Prospects, advances and biological applications of MOF-based platform for the treatment of lung cancer.

Nowadays in our society, lung cancer is exhibiting a high mortality rate and threat to human health. Conventional diagnostic techniques used in the field of lung cancer often necessitate the use of extensive instrumentation, exhibit a tendency for false positives, and are not suitable for widespread early screening purposes. Conventional approaches to treat lung cancer primarily involve surgery, chemotherapy, and radiotherapy. However, these broad-spectrum treatments suffer from drawbacks such as imprecise targeting and significant side effects, which restrict their widespread use. Metal-organic frameworks (MOFs) have attracted significant attention in the diagnosis and treatment of lung cancer owing to their tunable electronic properties and structures and potential applications. These porous nanomaterials are formed through the intricate assembly of metal centers and organic ligands, resulting in highly versatile frameworks. Compared to traditional diagnostic and therapeutic modalities, MOFs can improve the sensitivity of lung cancer biomarker detection in the diagnosis of lung cancer. In terms of treatment, they can significantly reduce side effects and improve therapeutic efficacy. Hence, this perspective provides an overview concerning the advancements made in the field of MOFs as potent biosensors for lung cancer biomarkers. It also delves into the latest research dealing with the use of MOFs as carriers for drug delivery. Additionally, it explores the applications of MOFs in various therapeutic approaches, including chemodynamic therapy, photodynamic therapy, photothermal therapy, and immunotherapy. Furthermore, this review comprehensively analyses potential applications of MOFs as biosensors in the field of lung cancer diagnosis and combines different therapeutic approaches aiming for enhanced therapeutic efficacy. It also presents a concise overview of the existing obstacles, aiming to pave the way for future advancements in lung cancer diagnosis and treatment.

Tae-miR397 Negatively Regulates Wheat Resistance to Blumeria graminis.

MicroRNA (miRNA) plays a crucial role in the interactions between plants and pathogens, and identifying disease-related miRNAs could help us understand the mechanisms underlying plant disease pathogenesis and breed resistant varieties. However, the role of miRNA in wheat defense responses remains largely unexplored. The miR397 family is highly conserved in plants and involved in plant development and defense response. Therefore, the purpose of this study was to investigate the function of tae-miR397 in wheat resistance to powdery mildew. The expression pattern analysis revealed that tae-miR397 expression was higher in young leaves than in other tissues and was significantly decreased in wheat Bainong207 leaves after Blumeria graminis (Bgt) infection and chitin treatment. Additionally, the expression of tae-miR397 was significantly down-regulated by salicylic acid and induced under jasmonate treatment. The overexpression of tae-miR397 in common wheat Bainong207 enhanced the wheat's susceptibility to powdery mildew in the seedling and adult stages. The rate of Bgt spore germination and mycelial growth in transgenic wheat plants overexpressing tae-miR397 was faster than in the untransformed wild-type plants. The target gene of tae-miR397 was predicted to be a wound-induced protein (Tae-WIP), and the function was investigated. We demonstrated that silencing of Tae-WIP via barley-stripe-mosaic-virus-induced gene silencing enhanced wheat's susceptibility to powdery mildew. qRT-PCR indicated that tae-miR397 regulated wheat immunity by controlling pathogenesis-related gene expressions. Moreover, the transgenic plants overexpressing tae-miR397 exhibited more tillers than the wild-type plants. This work suggests that tae-miR397 is a negative regulator of resistance against powdery mildew and has great potential for breeding disease-resistant cultivars.

Sex-specific association between regional gray matter volume and spicy food craving or consumption.

Both food cravings and long-term food consumption have been associated with brain changes. Sex differences in food craving are robust and substantial. The current study examined the potential sex-specific neuroanatomical correlates of spicy food craving and habitual spicy food consumption. One hundred and forty-nine participants completed the Spicy Food Consumption Questionnaire and the Spicy Food Craving Questionnaire while their structural brain images were acquired using a 3-T scanner. Multiple regression analysis was used to examine regional gray matter volume (GMV) in relation to questionnaire scores. GMV of the right supplementary motor area (SMA) and the dorsal superior frontal gyrus were significantly correlated with spicy food craving in women, whereas spicy food craving was associated with greater GMV of the inferior temporal gyrus and the occipital gyrus in men. In addition, habitual spicy food consumption was correlated with increased GMV of the bilateral putamen, left postcentral gyrus, and right paracentral lobule, which was more pronounced among female participants. These findings suggest distinct central neuroanatomical reflections of trait craving or habitual exposure to spicy flavors. The sex-specific correlation between spicy food craving and brain anatomical features may be related to food-related sensory imagery or cognitive control.

