Somatic Signs Research Articles

Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence.

Despite considerable efforts, few drugs are available for the treatment of alcohol (ethanol [EtOH]) use disorder (AUD). EtOH directly or indirectly modulates several aspects of the central nervous system, including neurotransmitter/neuromodulator systems. Relapse vulnerability is a challenge for the treatment of EtOH addiction. EtOH withdrawal symptoms create motivational states that lead to compulsive EtOH drinking and relapse even after long periods of abstinence. Among the therapeutics to treat AUD, naltrexone (NTX) is a pharmacological treatment for relapse. The present study evaluated the effect of NTX on EtOH drinking in male and female EtOH-dependent rats during abstinence. Wistar rats (males and females) were first trained to orally self-administer 10% EtOH. Half of the rats were then made dependent by chronic intermittent EtOH (CIE) vapor exposure, and the other half were exposed to air. Using this model, rats exhibit somatic and motivational signs of withdrawal. At the end of EtOH vapor (or air) exposure, the rats were tested for the effects of NTX (10mg/kg, oral) on EtOH self-administration at 3 abstinence time points: acute abstinence (A-Abst, 8hours), late abstinence (L-Abst, 2weeks), and protracted abstinence (P-Abst, 6weeks). NTX decreased EtOH intake in nondependent rats, regardless of sex and abstinence time point. In postdependent rats, NTX decreased EtOH intake only at a delayed abstinence time point (P-Abst) in males, whereas it similarly reduced EtOH drinking in females at all abstinence time points. The therapeutic efficacy of NTX depends on the time of intervention during abstinence and is different between males and females. The data further suggest that EtOH dependence causes different neuroadaptations in male and female rats, reflected by differential effects of NTX. The results underscore the significance of considering the duration of EtOH abstinence and sex as a biological variable as important factors when developing pharmacotherapies for AUD.

Chronic co-administration of nalbuphine attenuates the development of opioid dependence

Nalbuphine is an agonist of κ-opioid receptors and a partial agonist of μ-opioid receptors, which can stimulate κ-receptors and antagonize the acute rewarding effects of morphine. It is widely used either as an analgesic or as an adjuvant with morphine. This present study aimed to compare the acute and chronic effects of nalbuphine on the naloxone-precipitated opiate-withdrawal in rats. Male adult Wistar albino rats (150–175 g, n = 160) were made physically dependent by administrating increasing dose of morphine (5–25 mg/kg; i.p.). Motor activity was measured for 25 min at five-minute intervals on days 0, 1, 3, 5, and 6 using Activity Monitor (Coulbourn Instruments, Inc. USA) and True-scan software. The withdrawal was precipitated with intraperitoneal injections of naloxone (1 mg/kg) 4 h after the last injection of morphine. Somatic signs of withdrawal were scored using the global Gellert-Holtzman rating scale. Nalbuphine was co-administered acutely and chronically at various doses (0.1, 0.3, 1.0, and 3.0 mg/kg; i.p.) with morphine. In general, the opiate-dependent rats showed a significant increase in motor activity and Gellert-Holtzman score. Animals co-administered with chronic doses of nalbuphine showed a significant decrease in motor activity and naloxone-precipitated opiate withdrawal, but acute nalbuphine treatment did not attenuate the development of opioid dependence. These findings suggest that nalbuphine could be used as an effective pharmacological adjunct in the treatment of opioid addiction.

Assessment of rimonabant-like adverse effects of purported CB1R neutral antagonist / CB2R agonist aminoalkylindole derivatives in mice

