Psychopharmacology

Kaur, Manpreet; Aran, Khadga Raj; Paswan, Raju

doi: 10.1007/s00213-024-06708-4pmid: 39463207

RationaleNeurological conditions like Stroke and Alzheimer’s disease (AD) often include inflammatory responses in the nervous system. Stroke, linked to high disability and mortality rates, poses challenges related to organ-related complications. Recent focus on understanding the pathophysiology of ischemic stroke includes aspects like cellular excitotoxicity, oxidative stress, cell death mechanisms, and neuroinflammation.ObjectiveThe objective of this paper is to summarize and explore the pathophysiology of ischemic stroke, elucidates the gut-brain axis mechanism, and discusses recent clinical trials, shedding light on novel treatments and future possibilities.ResultsChanges in gut architecture and microbiota contribute to dementia by enhancing intestinal permeability, activating the immune system, elevating proinflammatory mediators, altering blood-brain barrier (BBB) permeability, and ultimately leading to neurodegenerative diseases (NDDs). The gut-brain axis’s potential role in disease pathophysiology offers new avenues for cell-based regenerative medicine in treating neurological conditions.ConclusionIn conclusion, the gut microbiome significantly impacts stroke prognosis by highlighting the role of the gut-brain axis in ischemic stroke mechanisms. This insight suggests potential therapeutic strategies for improving outcomes.

Brandner, Dieter D.; Mashal, Mohammed A.; Grissom, Nicola M.; Rothwell, Patrick E.

doi: 10.1007/s00213-024-06660-3pmid: 39083079

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice, using locomotor activity as a proxy for differences in opioid sensitivity that may be related to the pathophysiology and treatment of autism spectrum disorders. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

Cui, Changmeng; Zhu, Li; Han, Guangkui; Sun, Jianping; Zhang, Liang; Guo, Yujin; Jiang, Pei

doi: 10.1007/s00213-024-06691-wpmid: 39317770

RationaleTraumatic brain injury (TBI) is a critical condition associated with cognitive impairments, including dementia. This study is aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and explore molecular mechanisms underlying post-TBI dementia.MethodsGSE104687 and GSE205661 datasets were downloaded from Gene Expression Omnibus database. Molecular Signatures Database (MSigDB) was used to search oxidative stress-, metabolism- and immune-related genes as the target gene datasets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were carried out for functional annotation and enrichment analysis. A TBI mouse model was built to validate the expression of NF2, PLXNA2, NCBP2 and U2SURP in brain tissues.ResultsA total of 7 differentially expressed lncRNAs (DElncRNAs) and 191 DEmRNAs were obtained. Subsequent to differential expression (DE) analysis, a lncRNA-miRNA-mRNA network was established. Notably, 13 key DEmRNAs were identified, potentially playing pivotal roles in the pathogenesis of TBI-induced dementia. By comparing the target gene datasets with 13 DEmRNAs, we identified 4 target genes that overlap with the 13 DEGmRNAs, namely NF2, PLXNA2, NCBP2 and U2SURP. Functional enrichment analysis highlighted the involvement of neuronal projections in the dementia-enriched cluster, while the protective cluster showed associations with protein synthesis and ubiquitination pathways. Importantly, we explored potential drug interventions based on interactions with the above 4 target genes. Additionally, drug interaction prediction showed that NF2 could interact with SELUMETINIB, EVEROLIMUS and TEMSIROLIMUS.ConclusionOur study provides insights into the complex regulatory networks underlying post-TBI dementia and suggests a potential role for three classes of drugs in managing dementia symptoms in TBI-induced dementia.

Zamarripa, C. Austin; Pareek, Tanya; Pham, Loc M.; Blough, Bruce E.; Schrock, Hayley M.; Vallender, Eric J.; Sufka, Kenneth J.; Freeman, Kevin B.

doi: 10.1007/s00213-024-06690-xpmid: 39333403

RationaleG-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints.ObjectivesThe aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats.MethodsIn the self-administration study, four separate groups of Sprague–Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography.ResultsAll MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner.ConclusionThe present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics.