A Novel Platform of MOF for Sonodynamic Therapy Advanced Therapies.

Metal-organic frameworks (MOFs) combined with sonodynamic therapy (SDT) have been introduced as a new and efficient treatment method. The critical advantage of SDT is its ability to penetrate deep tissues and concentrate energy on the tumor site to achieve a non-invasive or minimally invasive effect. Using a sonosensitizer to generate reactive oxygen species (ROS) under ultrasound is the primary SDT-related method of killing tumor cells. In the presence of a sonosensitizer, SDT exhibits a more lethal effect on tumors. The fast development of micro/nanotechnology has effectively improved the efficiency of SDT, and MOFs have been broadly evaluated in SDT due to their easy synthesis, easy surface functionalization, high porosity, and high biocompatibility. This article reviews the main mechanism of action of sonodynamic therapy in cancer treatment, and also reviews the applications of MOFs in recent years. The application of MOFs in sonodynamic therapy can effectively improve the targeting ability of SDT and the conversion ability of reactive oxygen species, thus improving their killing ability on cancer cells. This provides new ideas for the application of micro/nano particles in SDT and cancer therapy.

Fluorescence detection platform of metal-organic frameworks for biomarkers.

Sensitive and selective detection of biomarkers is crucial in the study and early diagnosis of diseases. With the continuous development of biosensing technologies, fluorescent biosensors based on metal-organic frameworks have attracted increasing attention in the field of biomarker detection due to the combination of the advantages of MOFs, such as high specific surface area, large porosity, and structure with tunable functionality and the technical simplicity, sensitivity and efficiency and good applicability of fluorescent detection techniques. Therefore, researchers must understand the fluorescence response mechanism of such fluorescent biosensors and their specific applications in this field. Of all biomarkers applicable to such sensors, the chemical essence of nucleic acids, proteins, amino acids, dopamine, and other small molecules account for about a quarter of the total number of studies. This review systematically elaborates on four fluorescence response mechanisms: metal-centered emission (MC), ligand-centered emission (LC), charge transfer (CT), and guest-induced luminescence change (GI), presenting their applications in the detection of nucleic acids, proteins, amino acids, dopamine, and other small molecule biomarkers. In addition, the current challenges of MOFs-based fluorescent biosensors are also discussed, and their further development prospects are concerned.

Design, synthesis, and evaluation of 2,2'-bipyridyl derivatives as bifunctional agents against Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease. Metal ion dyshomeostasis and Aß aggregation have been proposed to contribute to AD progression. Metal ions can bind to Aß and promote Aß aggregation, and ultimately lead to neuronal death. Bifunctional (metal chelation and Aß interaction) compounds are showing promise against AD. In this work, eleven new 3,3'-diamino-2,2'-bipyridine derivatives 4a-4k were synthesized, and evaluated as bifunctional agents for AD treatment. In vitro Aß aggregation inhibition assay confirmed that most of the synthesized compounds exhibited significant self-induced Aß1-42 aggregation inhibition. Among them, compound 4d displayed the best inhibitory potency of self-induced Aß1-42 aggregation with IC50 value of 9.4 µM, and it could selectively chelate with Cu2+ and exhibited 66.2% inhibition of Cu2+-induced Aß1-42 aggregation. Meanwhile, compound 4d showed strong neuroprotective activity against Aß1-42 and Cu2+-treated Aß1-42 induced cell damage. Moreover, compound 4d in high dose significantly reversed Aß-induced memory impairment in mice.

MicroRNA Expression Profiles in Response to Phytophthora infestans and Oidium neolycopersici and Functional Identification of sly-miR397 in Tomato.