BackgroundCannabinoids may be useful in the treatment of CNS disorders including drug abuse and addiction, where both CB1R antagonists / inverse agonists and CB2R agonists have shown preclinical efficacy. TV-5-249 and TV-6-41, two novel aminoalkylindoles with dual action as neutral CB1R antagonists and CB2R agonists, previously attenuated abuse-related effects of ethanol in mice. PurposeTo further characterize these drugs, TV-5-249 and TV-6-41 were compared with the CB1R antagonist / inverse agonist rimonabant in assays relevant to adverse effects and cannabinoid withdrawal. Procedures and findingsThe cannabinoid tetrad confirmed that TV-5-249 and TV-6-41 were devoid of CB1R agonist effects at behaviorally-relevant doses, and neither of the novel drugs induced rimonabant-like scratching. Generalized aversive effects were assessed, and rimonabant and TV-5-249 induced taste aversion, but TV-6-41 did not. Schedule-controlled responding and observation of somatic signs were used to assess withdrawal-like effects precipitated by rimonabant or TV-6-41 in mice previously treated with the high-efficacy CB1R agonist JWH-018 or vehicle. Rimonabant and TV-6-41 dose-dependently suppressed response rates in all subjects, but TV-6-41 did so more potently in JWH-018-treated mice than in vehicle-treated mice, while rimonabant equally suppressed responding in both groups. Importantly, rimonabant elicited dramatic withdrawal signs, but TV-6-41 did not. ConclusionsThese findings suggest differences in both direct adverse effects and withdrawal-related effects elicited by rimonabant, TV-5-249, and TV-6-41, which could relate to neutral CB1R antagonism, CB2R agonism, or a combination of both. Both mechanisms should be explored and exploited in future drug design efforts to develop pharmacotherapies for drug dependence.

Early adolescent nicotine exposure affects later-life hippocampal mu-opioid receptors activity and morphine reward but not physical dependence in male mice

RationaleThere is extensive literature regarding nicotine-opioid functional interactions. The possibility that use of nicotine products during adolescence might increase the risk of substance abuse such as morphine later in adulthood is particularly relevant to the current opioid crisis. ObjectivesTo investigate the effects of nicotine exposure for seven days during adolescence in mice on morphine reward as well as morphine physical dependence later in adulthood. MethodsMice were exposed to nicotine in either early or late adolescence then evaluated for morphine reward and withdrawal symptoms in adulthood. A separate group of mice was exposed to nicotine during adolescent and tissue was evaluated for changes in MOR-mediated G-protein activity using [35S]GTPγS binding assays. ResultsWe report that a 7-day exposure to a low dose of nicotine during early adolescence significantly enhanced morphine preference in the CPP test in adult mice. In contrast, the same treatment with nicotine had no effect on expression of somatic withdrawal signs in morphine-dependent adult mice. MOR-mediated G-protein activity in hippocampus, but not thalamus and striatum of adult mice, was significantly altered by adolescent nicotine treatment. ConclusionsAdolescence is a unique developmental stage during which nicotine has long-term effects on future drug-taking behavior. Further studies are needed to identify the neurotransmitters and mechanisms involved in increased vulnerability to drug abuse.

Cannabidiol does not display drug abuse potential in mice behavior.

Recent evidence suggests that cannabidiol (CBD) may be useful for the treatment of different neuropsychiatric disorders. However, some controversy regarding its profile as a drug of abuse hampers the further development of basic and clinical studies. In this study, the behavioral profile of CBD as a potential drug of abuse was evaluated in C57BL/6J mice. Reinforcing properties of CBD (15, 30, and 60 mg/kg; i.p.) were assessed using the conditioned place preference (CPP) paradigm. Spontaneous withdrawal symptoms and motor activity in the open field were examined 12 h after the last CBD administration (30 mg/kg/12 h, i.p., 6 days). CBD plasma concentrations were measured at 2, 4, 8, 12, and 24 h after the administration of CBD (30 mg/kg, i.p.). Furthermore, an oral CBD self-administration paradigm (50 mg/kg; CBD water-soluble 1.2 mg/mL) was performed to evaluate whether this drug produced any effects on motivation compared with a non-reinforcing substance (water). We found that CBD failed to induce CPP, withdrawal symptoms, or altered motor behavior 12 h after its administration. At that time, only traces of CBD were detected, ensuring that the lack of alterations in somatic signs and locomotor activity was not due to residual drug in plasma. Interestingly, mice displayed similar motivation and consumption of CBD and water. Taken together, these results show that CBD lacks activity as a drug of abuse and should stimulate the development of the basic and clinical studies needed to elucidate its potential therapeutic use for the treatment of neuropsychiatric and drug use disorders.

Nicotine Modulates Cognitive Function in D-Galactose-Induced Senescence in Mice.

