprotective properties and capacity to modulate mitochondrial homeostasis, presents a promising candidate for intervention. This study investigated citicoline's therapeutic efficacy against behavioral and hippocampal molecular abnormalities induced by single prolonged stress (SPS) in male mice. Thirty-six mice were subdivided into control, citicoline (Citi) (100 mg/kg, p.o for 7 days), SPS (2-h restraint, 20-min forced swim, ether exposure), and SPS + Citi (SPS followed by citicoline for 7 days) groups. Citicoline administration effectively reversed stress-induced behavioral impairments in social novelty preference, marble burying, and cue-induced freezing. At the molecular level, citicoline restored ER homeostasis by attenuating the toxic unfolded protein response characterized by reductions in phosphorylated protein kinase RNA-like ER kinase, activating transcription factor (ATF) 4, and ATF6 while upregulating the protective X-box binding protein 1. Such improvements were accompanied by reactivation of impaired mitophagy through enhanced PTEN-induced kinase 1 and parkin expression, facilitating clearance of damaged mitochondria and reactive oxygen species. Furthermore, citicoline effectively countered oxidative stress, evidenced by suppressing malondialdehyde-mediated lipid peroxidation while restoring glutathione antioxidant reserves. Citicoline also normalized mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha and prevented neuronal apoptosis by suppressing caspase-3. Collectively, these findings establish citicoline as a promising multi-targeted therapeutic candidate for behavioral and hippocampal molecular abnormalities after SPS in male mice.
The α1 subunit-containing GABA receptor-mediated inhibitory transmission in the lateral orbitofrontal cortex contributes to anxiety- and depression-like behaviors in Parkinsonian rats.
Bai Y, Hui Y, Sun Q … +7 more , Gao S, Li R, Wu X, Wang Y, Yang Y, Zhang Q, Li L
Neuropharmacology · 2026 Jun · PMID 42309222 · Publisher ↗
The lateral orbitofrontal cortex (LO) is critically involved in the modulation of anxiety and depression. However, the involvement of GABA receptor-mediated inhibitory transmission within the LO in Parkinson's disease (P...
The lateral orbitofrontal cortex (LO) is critically involved in the modulation of anxiety and depression. However, the involvement of GABA receptor-mediated inhibitory transmission within the LO in Parkinson's disease (PD)-associated anxiety and depression remains unclear. In this study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in adult male Sprague-Dawley rats induced anxiety- and depression-like behaviors, accompanied by hyperactivity of glutamatergic neurons, decreased synthesis and release of GABA and increased release of glutamate, as well as down-regulation of the expression of α1 subunit-containing GABA receptors in the LO. Intra-LO injection of GABA receptor agonist muscimol elicited anxiety- and depression-like behaviors, while injection of GABA receptor antagonist bicuculline exerted anti effects in both sham and the lesioned rats. The doses producing behavioral effects in the lesioned rats were higher than those in sham rats. Intra-LO injection of muscimol decreased the firing rate of glutamatergic neurons and reduced extracellular dopamine (DA) and serotonin (5-HT) levels in the LO; conversely, bicuculline increased the firing rate of the neurons and elevated DA and 5-HT levels in both groups. Notably, the duration of muscimol and bicuculline action on the firing rate of glutamatergic neurons and monoamine release was shortened in the lesioned rats compared to sham rats, which were attributed to down-regulation of the expression of α1 subunit-containing GABA receptors. Collectively, our findings suggest that degeneration of the nigrostriatal pathway suppresses GABA receptor-mediated inhibitory transmission in the LO, which is crucial for regulating PD-associated anxiety and depression.
Fear conditioning enhances subsequent cocaine self-administration and amygdala neuronal activity only in male rats.
Rich MT, Sacko TJ, Rohilla HK … +3 more , Yazigi JV, Khondaker SK, Pierce RC
Neuropharmacology · 2026 Jun · PMID 42297209 · Publisher ↗
Pathological fear resulting from traumatic experiences plays a critical role in the development of post-traumatic stress disorder (PTSD) and substance use disorders (SUDs), which frequently co-occur and worsen clinical o...
