Neuropharmacology最新文献

Cannabinoid CB₂ agonists show promise as analgesics because they lack unwanted side effects associated with direct activation of CB₁ receptors. CB₂ receptor activation suppresses pathological pain in animal models, but the types of pain that best respond to CB₂ agonists are incompletely understood. This gap in knowledge may contribute to failures in clinical translation. We previously showed that the G protein-biased CB₂ receptor agonist LY2828360 attenuated the maintenance of neuropathic pain behavior in mouse models of inflammatory and neuropathic pain. Whether this finding generalizes to neuropathic pain induced by traumatic nerve injury or occurs in multiple rodent species remains unknown. Here we show that LY2828360 (3 and 10 mg/kg i.p.), administered acutely, reversed paclitaxel-induced mechanical hypersensitivity in male rats. By contrast, LY2828360 (10 mg/kg i.p.), administered acutely, attenuated mechanical hypersensitivity in a spared nerve injury (SNI) rat model, whereas the low dose (3 mg/kg i.p.) was ineffective. In both models, efficacy of LY2828360 was sustained following 10 days of repeated dosing. LY2828360 (3 mg/kg i.p.) also prevented development of tolerance to the opioid analgesic morphine (6 mg/kg i.p.) in rats with SNI when co-administered. LY2828360 (3 mg/kg i.p.) did not produce preference or aversion in the conditioned place preference (CPP) test in rats when administered alone but blocked CPP to morphine (6 mg/kg i.p.). Lastly, LY2828360 (3 mg/kg i.p.) did not alter the acquisition of i.v. morphine self-administration under fixed ratio 1 (FR1) and 3 (FR3) or motivation to work for morphine under a progressive ratio (PR) schedule of reinforcement.

Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model in male and female mice to assess changes in locomotor responses after repeated cocaine (10 mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.

Serotonin 5-HT_1A receptor agonists are prime candidates for CNS drug discovery due to their involvement physiological and pathological processes relevant to neurology and psychiatry. However, the lack of target specificity of many previously characterized agonists has long been a barrier to pharmacological and therapeutic progress. Some of the obstacles may be overcome through the recent concept of biased agonism, which has attracted considerable attention to the development of novel chemical entities at 5-HT, and particularly 5-HT_1A receptors, by specifically targeting intracellular signalling pathways that may themselves be linked to specific brain regions and therapeutic indications. There is now abundant translational data demonstrating distinct molecular and functional pharmacological signatures between different 5-HT_1A receptor agonists, opening new opportunities for research in neurology and psychiatry. Nevertheless, important limitations need to be overcome, including understanding the precise molecular basis for biased agonism, the need for improved translatable models, and the currently limited clinical data on biased agonists. Here, we review the current limits of our knowledge of 5-HT_1A receptor biased agonists and the limitations of available pharmacological tools, counterbalanced by the translational possibilities and therapeutic perspectives opened by novel, highly selective 5-HT1A receptor drug-candidates. This article is part of the Special Issue on "Ligand Bias".

Heavy alcohol use during adolescence has a significant impact on cognitive functions, such as episodic memory, even after detoxification. However, in animal models, defects in episodic memory by adolescent alcohol exposure have not been consistently replicated, and thus, the brain regions and systems that are involved remain to be elucidated. Here, we show that adolescent alcohol exposure impairs episodic memory through the impairment of the dopamine system in the prelimbic region (PrL) of the medial prefrontal cortex in both females and males. Using mice as a model, we first show that adolescent alcohol exposure disrupts episodic-like memory in female and male adult mice. We then show that adolescent alcohol exposure decreases dopaminergic presynaptic terminals in the PrL in female and male mice. This decrease persists into adulthood. Finally, we show that the adult application of a D1 dopamine receptor agonist into the PrL of adolescent alcohol-exposed mice rescues episodic-like memory in female and male mice. Together, our results identify that dopaminergic synapses in the PrL play critical roles in the effects of adolescent alcohol use on episodic memory and provide a potential strategy to reverse memory deficits caused by adolescent alcohol use in both sexes.

Bipolar disorder (BD) is psychiatric disorder of not fully acknowledged pathophysiology. Studies show the involvement of innate-immune system activation and inflammation in BD course and treatment efficiency. Microglia are crucial players in the inflammatory response possibly responsible for BD innate-immune activity. Lithium is a mood stabilizer used in treatment for 75 years. Immunomodulation was previously described as one of the potential modes of its action. We hypothesized that lithium might modulate the microglia response to innate-immune-associated cytokines (10 ng/mL TNF-α, 50 ng/mL IL-1β, 20 ng/mL IFN-γ). We aimed to investigate whether lithium treatment and pretreatment of microglia modify the expression of genes associated with NLRP3 inflammasome. We also aimed to verify lithium treatment effect on caspase activity and extracellular IL-1β concentration. For the first time, our study used human microglial cell line - HMC3, the cytokine stimuli and lithium in concentration corresponding to that in the brains of patients. To analyze lithium mode of action, we analyzed the short- and long-term treatment and pretreatment. To assess the influence on microglia responding to innate-immune cytokines, we analyzed the expression of genes involved in innate-immune and inflammasome (TSPO, TLR4, NFKB1, CASP1, CASP4, NLRP3, IL-1β, IL-6), caspase activity, extracellular IL-1β concentration, phospho-GSK-3β(Ser9) expression and lactate concentration. We found that lithium treatment significantly reduced NLRP3 inflammasome-related genes expression. We observed that lithium treatment reduces inflammasome activity, which may attenuate the inflammatory state. Interestingly, the lithium pretreatment resulted in significantly elevated inflammasome activity, suggesting that lithium does not impair the immune response to additional stimuli.