Late blight and powdery mildew are two widespread tomato diseases caused by Phytophthora infestans and Oidium neolycopersici, respectively, which reduce the quantity and quality of tomato. MicroRNAs (miRNAs) play critical roles in tomato resistance to various pathogens. Investigating the function of miRNAs is of great significance in controlling tomato diseases. To identify potential miRNAs involved in the interaction of tomato with P. infestans or O. neolycopersici, we analyzed the expression profiles of small RNAs in tomato leaves infected with these two pathogens using RNA-seq technology. A total of 330 and 288 miRNAs exhibited differences in expression levels after exposure to P. infestans and O. neolycopersici, respectively. One hundred and forty-six commonly differentially expressed (DE) miRNAs responsive to P. infestans and O. neolycopersici infestation were detected, including 10 commonly known conserved DE miRNAs and 136 novel miRNAs. Among these known DE miRNAs, sly-miR397 was strongly downregulated in response to P. infestans or O. neolycopersici infection. Silencing of sly-miR397 resulted in enhanced tolerance to the pathogens, whereas overexpression of sly-miR397 showed increased susceptibility. Furthermore, changes in sly-miR397 expression could also affect expression levels of pathogenesis-related genes and reactive oxygen species-scavenging genes, leading to altered necrotic cells and H2O2 levels. In addition, the number of lateral branches significantly changed in transgenic plants. Taken together, our results provide potential miRNA resources for further research of miRNA-disease associations and indicates that sly-miR397 acts as a negative regulator of disease resistance and influences lateral branch development in tomato.

Olfactory metacognition and memory in individuals with different subjective odor imagery abilities.

Imagery vividness is one of the key indicators to evaluate the ability to generate mental images. There is large inter-individual variability in olfactory imagery (OI) abilities, however, little is known about the underlying factors for individual OI abilities. Using a word cueing imagery paradigm and the trial-by-trial imagery vividness rating method, participants with high or low OI abilities (differentiated by the Vividness of Olfactory Imagery Questionnaire) completed two OI tasks with either shorter (2 s) or longer (8 s) image generation time. Participants' olfactory function, olfactory-related working memory and episodic recognition memory were measured using validated methods. Moreover, olfactory metacognition was assessed using the Odor Awareness Scale (OAS) and the Importance of Olfaction Questionnaire (IOQ). Compared to participants with high OI abilities, those with low OI abilities reported less vivid odor images during OI tasks. For participants with low OI abilities, the imagery vividness significantly improved as the image generation time increased. There was no difference regarding olfactory perception or olfactory-related memory performances between the high and the low OI ability groups. However, participants with higher OI abilities had significant higher scores on the OAS and the IOQ, indicating a superior olfactory-related metacognition. These results provide evidences supporting the underlying factors that related to variances of subjective ability of generating vivid odor mental images.

A multimodal Metal-Organic framework based on unsaturated metal site for enhancing antitumor cytotoxicity through Chemo-Photodynamic therapy.

Chemodynamic therapy when combined with chemotherapy opens up a new avenue for treatment of cancer. However, its development is still restricted by low targeting, high dose and toxic side effects. Herein, rational designing and construction of a new multifunctional platform with the core-shell structure 5-ALA@UiO-66-NH-FAM@CP1 (ALA = 5-aminolevulinic acid, CP1 = zirconium-pemetrexed (Zr-MTA)) has been performed. In this platform, CP1 acting as a shell is encapsulated with the UiO-66-NH2 to engender a core-shell structure that promotes and achieves a high MTA loading rate through high affinity between MTA and unsaturated Zr site of UiO-66-NH2. The 5-ALA and 5-carboxyl fluorescein (5-FAM) was successfully loaded and covalently combined with UiO-66-NH2 due to its high porosity and presence of amino groups. The characterization results indicated that the loading rate of MTA (41.03 wt%) of platform is higher than the reported values. More importantly, the in vitro and in vivo results also demonstrated that it has a good folate targeting ability and realizes high efficient antitumor activity by chemotherapy combied with photodynamic therapy (PDT). This newly developed multifunctional platform could provide a new idea for designing and constructing the carrier with chemotherapy and PDT therapy.