Pathological fear resulting from traumatic experiences plays a critical role in the development of post-traumatic stress disorder (PTSD) and substance use disorders (SUDs), which frequently co-occur and worsen clinical outcomes. However, the neuronal mechanisms underlying fear memory interactions with drug-seeking behaviors remain poorly understood. In this study, we employed a novel rodent model combining Pavlovian fear conditioning and cocaine self-administration to investigate the behavioral effects and neuronal mechanisms underlying the interaction between fear conditioning and substance use. We hypothesized that pre-existing fear memories would enhance subsequent cocaine-related behaviors and alter neuronal activity in the basolateral amygdala (BLA), a key brain region involved in fear and reward memory processing. Our results showed that in male, but not female, rats prior cued fear conditioning increased cocaine intake and cue-induced cocaine seeking. These effects were specific to cue-dependent fear learning, as rats exposed to unpaired footshocks did not exhibit similar increases in cocaine-associated behaviors. Electrophysiological recordings from the BLA revealed distinct patterns of neuronal activity. Cocaine self-administration enhanced synaptic activity independent of footshock exposure, while fear conditioning increased intrinsic activity independent of cocaine exposure. These findings indicate that persistent fear memory enhances cocaine-mediated behaviors in male rats through distinct changes in the BLA, providing new insights into the neurobiological basis of comorbid PTSD and SUD.
Third trimester-equivalent alcohol exposure reduces neurons in males and increases Vglut2 neurons with reduced intrinsic bursting in females in the murine dorsal subiculum.
Lopez KM, Choi H, Feng A … +6 more , Cazares L, Roman JK, Chavez GJ, Garcia MM, Jaramillo J, Valenzuela CF
Neuropharmacology · 2026 Jun · PMID 42297208 · Publisher ↗
Individuals with Fetal Alcohol Spectrum Disorders (FASDs) show reduced subicular volume, and preclinical studies complement this by demonstrating that third-trimester-equivalent ethanol exposure induces apoptosis in cort...
Individuals with Fetal Alcohol Spectrum Disorders (FASDs) show reduced subicular volume, and preclinical studies complement this by demonstrating that third-trimester-equivalent ethanol exposure induces apoptosis in corticolimbic regions, including the subiculum. The subiculum mediates hippocampal-cortical communication critical for long-term memory consolidation. Within the distal dorsal subiculum, a population of bursting neurons uniquely expresses VGLUT2 and plays a key role in memory processing. We hypothesized that third-trimester-equivalent ethanol exposure would reduce neuronal and VGLUT2+ cell density in the dorsal subiculum and reduce the excitability of bursting neurons, providing a mechanism for long-term memory impairments observed in FASD. To test this, postnatal day (P) 7 mice received subcutaneous injections of ethanol, and long-term effects were assessed in adolescence (P35-62). Using transgenic mice with fluorescently labeled VGLUT2+ neurons and immunohistochemistry, we observed a significant reduction in neuronal density in males and an increase in VGLUT2+ cell density in females. Using whole-cell patch-clamp electrophysiology, we observed a reduction in the number of action potentials per burst in both sexes. Additionally, females showed reduced overall excitability, and a subset of neurons exhibited a shift to regular spiking. These findings suggest that developmental ethanol exposure disrupts subicular output by impairing burst firing, potentially weakening hippocampal-cortical communication and contributing to the cognitive deficits associated with FASD.
Chronic alcohol disrupts premotor cortex intrinsic excitability and transmission.
Oesch NW, Gremel CM
Neuropharmacology · 2026 Jun · PMID 42288197 · Publisher ↗
Alcohol dependence induced alterations to decision-making are hypothesized to occur in part through long-lasting changes to cortical function. Animal models of chronic alcohol exposure have been used to identify alcohol-...
Alcohol dependence induced alterations to decision-making are hypothesized to occur in part through long-lasting changes to cortical function. Animal models of chronic alcohol exposure have been used to identify alcohol-related changes to the activity and intrinsic function of cortical neurons, but the extent of such changes across involved cortical circuits is unclear. The secondary or premotor cortex (M2), which is necessary for goal-directed decision-making, shows aberrant in vivo activity during decision-making following chronic alcohol exposure, and targeting M2 activity can restore appropriate decision-making. Here we investigate whether chronic alcohol exposure alters the intrinsic properties and spontaneous transmission of M2 pyramidal neurons in male and female mice. Using a well-validated model of alcohol dependence, chronic intermittent ethanol exposure and repeated withdrawal (CIE), we find that prior CIE exposure reduced intrinsic excitability of M2 pyramidal neurons and altered glutamatergic, but not GABAergic transmission. One to two weeks into withdrawal, M2 neurons from CIE-exposed mice showed a decrease in intrinsic excitability that recovered with additional time in withdrawal. Prior CIE exposure also altered excitatory, but not inhibitory transmission within M2. Early in withdrawal there was an increase in the frequency of excitatory transmission. This change showed adaptation; with additional time in alcohol withdrawal we observed restored frequency but increased amplitude of M2 excitatory transmission. Together, this suggests that chronic alcohol exposure and withdrawal alters M2 neuron function and induces increases in excitatory modulation of M2 circuits.