Xu, Jingyi; Shen, Rongjing; Qian, Mengting; Ning, Luying; Zhang, Xinyu; Xie, Bingqing; Jiang, Yong; Zhou, Zhengjun; Dong, Wei

doi: 10.1007/s00213-024-06689-4pmid: 39488807

RationaleDiabetic retinopathy (DR) is linked to an increased risk of psychiatric and neurological conditions, largely due to chronic inflammation, oxidative stress, and microvascular damage associated with the disease. Emerging evidence suggests that Cassia seed extract has significant anti-inflammatory and antioxidant properties. However, the therapeutic potential of obtusin, a major compound in Cassia seed, and its underlying mechanisms remain unclear.ObjectiveThis study aimed to evaluate the therapeutic efficacy of obtusin in the treatment of DR.MethodsDb/db mice were treated with obtusin (5 and 10 mg/kg/day) for 12 weeks. Throughout the study, body weight, blood glucose levels, and lipid profiles were monitored. Retinal histopathology and transmission electron microscopy were used to assess the pharmacological effects of obtusin in vivo. Additionally, in vitro assays were conducted on human retinal microvascular endothelial cells cultured under high glucose conditions to explore obtusin’s potential role in mitigating DR.ResultsObtusin treatment in diabetic mice significantly reduced blood glucose levels, improved dyslipidemia, thickened retinal layers, reduced retinal oxidative stress, and inhibited the upregulation of inflammatory cytokines. It also lessened fundus microangiopathy and preserved the retina’s normal barrier function. Mechanistic in vitro analysis suggested that obtusin targets the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway, both of which are implicated in DR.ConclusionsOur findings suggest that the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway could be therapeutic targets for obtusin in the treatment of DR and its associated psychiatric and neurological conditions.

Nianpanich, Saranda; Rodsiri, Ratchanee; Islamie, Ridho; Limpikirati, Patanachai; Thanusuwannasak, Thanundorn; Vajragupta, Opa; Kanasuwan, Apinan; Sarasamkan, Jiradanai

doi: 10.1007/s00213-024-06675-wpmid: 39177808

ObjectivesSubstance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR).MethodsThe effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice.ResultsThe results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10 mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10 mg/kg) and (S)-T2 (10 mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC).ConclusionsThese findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

Bossert, Jennifer M.; Caldwell, Kiera E.; Korah, Hannah; Batista, Ashley; Bonbrest, Hannah; Fredriksson, Ida; Jackson, Shelley N.; Sulima, Agnieszka; Rice, Kenner C.; Zaveri, Nurulain T.; Shaham, Yavin

doi: 10.1007/s00213-024-06678-7pmid: 39269500

RationaleThe opioid crisis persists despite availability of effective opioid agonist maintenance treatments (methadone and buprenorphine). Thus, there is a need to advance novel medications for the treatment of opioid use and relapse.ObjectivesWe recently modeled maintenance treatment in rats and found that chronic delivery of buprenorphine and the mu opioid receptor (MOR) partial agonist TRV130 decreases relapse to oxycodone seeking and taking. In contrast, chronic delivery of the buprenorphine analog BU08028 had mixed effects on different heroin relapse-related measures. Here, we tested the effect of the mixed nociceptin (NOP) receptor/MOR partial agonist AT-201 and the NOP receptor antagonist J-113397 on different heroin relapse-related measures.MethodsWe trained male and female rats to self-administer heroin (6-h/d, 14-d) in context A and then implanted osmotic minipumps containing AT-201 (0, 3.8, or 12 mg/kg/d) or J-113397 (0, 12.6, or 40 mg/kg/d). Next, we tested the effect of chronic delivery of the compounds on (1) incubation of heroin seeking in a non-drug context B, (2) extinction responding reinforced by heroin-associated discrete cues in context B, (3) context A-induced reinstatement of heroin seeking, and (4) reacquisition of heroin self-administration in context A.ResultsIn females, AT-201 modestly increased reacquisition of heroin self-administration and J-113397 modestly decreased incubation of heroin seeking. The compounds had no effect on the other relapse-related measures in females, and no effect on any of the measures in males.ConclusionThe NOP/MOR partial agonist AT-201 and the NOP antagonist J-113397 did not mimic buprenorphine’s inhibitory effects on relapse in a rat model of opioid maintenance treatment.