Generating odour imagery enhances brain activity in individuals with low subjective olfactory imagery ability.

Olfactory imagery (OI) is defined as the generation of odour images in the mind. There are large inter-individual differences regarding OI abilities. However, the neural representations of OI among individuals with high or low OI abilities are less understood. Participants with high or low OI abilities evaluated using the Vividness of Olfactory Imagery Questionnaire were recruited in this study. Brain activations were measured during a word cueing OI and visual imagery (VI) tasks using functional magnetic resonance imaging (fMRI). In addition, the OI task was divided into two parts. In one part, OI was performed for 8 s (long imagery generation time) and in the other part for 2 s (short imagery generation time). Ratings of the overall imagery vividness were collected at the end of each task. The vividness of OI during short OI was lower among participants with low OI abilities compared to participants with high OI abilities. Brain imaging results showed that participants with low OI ability had stronger brain activation of the supplementary motor area and the superior frontal cortex, compared to participants with higher OI abilities during the short versus long imagery generation time conditions. These results suggest that when generating odour images in a relatively short period of time (e.g., 2 s), people with either high or low OI abilities may have adopted different approaches, resulting in diverse brain activation.

Design, Synthesis, and Evaluation of Chalcone Derivatives as Multifunctional Agents against Alzheimer's Disease.

Fifteen chalcone derivatives 3a-3o were synthesized, and evaluated as multifunctional agents against Alzheimer's disease. In vitro studies revealed that these compounds inhibited self-induced Aß1-42 aggregation effectively ranged from 45.9-94.5 % at 20 µM, and acted as potential antioxidants. Their structure-activity relationships were summarized. In particular, (2E)-3-[4-(dimethylamino)phenyl]-1-(pyridin-2-yl)prop-2-en-1-one (3g) exhibited an excellent inhibitory activity of 94.5 % at 20 µM, and it could disassemble the self-induced Aß1-42 aggregation fibrils with ratio of 57.1 % at 20 µM concentration. In addition, compound 3g displayed good chelating ability for Cu2+ , and could effectively inhibit and disaggregate Cu2+ -induced Aß aggregation. Moreover, compound 3g exerted low cytotoxicity, significantly reversed Aß1-42 -induced SH-SY5Y cell damage. More importantly, compound 3g remarkably ameliorated scopolamine-induced memory impairment in mice. In summary, all the results revealed compound 3g was a potential multifunctional agent for AD therapy.

Recent developments on MOF-based platforms for antibacterial therapy.

With increasing pathogenic bacterial infection that is occurring worldwide, antibacterial therapy has become an important research field. There is great antimicrobial potential in the nanomaterial-based metal-organic framework (MOF) platform because it is highly biocompatible, biodegradable, and nontoxic, and it is now widely used in the anticancer agent industry and in the production of medical products. This review summarizes the possible mechanisms of representative MOF-based nanomaterials, and recounts recent progress in the design and development of MOF-based antibacterial materials for the remedy of postoperative infection. The existing shortcomings and future perspectives of the rapidly growing field of antimicrobial therapy addressing patient quality of life issues are also briefly discussed. Because of their wide applicability, further studies on the use of different MOF antimicrobial therapies will be of great interest.

The Notch Ligand Jagged1 Is Required for the Formation, Maintenance, and Survival of Hensen's Cells in the Mouse Cochlea.