Context-dependent effects of microglial MyD88 removal on voluntary ethanol consumption in mice.
Dziabis JE, Rogers N, Horvath BL … +7 more , Patton MS, Jonathan IO, Freeman EJ, Sun W, Moulden J, Zhang G, Bilbo SD
Neuropharmacology · 2026 Jun · PMID 42288196 · Publisher ↗
Neuroimmune signaling is increasingly implicated in alcohol use disorder (AUD). Microglia, the brain's resident immune cells, signal in part through the adaptor protein myeloid differentiation primary response 88 (MyD88)...
Neuroimmune signaling is increasingly implicated in alcohol use disorder (AUD). Microglia, the brain's resident immune cells, signal in part through the adaptor protein myeloid differentiation primary response 88 (MyD88), a key mediator of innate immune responses. Here, we investigated whether microglial-specific MyD88 signaling regulates voluntary alcohol consumption in adulthood, as whole-body loss of MyD88 was previously shown to increase drinking. We further determined if alcohol altered parvalbumin-expressing interneurons (PVIs) and microglia within the pre-frontal cortex, based on our previously described role for MyD88 signaling on perineuronal net (PNN) deposition on PVIs in several brain regions, and the well characterized role of inhibitory signaling in alcohol use disorders. Loss of microglial-MyD88 had minimal effects on voluntary alcohol intake and anxiety-like behaviors. Alcohol exposure did not modify observed MyD88-dependent changes in PVIs/PNNs, despite altering microglial morphology in the male prefrontal cortex independent of genotype. The addition of an early life endotoxin challenge was sufficient to induce an increase in adult alcohol consumption in both MyD88-deficient and control males. However, injection of saline alone also induced an increase in adult drinking in MyD88-deficient males. These findings suggest that microglial-MyD88 signaling does not strongly regulate alcohol intake under baseline conditions in a one-bottle, voluntary binge-drinking paradigm, however there may be a role for microglial-MyD88 signaling in modulating the impact of developmental environmental contexts, such as stress, in later-life male drinking behavior. This work highlights the importance of developmental context, such as stress or inflammatory history, in understanding underlying microglia signaling mechanisms in conferring AUD risk.
Sex differences in hippocampal and prefrontal gene expression of endocannabinoid, glutamatergic and GABAergic systems and amino acids profile underlie cocaine plus ethanol seeking incubation.
Garrido-Matilla L, Vera-Fernández C, Puig-Martínez N … +3 more , Spano E, Marcos A, Ambrosio E
Neuropharmacology · 2026 Jun · PMID 42288195 · Publisher ↗
Addiction is conceptualized as a maladaptive form of learning in which drug-associated memories progressively strengthen during abstinence and increasing relapse vulnerability. This process may be particularly complex in...
Addiction is conceptualized as a maladaptive form of learning in which drug-associated memories progressively strengthen during abstinence and increasing relapse vulnerability. This process may be particularly complex in the context of cocaine and ethanol abuse, a prevalent pattern of polyconsumption linked to greater clinical severity. To model this condition, in our previous work male and female rats were subjected to an incubation of drug-seeking paradigm. While females exhibited robust incubation of cocaine plus ethanol seeking after prolonged withdrawal, males did not (Garrido-Matilla et al., 2025). In the present study, we characterized neurobiological alterations in the same cohort by analysing gene expression of endocannabinoid, glutamatergic, and GABAergic systems, as well as neurotransmission-related amino acids in the hippocampus and PFC. In the hippocampus, females showed increased cannabinoid receptor 1 expression and reduced monoacylglycerol lipase levels, together with upregulation of GABA receptor subunits, suggesting persistent adaptations in synaptic plasticity. In contrast, males exhibited downregulation of glutamatergic-related genes along with increased taurine and L-glutamine levels. In the PFC, females displayed increased cannabinoid receptor 1 and NMDA receptor subunit 2B expression, reduced GABAergic-related gene expression, and decreased taurine and L-glutamine levels, consistent with an altered excitatory-inhibitory balance. Moreover, prefrontal glutamate levels positively correlated with cocaine plus ethanol intake in females. Overall, these findings reveal sex-dependent neuroadaptations within the hippocampus and PFC following cocaine plus ethanol polyconsumption, with pronounced endocannabinoid and GABAergic alterations in females, and glutamatergic changes in males that may reflect compensatory mechanisms potentially limiting relapse vulnerability.