Bertagna, Natalia B.; Holmgren, Eleanor B.; Engi, Sheila A.; Ha, Linh; Cruz, Fabio C.; Albrechet-Souza, Lucas; Wills, Tiffany A.

doi: 10.1007/s00213-024-06693-8pmid: 39348004

RationaleAlcohol exposure during adolescence has been linked to long-lasting behavioral consequences, contributing to the development of alcohol use disorder. Negative affect and chronic pain during alcohol withdrawal are critical factors influencing problematic alcohol use and relapse. Our previous research demonstrated that adolescent intermittent ethanol (AIE) vapor exposure elicits sex-specific negative affect-like behavior in adult mice following stress exposure. Additionally, AIE induces persistent mechanical hypersensitivity, which is accompanied by increased activation of corticotropin-releasing factor receptor type 1 (CRFR1) neurons in the dorsolateral bed nucleus of the stria terminalis (dlBNST).ObjectivesThis study extends previous work by investigating plasma corticosterone levels and CRFR1 protein expression in the dlBNST following restraint stress exposure in adult mice with an AIE history. We also aim to explore the role of dlBNST CRFR1 signaling in mediating negative affect-like behavior and mechanical hypersensitivity.ResultsFemale mice exhibited elevated plasma corticosterone levels compared to males following restraint stress. Moreover, females with AIE history showed higher expression of CRFR1 protein in the dlBNST compared to air controls. Antagonism of CRFR1 in the dlBNST blocked AIE-induced mechanical hypersensitivity in adult females but did not affect stress-induced negative affect-like behavior. In alcohol-naïve females, intra-dlBNST administration of a CRFR1 agonist induced mechanical hypersensitivity.ConclusionsThese findings provide new insights into the neurobiological mechanisms underlying stress-induced negative affect and pain-related behavior, both influenced by a history of adolescent alcohol exposure. The results suggest that CRFR1 antagonists warrant further investigation for their potential in addressing alcohol-related chronic pain.

Dai, Shanghua; Dong, Yigang; Shi, Haifeng; Jin, Jiawei; Gan, Yixia; Li, Xinyi; Wu, Yongkang; Wang, Fanglin; Zhu, Xinrui; Hu, Qingmiao; Dong, Yi; Fu, Yingmei

doi: 10.1007/s00213-024-06698-3

Arnold, Miranda E.; Harber, Cecelia E.; Beugelsdyk, Lauren A.; Decker Ramirez, Ellie B.; Phillips, Grace B.; Schank, Jesse R.

doi: 10.1007/s00213-024-06707-5pmid: 39466414

RationaleAlcohol consumption despite negative consequences is a core symptom of Alcohol Use Disorder. In animal models, this is studied by pairing aversive stimuli with alcohol access, and continuation of drinking under these conditions is known as aversion resistance. Previously, we found that female mice are more aversion resistant than males. Corticotropin releasing hormone (Crh) and the Crh receptor 1 (Crhr1) regulate stress-induced reinstatement, alcohol dependence, and binge-like drinking. However, the role of the Crh system in aversion resistance has not been assessed.ObjectivesWe aimed to identify sex differences in the Crh system during quinine-adulterated alcohol intake.MethodsWe used two-bottle choice and adulterated the alcohol solution with quinine. Next, we measured Crh and Crhr1 levels in brain tissue using real-time polymerase chain reaction (RT-qPCR) and RNAscope in situ hybridization. We then infused a Crhr1 antagonist into the medial prefrontal cortex (mPFC) prior to quinine-alcohol intake.ResultsAfter quinine-alcohol consumption, females exhibited increased mPFC Crhr1 mRNA levels as measured by RT-qPCR. This was confirmed with greater anatomical specificity using RNAscope, with females exhibiting an increased number of Crhr1 + cells in the dorsomedial PFC and the ventromedial PFC. mPFC Crhr1 antagonist treatment reduced quinine-alcohol consumption in females but did not impact consumption in males. Quinine-free alcohol intake was unaffected by Crhr1 antagonist treatment.ConclusionsOur findings suggest that Crhr1 in mPFC plays a role in aversion resistant alcohol intake in females. Future experiments will examine the sources of Crh innervation to the mPFC and their distinct roles in alcohol seeking.