During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1's expression is maintained in SCs through adulthood, the function of JAG1 in SC development is unknown. Here, we demonstrate that JAG1 is essential for the formation and maintenance of Hensen's cells, a highly specialized SC subtype located at the edge of the auditory epithelium. Using Sox2CreERT2/+::Jag1loxP/loxP mice of both genders, we show that Jag1 deletion at the onset of differentiation, at embryonic day 14.5, disrupted Hensen's cell formation. Similar loss of Hensen's cells was observed when Jag1 was deleted after Hensen's cell formation at postnatal day (P) 0/P1 and fate-mapping analysis revealed that in the absence of Jag1, some Hensen's cells die, but others convert into neighboring Claudius cells. In support of a role for JAG1 in cell survival, genes involved in mitochondrial function and protein synthesis were downregulated in the sensory epithelium of P0 cochlea lacking Jag1 Finally, using Fgfr3-iCreERT2 ::Jag1loxP/loxP mice to delete Jag1 at P0, we observed a similar loss of Hensen's cells and found that adult Jag1 mutant mice have hearing deficits at the low-frequency range.SIGNIFICANCE STATEMENT Hensen's cells play an essential role in the development and homeostasis of the cochlea. Defects in the biophysical or functional properties of Hensen's cells have been linked to auditory dysfunction and hearing loss. Despite their importance, surprisingly little is known about the molecular mechanisms that guide their development. Morphologic and fate-mapping analyses in our study revealed that, in the absence of the Notch ligand JAGGED1, Hensen's cells died or converted into Claudius cells, which are specialized epithelium-like cells outside the sensory epithelium. Confirming a link between JAGGED1 and cell survival, transcriptional profiling showed that JAGGED1 maintains genes critical for mitochondrial function and tissue homeostasis. Finally, auditory phenotyping revealed that JAGGED1's function in supporting cells is necessary for low-frequency hearing.

Spontaneous Hair Cell Regeneration Is Prevented by Increased Notch Signaling in Supporting Cells.

During embryonic development, differentiation of cochlear progenitor cells into hair cells (HCs) or supporting cells (SCs) is partially controlled through Notch signaling. Many studies have shown that inhibition of Notch signaling allows SCs to convert into HCs in both normal and drug damaged neonatal mouse cochleae. This mechanism is also implicated during HC regeneration in non-mammalian vertebrates; however, the mechanism of spontaneous HC regeneration in the neonatal mouse cochlea is less understood. While inhibition of Notch signaling can force SCs to convert into HCs and increase the number of regenerated HCs, it is currently unknown whether this pathway is involved in spontaneous HC regeneration observed in vivo. Therefore, we investigated the role of Notch signaling during the spontaneous HC regeneration process using Atoh1-CreERTM::Rosa26loxP-stop-loxP-DTA/+ mice injected with tamoxifen at postnatal day (P) 0 and P1 to ablate HCs and stimulate spontaneous HC regeneration. Expression changes of genes in the Notch pathway were measured using immunostaining and in situ hybridization, with most changes observed in the apical one-third of the cochlea where the majority of HC regeneration occurs. Expression of the Notch target genes Hes1, Hes5, Hey1, HeyL, and Jagged1 were decreased. To investigate whether reduction of Notch signaling is involved in the spontaneous HC regeneration process, we overexpressed the Notch1 intracellular fragment (N1ICD) in cochlear SCs and other non-sensory epithelial cells in the context of HC damage. Specifically, Atoh1-CreERTM::Rosa26loxP-stop-loxP-DTA/+::Sox10rtTA::TetO-LacZ::TetO-N1ICD mice were injected with tamoxifen at P0/P1 to stimulate spontaneous HC regeneration and given doxycycline from P0-P7 to induce expression of N1ICD as well as LacZ for fate-mapping. We observed a 92% reduction in the number of fate-mapped regenerated HCs in mice with N1ICD overexpression compared to controls with HC damage but no manipulation of Notch signaling. Therefore, we conclude that increased Notch signaling prevents spontaneous HC regeneration from occurring in the neonatal mouse cochlea. Understanding which components of the Notch pathway regulates regenerative plasticity in the neonatal mouse cochlea will inform investigations focused on stimulating HC regeneration in mature cochlea and eventually in humans to treat hearing loss.

Simultaneous determination of three flavonoids and one coumarin by LC-MS/MS: Application to a comparative pharmacokinetic study in normal and arthritic rats after oral administration of Daphne genkwa extract.

