Prescription opioid abuse is an increasing public health concern in the USA. A vaccine comprising a hapten (OXY) conjugated to the carrier protein keyhole limpet hemocyanin (OXY-KLH) has been shown ...to attenuate the antinociceptive effects of oxycodone. Here, the vaccine's ability to prevent acquisition of intravenous (i.v.) oxycodone self-administration was studied in rats. Effects of vaccination on oxycodone-induced changes in the expression of several genes within the mesolimbic system, which are regulated by chronic opiate use, were also examined. Vaccination with OXY-KLH reduced the proportion of rats acquiring i.v. self-administration of oxycodone under a fixed ratio (FR) 3 schedule of reinforcement compared to control rats immunized with the unconjugated KLH carrier protein. Vaccination significantly reduced the mean number of infusions at FR3, total number of infusions, and total oxycodone intake during the entire protocol. Compared to oxycodone self-administering control rats immunized with the carrier alone, rats vaccinated with the OXY-KLH immunogen showed increased levels of adenylate cyclase 5 (Adcy5) and decreased levels of early growth response protein 2 (Egr2) and the early immediate gene c-Fos in the striatum. These data suggest that vaccination with OXY-KLH can attenuate the reinforcing effects of oxycodone at a clinically-relevant exposure level. Analysis of mRNA expression identified some addiction-relevant markers that may be of interest in understanding oxycodone effects or the protection provided by vaccination.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • We tested effects of tobacco alkaloids on intracranial self-stimulation (ICSS). • Moderate nicotine doses reduced while high nicotine doses increased ICSS thresholds. • Nornicotine and ...anabasine produced similar effects, although with lower potency. • High-dose myosmine elevated thresholds, while anatabine and cotinine had no effect. • Some minor alkaloids can either fully or partially mimic nicotine's effects on ICSS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions ...required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models, including evaluation of more clinically relevant nicotine dosing regimens and other measures of nicotine withdrawal (e.g., anxiety-like behavior, somatic signs), may be useful for understanding the development of the nicotine withdrawal syndrome.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Preclinical models are needed to inform regulation of tobacco products by the Food and Drug Administration (FDA). Typically, animal models of tobacco addiction involve exposure to ...nicotine alone or nicotine combined with isolated tobacco constituents (e.g. minor alkaloids). The goal of this study was to develop a model using extracts derived from tobacco products that contain a range of tobacco constituents to more closely model product exposure in humans. Methods This study compared the addiction-related effects of nicotine alone and nicotine dose-equivalent concentrations of aqueous smokeless tobacco extracts on intracranial self-stimulation (ICSS) in rats. Extracts were prepared from Kodiak Wintergreen, a conventional product, or Camel Snus, a potential “modified risk tobacco product”. Binding affinities of nicotine alone and extracts at various nicotinic acetylcholine receptor (nAChR) subtypes were also compared. Results Kodiak and Camel Snus extracts contained levels of minor alkaloids within the range of those shown to enhance nicotine's behavioral effects when studied in isolation. Nonetheless, acute injection of both extracts produced reinforcement-enhancing (ICSS threshold-decreasing) effects similar to those of nicotine alone at low to moderate nicotine doses, as well as similar reinforcement-attenuating/aversive (ICSS threshold-increasing) effects at high nicotine doses. Extracts and nicotine alone also had similar binding affinity at all nAChRs studied. Conclusions Relative nicotine content is the primary pharmacological determinant of the abuse liability of Kodiak and Camel Snus as measured using ICSS. These models may be useful to compare the relative abuse liability of other tobacco products and to model FDA-mandated changes in product performance standards.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Avoidance of the negative affective (emotional) symptoms of nicotine withdrawal (e.g., anhedonia, anxiety) contributes to tobacco addiction. Establishing the minimal nicotine exposure conditions ...required to demonstrate negative affective withdrawal signs in animals, as well as understanding moderators of these conditions, could inform tobacco addiction-related research, treatment, and policy. The goal of this study was to determine the minimal duration of continuous nicotine infusion required to demonstrate nicotine withdrawal in rats as measured by elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior). Administration of the nicotinic acetylcholine receptor antagonist mecamylamine (3.0 mg/kg, s.c.) on alternate test days throughout the course of a 2-week continuous nicotine infusion (3.2 mg/kg/day via osmotic minipump) elicited elevations in ICSS thresholds beginning on the second day of infusion. Magnitude of antagonist-precipitated withdrawal did not change with further nicotine exposure and mecamylamine injections, and was similar to that observed in a positive control group receiving mecamylamine following a 14-day nicotine infusion. Expression of a significant withdrawal effect was delayed in nicotine-infused rats receiving mecamylamine on all test days rather than on alternate test days. In a separate study, rats exhibited a transient increase in ICSS thresholds following cessation of a 2-day continuous nicotine infusion (3.2 mg/kg/day). Magnitude of this spontaneous withdrawal effect was similar to that observed in rats receiving a 9-day nicotine infusion. Our findings demonstrate that rats exhibit antagonist-precipitated and spontaneous nicotine withdrawal following a 2-day continuous nicotine infusion, at least under the experimental conditions studied here. Magnitude of these effects were similar to those observed in traditional models involving more prolonged nicotine exposure. Further development of these models, including evaluation of more clinically relevant nicotine dosing regimens and other measures of nicotine withdrawal (e.g., anxiety-like behavior, somatic signs), may be useful for understanding the development of the nicotine withdrawal syndrome.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Moving is an indispensable component of travelling. This paper discusses the experiences of persons with disabilities when moving around cities on foot or wheels, based on research conducted during ...the EU-funded project TRIPS. Findings comprise participants’ vignettes from 49 interviews in seven European cities, views on smart assistive technologies (e.g., Augmented Reality) from a pan-European quantitative survey, and design concepts related to walking based on a co-creation workshop that actively engaged persons with various types of disabilities in ideation. Findings suggest that people need reliable and clear wayfaring information on accessible travel routes featuring the coordinated design of streets, pavement, stops, stations, and vehicles to ensure seamless, step-free, and obstacle-free access, as well as disability-sensitive management of disruptions such as maintenance works, for example. Findings also suggest that users are open to using any assistive technology that can enable them to live more independently, assuming it is accessible, and are keen to co-innovate. Finally, we make recommendations for policy changes that can facilitate the redesign of urban infrastructure to make cities more accessible for people with disabilities and drive structural changes in urban planning.