Disruption of dopamine transmission by cholesterol depletion is associated with alterations in protein lipid raft partitioning and actin dynamics.
Neel AI, Lee ET, West AM … +6 more , Dawes MH, Schlitzer RD, Suddaby RA, Marrs GS, Jones SR, Chen R
Neuropharmacology · 2026 Jun · PMID 42288194 · Full text
Disrupted brain cholesterol homeostasis is implicated in neurological disorders involving aberrant dopamine (DA) signaling; however, the direct effects of cholesterol on DA transmission in native tissue have not yet been...
Disrupted brain cholesterol homeostasis is implicated in neurological disorders involving aberrant dopamine (DA) signaling; however, the direct effects of cholesterol on DA transmission in native tissue have not yet been demonstrated. Using ex vivo fast-scan cyclic voltammetry in nucleus accumbens slices from male rats, we found that membrane cholesterol depletion with methyl-β-cyclodextrin (MβCD, 3-10 mM) significantly reduced evoked DA release and decreased the apparent maximal rate of DA reuptake via the dopamine transporter (DAT). Because cholesterol is critical for the formation of lipid raft microdomains, cholesterol depletion could disrupt DA transmission by altering the membrane localization of proteins involved in neurotransmitter release. Using sucrose density gradient fractionation, we found that MβCD decreased the raft association of vesicle-associated membrane protein 2 (VAMP2) without altering the localization of syntaxin-1A, synaptosomal-associated protein 25, synaptotagmin-1, and N-type voltage-gated calcium channels. Therefore, MβCD may reduce DA release by disrupting localization of VAMP2, a core component of the vesicle fusion machinery. We also examined actin polymerization, a key regulator of vesicle docking and fusion, and found that MβCD treatment decreased actin polymerization, as evidenced by an increased globular-to-filamentous actin ratio and reduced phalloidin labeling of filamentous actin in striatal slices. Finally, although DAT lipid raft localization was unchanged, MβCD attenuated cocaine's ability to inhibit DAT reuptake function, suggesting that cholesterol depletion disrupts the outward-facing conformation of DAT required for high-affinity ligand binding. Overall, these findings provide new mechanistic insights into how cholesterol depletion may contribute to dysregulated DA signaling in diseases involving altered brain cholesterol metabolism.
Cerebellar Kv2.1 downregulation, cytoarchitectural alterations, and persistent motor impairments following subchronic phencyclidine exposure.
Lagojda L, MacGregor L, Maisha M … +4 more , Abdi S, Janchivlamdan D, Forsythe I, Zhu L
Neuropharmacology · 2026 Jun · PMID 42285199 · Publisher ↗
Dysfunction of the cerebellum is increasingly recognised as a contributor to schizophrenia. As one of the most ubiquitous voltage-gated potassium channels in the brain, the expression and function of Kv2.1 remains undere...
Dysfunction of the cerebellum is increasingly recognised as a contributor to schizophrenia. As one of the most ubiquitous voltage-gated potassium channels in the brain, the expression and function of Kv2.1 remains underexplored in the cerebellum, and its potential involvement in cerebellar pathophysiology in schizophrenia is unknown. Here, we characterised the expression pattern of Kv2.1 in the cerebellar cortex and examined its changes, along with cerebellar cytoarchitecture, in a subchronic phencyclidine male mouse model of schizophrenia. Behavioural performance was assessed throughout phencyclidine treatment and during a one-week washout using the horizontal bar, vertical pole, and beam walk tests, focusing on indices of fine motor coordination and balance. Significant alterations emerged during treatment. Notably, four parameters, the number of swings on the bar, time to complete the T-turn, time to cross the beam, and number of foot slips, remained impaired after washout, indicating persistent deficits in motor coordination and balance. Fluorescence imaging showed Kv2.1 expression on the soma, proximal dendrite, and axon initial segment of Purkinje cells, and in granule cell somata and dendrites. After washout, Western blot revealed reduced cerebellar Kv2.1 levels, corroborated by fluorescence analyses showing downregulation in both Purkinje and granule cells. In addition, cytoarchitectural changes were detected, including globally reduced Purkinje cell soma size and a hemisphere-specific decrease in NeuN-positive granule cell density. Overall, this study provides a descriptive account of cerebellar cytoarchitectural and Kv2.1 expression changes, alongside persistent motor impairments, associated with subchronic phencyclidine exposure, warranting future studies on mechanistic links between cerebellar neuropathology and behavioural performance.