A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for investigating the pharmacokinetics of umbelliferone, apigenin, genkwanin and hydroxygenkwanin after oral administration of Daphne genkwa extract. Plasma samples were treated by protein precipitation with acetonitrile. Analytes were detected by triple-quadrupole MS/MS with an ESI source in negative selection reaction monitoring mode. The transitions of m/z 161 → 133 for umbelliferone, m/z 269 → 117 for apigenin, m/z 283 → 268 for genkwanin and m/z 299 → 284 for hydroxygenkwanin were confirmed for quantification. Chromatographic separation was conducted using an Eclipse XDB-C18 column, and the applied isocratic elution program allowed for simultaneous determination of the four analytes for a total run time of 2.5 min. The linearity was validated over the plasma concentration ranges of 1.421-1421 ng/mL for umbelliferone, 0.845-845 ng/mL for apigenin, 1.025-1025 ng/mL for genkwanin and 0.845-845 ng/mL for hydroxygenkwanin. The extraction recovery rate was >82.7% for each analyte. No apparent matrix effect was observed during the bioanalysis. After full validation, the proposed method was successfully applied to compare the pharmacokinetics of these analytes between normal and arthritic rats.

Neuregulin 3 Signaling Mediates Nicotine-Dependent Synaptic Plasticity in the Orbitofrontal Cortex and Cognition.

Neuregulin 3 (NRG3) and ErbB4 have been linked to nicotine addiction; however, the neuronal mechanisms and behavioral consequences of NRG3-ErbB4 sensitivity to nicotine remain elusive. Recent literature suggests that relapse to smoking is due to a lack of impulsive control, which is thought to be due to altered functioning within the orbitofrontal cortex (OFC). Therefore, we examined circuitry changes within this structure following nicotine application. We report that nicotine controls synaptic plasticity in the OFC through NRG3/ErbB4-dependent regulation of GABAergic inhibition. We observed that both nicotine and NRG3 facilitated the conversion of long-term potentiation into long-term depression at cortical layer 3/5 synapses. Induction of long-term depression by nicotine relied on nicotinic receptor activation and key regulators of NRG3 signaling: (1) release of intracellular calcium, (2) activation of the BACE1 beta-secretase, and (3) ErbB4 receptor activation. Nicotine-induced synaptic plasticity was also associated with accumulation of intracellular GABA and was completely blocked by GABAA/GABAB antagonists. To test whether these mechanisms underlie OFC-dependent behavior, we evaluated the effects of nicotine in the go/no-go task. Nicotine-impaired stimulus discrimination in this task was rescued by pharmacologic disruption of the NRG3 receptor, ErbB4. Altogether, our data indicate that nicotine-induced synaptic plasticity in the OFC and cognitive changes depend on NRG3-ErbB4 signaling. We propose that nicotine activation of this pathway may contribute to nicotine addiction, particularly in individuals with genetic variation in NRG3.

Distinct Roles of CREB Within the Ventral and Dorsal Hippocampus in Mediating Nicotine Withdrawal Phenotypes.

Addiction to nicotine and the inability to quit smoking are influenced by genetic factors, emphasizing the importance of understanding how genes and drugs of abuse mechanistically impact each other. One well-characterized protein responsible for regulating both response to drugs and gene expression is the transcription factor CREB (cAMP-responsive element binding protein). Previous work indicates that hippocampal-specific alterations in CREB signaling and synaptic plasticity may underlie certain nicotine withdrawal phenotypes. However, the structure of the hippocampus possesses dorsal and ventral subregions, each differing in behavioral, anatomic and gene expression characteristics. This study examines the effects of CREB deletion specifically in the ventral or dorsal hippocampus of animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. After region-specific viral injections of AAV-GFP or AAV-CRE in CREBloxP/loxP animals, behavioral testing measured anxiety levels, using the Novelty-Induced Hypophagia test, and cognition, using a contextual fear conditioning paradigm. Deletion of CREB in the ventral, but not dorsal, hippocampus resulted in amelioration of nicotine withdrawal-induced anxiety-like behavior in the Novelty-Induced Hypophagia test. In contrast, CREB deletion in the dorsal hippocampus resulted in learning and memory deficits in fear conditioning, whereas CREB deletion in the ventral hippocampus showed an enhancement in learning. Gene expression analysis showed differential treatment- and region-dependent alterations of several CREB target genes that are well-known markers of neuroplasticity within the hippocampus. Collectively, these data provide persuasive evidence towards the distinct roles of CREB within the dorsal and ventral hippocampus separately in mediating select nicotine withdrawal phenotypes.