Introduction
Shared on-demand mobility services emerge at a fast pace, changing the landscape of public transport. However, shared mobility services are largely designed without considering the ...access needs of people with disabilities, putting these passengers at risk of exclusion. Recognising that accessibility is best addressed at the design stage and through direct participation of persons with disabilities, the objective of this study was to explore disabled users’ views on the following emerging shared mobility services: (a) ride pooling, (b) microtransit, (c) motorbike taxis, (d) robotaxis, (f) e-scooter sharing, and (g) bike sharing.
Methodolgy
Using an online mobility survey, we sampled disabled users’ (1) views on accessibility, (2) use intention, and (3) suggestions for improving accessibility. The results reflect the responses of 553 individuals with different types of disabilities from 21 European countries.
Results
Projected accessibility and use intention were greatest for microtransit, robotaxis, and ride pooling across different disabilities. In contrast, motorbike taxis, e-scooter sharing, and bike sharing were viewed as least accessible and least attractive to use, especially by persons with physical, visual, and multiple disabilities. Despite differences in projected accessibility, none of the shared mobility services would fulfil the access needs of disabled persons in their current form. Suggestions for increasing the accessibility of these services included (a) an ondemand door-to-door service, (b) an accessible booking app, (c) real-time travel information, and (d) the necessity of accommodating wheelchairs.
Conclusions
Our findings highlight the need for improving both vehicles and service designs to cater for the access needs of persons with disabilities and provide policymakers with recommendations for the design of accessible mobility solutions.
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CEKLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Steroidal alkaloids (SAs) are triterpene-derived specialized metabolites found in members of the Solanaceae family that provide plants with a chemical barrier against a broad range of pathogens. ...Their biosynthesis involves the action of glycosyltransferases to form steroidal glycoalkaloids (SGAs). To elucidate the metabolism of SGAs in the Solanaceae family, we examined the tomato (Solanum lycopersicum) GLYCOALKALOID METABOLISM1 (GAME1) gene. Our findings imply that GAME1 is a galactosyltransferase, largely performing glycosylation of the aglycone tomatidine, resulting in SGA production in green tissues. Downregulation of GAME1 resulted in an almost 50% reduction in α-tomatine levels (the major SGA in tomato) and a large increase in its precursors (i.e., tomatidenol and tomatidine). Surprisingly, GAME1-silenced plants displayed growth retardation and severe morphological phenotypes that we suggest occur as a result of altered membrane sterol levels caused by the accumulation of the aglycone tomatidine. Together, these findings highlight the role of GAME1 in the glycosylation of SAs and in reducing the toxicity of SA metabolites to the plant cell.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently, ...their activity has been related to the block of N-type voltage-gated Ca2+ channels (Cav2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A3AR agonists in reducing postinflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intracolonic instillation of 2,4-dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 mL 50% EtOH). Visceral hypersensitivity was assessed by measuring the visceromotor response and the abdominal withdrawal reflex to colorectal distension. The effects of A3AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Cav2.2 blocker PD173212, and the clinically used drug linaclotide. A3AR agonists significantly reduced DNBS-evoked visceral pain both in the postinflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Cav2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A3AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A3AR agonists inhibited Cav2.2 in dorsal root ganglia neurons isolated from either control or DNBS-treated rats. The effect on Ca2+ current was PD173212-sensitive and prevented by MRS1523. A3AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.
This review provides recommendations for the evaluation and management of individuals with beta‐propeller protein‐associated neurodegeneration (BPAN). BPAN is one of several neurodegenerative ...disorders with brain iron accumulation along with pantothenate kinase‐associated neurodegeneration, PLA2G6‐associated neurodegeneration, mitochondrial membrane protein‐associated neurodegeneration, fatty acid hydroxylase‐associated neurodegeneration, and COASY protein‐associated neurodegeneration. BPAN typically presents with global developmental delay and epilepsy in childhood, which is followed by the onset of dystonia and parkinsonism in mid‐adolescence or adulthood. BPAN is an X‐linked dominant disorder caused by pathogenic variants in WDR45, resulting in a broad clinical phenotype and imaging spectrum. This review, informed by an evaluation of the literature and expert opinion, discusses the clinical phenotype and progression of the disease, imaging findings, epilepsy features, and genetics, and proposes an approach to the initial evaluation and management of disease manifestations across the life span in individuals with BPAN.
What this paper adds
The complex epilepsy profile of beta‐propeller protein‐associated neurodegeneration (BPAN) often resolves in adolescence.
The treatment for an individual with BPAN is supportive, with attention to sleep disorders, complex epilepsy, and behavioral problems.
Individuals with BPAN have shifting needs throughout their life span requiring multidisciplinary care.
What this paper adds
The complex epilepsy profile of beta‐propeller protein‐associated neurodegeneration (BPAN) often resolves in adolescence.
The treatment for an individual with BPAN is supportive, with attention to sleep disorders, complex epilepsy, and behavioral problems.
Individuals with BPAN have shifting needs throughout their life span requiring multidisciplinary care.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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