Obesity and its related complications are growing in prevalence worldwide, with increasing impact to individuals and healthcare systems alike. Currently, the leading treatment approaches for effective and sustained weight loss are bariatric surgery and gut peptide therapeutics. At a high level, both treatment strategies work by hijacking gut-brain axis signaling to reduce food intake. However, we predict that each modality has distinct neuronal mechanisms that are responsible for their success and complications. This review compares the neurobiology of feeding behavior between these two weight loss strategies via a discussion of both clinical and pre-clinical data. The most compelling evidence points to signaling within the hindbrain, hypothalamus, and reward circuits contributing to weight loss. Considerations for treatment, including differing complications between the two treatment approaches, will also be discussed. Based on the data, we pose the hypothesis that these two interventions are acting via distinct mechanisms to induce weight loss. Both interventions have variable degrees of weight loss across the patient population, thus, understanding these distinct mechanisms could help drive individualized medicine to optimize weight loss. This article is part of the Special Issue on "Food intake and feeding states".

Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. Recently, we have shown that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking ACSS2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we further explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consume significantly less alcohol in a model of binge drinking, an effect primarily driven by males. Genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use revealed that, following drinking, Acss2 KO mice exhibit blunted gene expression in the ventral striatum. Similarly to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that ACSS2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue.

The physiological role of GPR88, an orphan G protein-coupled receptor (GPCR) predominantly expressed in the striatum, remains unclear, despite its altered expression in parkinsonian animal models. GPR88 is known to interact with other GPCRs. Specifically, GPR88 expression inhibits signaling mediated by the μ-opioid receptor in cells coexpressing both receptors. The effect of GPR88 on the kappa-opioid receptor (KOR) is less understood. In this study, we examine the interaction between GPR88 and KOR, and the impact of GPR88 expression on KOR-mediated signaling in heterologous cells and primary striatal neurons. Bioluminescence resonance energy transfer and proximity ligation assays revealed an interaction between GPR88 and KOR. Functional assays showed that GPR88 antagonized the effects of U69,593, a selective KOR agonist, on forskolin-stimulated cAMP levels, β-arrestin-2 recruitment, and phosphorylation of extracellular signal-regulated kinases (ERK1/2) in HEK-293T cells coexpressing both receptors. In primary striatal neurons, GPR88 and KOR complexes were observed, with KOR activation effects enhanced when GPR88 expression was suppressed using RNA interference. These results suggest that GPR88 and KOR are coexpressed in striatal neurons, where GPR88 inhibits KOR activation. Notably, the GPR88-KOR heteromer was more prevalent in dopamine D₁-receptor-containing neurons of the direct pathway of the basal ganglia. Given the roles of KORs in dopamine release, motor function regulation, and pain and reward perception, the GPR88-KOR interaction warrants further investigation in the context of neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.

Neurotransmitter and neuromodulator release by Ca²⁺-regulated exocytosis is essential for information transmisson between cells. Formation of SNARE complex (soluble N-ethylmaleimide sensitive factor attachment protein receptors) provide energy to bring vesicles and the plasma membranes together and catalyze membrane fusion. The "Ca²⁺-dependent activator protein for secretion" (CAPS) assumes a pivotal role in facilitating vesicle content release, not only in the nervous system but also in various other secretory tissues. In recent years, great progress has been made in the study of the mechanism of CAPS regulating vesicle secretion. In this review, we summarize recent advances toward the functions and molecular mechanisms of CAPSs in vesicle exocytosis, and contemplate future research directions that will illuminate the molecular mechanisms of neurodegeneration.

Postoperative cognitive dysfunction (POCD) is a prevalent neurocognitive complication of anesthesia and surgery. Metformin, a widely used antidiabetic drug, has neuroprotective properties and improves cognitive impairment and memory deficits. However, the mechanisms underlying its action in improving cognitive dysfunction after anesthesia and surgery remain unclear. This study aimed to explore the effects of metformin on POCD and the underlying mechanisms at play. We established an in vivo POCD model using isoflurane inhalation anesthesia with exploratory laparotomy. We found that pretreatment with metformin significantly improved cognitive function and anxiety-like behaviors in mice. Additionally, metformin attenuated the impairment of synaptic plasticity induced by POCD and restored levels of synaptic proteins and dendritic density in the hippocampus. Furthermore, metformin attenuated neuroinflammation by downregulating the expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α, and reducing neuronal apoptosis. It also activates the PI3K/AKT signaling pathway, resulting in increased expression of brain-derived neurotrophic factor (BDNF). Finally, the PI3K inhibitor, LY294002, reversed the effects of metformin on the levels of PI3K, AKT phosphorylation, and BDNF in vitro cultured HT-22 cells. Additionally, in an in vivo model of POCD, it was observed that cognitive function in mice was significantly suppressed by treatment with the PI3K inhibitor LY294002. These results reveal that metformin may alleviate POCD by modulating the PI3K/AKT/BDNF axis. Our study may provide a novel strategy for preventing and treating POCD with this medication.