Selective photostimulation of locus coeruleus terminals in hippocampal-CA1 induces LTP and enhances spatial memory in free-moving mice.
Gálvez-Márquez DK, Hernández-Ortiz E, Bermúdez-Rattoni F
Neuropharmacology · 2026 Jun · PMID 42285198 · Publisher ↗
Long-term potentiation (LTP) represents a fundamental form of synaptic plasticity that underlies long-term memory. Catecholaminergic projections from the locus coeruleus (LC) to the hippocampal CA1 region modulate spatia...
Long-term potentiation (LTP) represents a fundamental form of synaptic plasticity that underlies long-term memory. Catecholaminergic projections from the locus coeruleus (LC) to the hippocampal CA1 region modulate spatial memory consolidation; however, it remains unclear whether activity in this pathway directly induces in vivo synaptic potentiation. The present study demonstrates that selective photostimulation of tyrosine hydroxylase-positive (TH) LC axon terminals in CA1 induces robust optogenetic LTP (oLTP) in the Schaffer collateral pathway. Induction of oLTP is associated with increased extracellular concentrations of noradrenaline, dopamine, and glutamate in CA1, and is abolished by local blockade of β-adrenergic, D1 dopamine, or NMDA receptors. In awake, freely moving mice, post-training induction of oLTP enhances consolidation of weak object-location memories and promotes long-term persistence of spatial memory in the Morris water maze and Barnes maze for up to 10 days. These findings establish a causal relationship between LC-derived catecholaminergic input, in vivo hippocampal LTP induction, and durable spatial memory, and identify a circuit-specific neuromodulatory mechanism that regulates synaptic plasticity during memory consolidation.
Thalamic 5-HT receptor activation reduces GABA uptake, increases tonic GABA inhibition and induces absence seizures in Wistar rats.
Crunelli V, Morais TP, Connelly WM … +5 more , Salamanca G, Vaz SH, Sebastião AM, Bombardi C, Di Giovanni G
Neuropharmacology · 2026 Jun · PMID 42276206 · Publisher ↗
Renewed interest in psychedelic therapeutics has brought serotonin 5-HT receptors (5-HTRs) back into focus. Given the role of the thalamus in sensory integration and network synchronization, we examined the expression, d...
Renewed interest in psychedelic therapeutics has brought serotonin 5-HT receptors (5-HTRs) back into focus. Given the role of the thalamus in sensory integration and network synchronization, we examined the expression, developmental regulation, and functional impact of thalamic 5-HTRs, with particular emphasis on their interaction with extrasynaptic GABA receptors and the generation of aberrant thalamocortical rhythms in Wistar rats. Immunofluorescence revealed a developmental increase of 5-HTR expression in both the reticular thalamic nucleus (NRT) and ventrobasal (VB) thalamus, that is accompanied by a shift in VB expression from GABAergic interneurons in juveniles to thalamocortical (TC) neurons in adults. Astrocyte density increased in both regions, more prominently in the NRT than in the VB, with approximately half of astrocytes expressing 5-HTRs regardless of age or region. Activation of 5-HTRs with the potent agonist TCB-2 reduced thalamic GABA uptake, an effect that was occluded in the presence of GAT1 inhibitor NO711. Patch-clamp recordings showed that TCB-2 enhanced tonic GABA currents in VB TC neurons. This effect was absent in δ-subunit KO mice and was unaffected by blockade of postsynaptic G-protein signaling or phospholipase C pathways in TC neurons, suggesting that it is not dependent on postsynaptic signaling mechanisms. EEG recordings in freely moving rats showed that bilateral microinjection of TCB-2 into the VB induced spike-and-wave discharges accompanied by behavioral arrest that were blocked by ethosuximide, indicating that they were absence seizures. In summary, these findings support a mechanism, through which serotonergic signaling via 5-HTRs can shape thalamocortical network dynamics and increase susceptibility to aberrant rhythmic activity, which could potentially occur under conditions of altered serotonergic tone.
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