Behavioral History of Withdrawal Influences Regulation of Cocaine Seeking by Glutamate Re-Uptake.

Withdrawal from cocaine regulates expression of distinct glutamate re-uptake transporters in the nucleus accumbens (NAc). In this study, we examined the cumulative effect of glutamate re-uptake by multiple excitatory amino acid transporters (EAATs) on drug-seeking at two different stages of withdrawal from self-administered cocaine. Rats were trained on fixed ratio 1 (FR1), progressing to FR5 schedule of reinforcement. After one day of withdrawal, microinfusion of a broad non-transportable EAAT antagonist, DL-threo-beta-benzyloxyaspartate (DL-TBOA), into the NAc shell dose-dependently attenuated self-administration of cocaine. Sucrose self-administration was not affected by DL-TBOA, indicating an effect specific to reinforcing properties of cocaine. The attenuating effect on cocaine seeking was not due to suppression of locomotor response, as DL-TBOA was found to transiently increase spontaneous locomotor activity. Previous studies have established a role for EAAT2-mediated re-uptake on reinstatement of cocaine seeking following extended withdrawal and extinction training. We found that blockade of NAc shell EAATs did not affect cocaine-primed reinstatement of cocaine seeking. These results indicate that behavioral history of withdrawal influences the effect of re-uptake mediated glutamate clearance on cocaine seeking. Dynamic regulation of glutamate availability by re-uptake mechanisms may impact other glutamate signaling pathways to account for such differences.

Sex differences in behavioral and PKA cascade responses to repeated cocaine administration.

Previous studies have shown sex different patterns in behavioral responses to cocaine. Here, we used between-subject experiment design to study whether sex differences exist in the development of behavioral sensitization and tolerance to repeated cocaine, as well as the role of protein kinase A (PKA) signaling cascade in this process. Ambulatory and rearing responses were recorded in male and female rats after 1 to 14 days of administration of saline or cocaine (15 mg/kg; ip). Correspondent PKA-associated signaling in the nucleus accumbens (NAc) and caudate-putamen (CPu) was measured at each time point. Our results showed that females exhibited higher cocaine-induced behavioral responses and developed behavioral sensitization and tolerance faster than males. Whereas females developed behavioral sensitization to cocaine after 2 days and tolerance after 14 days, male rats developed sensitization after 5 days. In addition, cocaine induced a sexual dimorphic pattern in the progression of neuronal adaptations on the PKA cascade signaling in region (NAc vs. CPu) and time (days of cocaine administration)-dependent manners. In general, more PKA signaling cascade changes were found in the NAc of males on day 5 and in the CPu of females with repeated cocaine injection. In addition, in females, behavioral activities positively correlated with FosB levels in the NAc and CPu and negatively correlated with Cdk5 and p35 in the CPu, while no correlation was observed in males. Our studies suggest that repeated cocaine administration induced different patterns of behavioral and molecular responses in the PKA cascade in male and female rats.

Oxytocin decreases cocaine taking, cocaine seeking, and locomotor activity in female rats.

Oxytocin has been shown to decrease cocaine taking and seeking in male rats, suggesting potential treatment efficacy for drug addiction. In the present study, we extended these findings to the assessment of cocaine seeking and taking in female rats. Further, we made direct comparisons of oxytocin's impact on cocaine induced locomotor activity in both males and females. In females, systemic oxytocin (0.3, 1.0, 3.0 mg/kg) attenuated lever pressing for cocaine during self-administration and oxytocin (1.0 mg/kg) attenuated cue-induced cocaine seeking following extinction. Cocaine increased baseline locomotor activity to a greater degree in females relative to males. Oxytocin (0.1, 0.3, 1.0, and 3.0 mg/kg) reduced cocaine-induced locomotor activity in females, but not significantly in males. These data illustrate sex similarities in oxytocin's attenuation of cocaine seeking, but sex differences in cocaine-induced locomotor effects. While reductions in cocaine seeking cannot be attributed to a reduction in locomotor activity in males, attenuation of locomotor function cannot be entirely ruled out as an explanation for a decrease in cocaine seeking in females suggesting that oxytocin's effect on cocaine seeking may be mediated by different mechanisms in male and females.