Here, we tested the claim that nicotine attenuates the signs of brain dysfunction in the model of brain aging induced by D-galactose (DGal) in mice. We administered nicotine at doses of 0.1, 0.5 and 1 mg/kg by the subcutaneous (s.c.) or at 0.1 mg/kg by the intranasal (i.n.) routes in mice that had received DGal at the dose of 500 mg/kg subcutaneous (s.c.) for 6 weeks. We assessed animal withdrawal signs as the number of presented somatic signs, thermal hyperalgesia, elevated plus maze (EPM) and open field tests. We evaluated spatial memory and recognition with Barnes maze and novel object recognition (NOR) tests. We tested brain tissue for reactive oxygen species (ROS), mitochondrial membrane potential, caspase-3, Bax, Bcl-2, cytochrome C, brain-derived neurotrophic factor and nerve growth factor levels. Nicotine administration in model groups (0.5 mg/kg s.c. and 0.1 mg/kg i.n. doses) significantly attenuated impairment of spatial and episodic memories in comparison to normal saline-received model group. These doses also reduced mito-oxidative damage as well as apoptosis and raised neurotrophic factors level in model groups in comparison to normal saline-received model group. The 1 mg/kg s.c. dose nicotine revealed withdrawal signs compared with the other nicotine-received groups. Nicotine at specific doses and routes has the potential to attenuate age-related cognitive impairment, mito-oxidative damage, and apoptosis. The doses raise neurotrophic factors without producing withdrawal signs.

Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice

BackgroundA subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence. MethodsC57BL/6 J mice were repeatedly administered the phytocannabinoid Δ9-tetrahydrocannabinol (THC; 1, 10 or 50 mg/kg, s.c.), the synthetic cannabinoid receptor agonist JWH-018 (1 mg/kg, s.c.), or vehicle (1:1:18 parts ethanol:Kolliphor EL:saline, s.c.) for 6 days. Withdrawal was precipitated with the cannabinoid receptor inverse agonist rimonabant (3 mg/kg, i.p.) or elicited via abstinence (i.e., spontaneous withdrawal), and putative stress-related behavior was scored. Classic somatic signs of cannabinoid withdrawal were also quantified. ResultsPrecipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24–48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors. ConclusionOutcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.

Differential effects of withdrawal from intermittent and continuous nicotine exposure on reward deficit and somatic aspects of nicotine withdrawal and expression of α4β2* nAChRs in Wistar male rats

BackgroundChronic nicotine exposure produces neuroadaptations in brain reward systems and α4β2 nicotinic acetylcholine receptors (nAChRs) in the corticolimbic brain areas. We previously demonstrated opposite effects of nicotine exposure delivered by self-administration or pumps on brain reward thresholds that can be attributed to the different temporal pattern and contingency of nicotine exposure. We investigated the effects of these two factors on reward thresholds and somatic signs during nicotine withdrawal, and on nAChRs binding in corticolimbic brain areas. MethodsThe intracranial self-stimulation procedure was used to assess reward thresholds in rats prepared with pumps delivering various doses of nicotine continuously or intermittently. Separate group of rats were randomly exposed to nicotine via pumps (non-contingent) or nicotine self-administration (contingent) to determine [125I]-epibatidine binding at α4β2* nAChRs. ResultsWithdrawal from continuous non-contingent nicotine exposure led to significant elevations in thresholds and increases in somatic signs in rats, while there was no significant effect of withdrawal from intermittent non-contingent nicotine exposure at the same doses. nAChRs were upregulated during withdrawal from continuous non-contingent nicotine exposure. α4β2* nAChRs were upregulated in the ventral tegmental area and prelimbic cortex during withdrawal from non-contingent intermittent exposure and in the nucleus accumbens during withdrawal from contingent intermittent nicotine exposure to the same dose. ConclusionsDuring non-contingent nicotine exposure, the temporal pattern of nicotine delivery differentially affected thresholds and somatic signs of withdrawal. Upregulation of α4β2* nAChRs was brain site-specific and depended on both temporal pattern and contingency of nicotine exposure.

New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice

Varenicline, a partial agonist for α4β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist for α3β4 and α7 nAChRs, is approved for smoking cessation treatment. Although, partial agonism at α4β2* nAChRs is believed to be the mechanism underlying the effects of varenicline on nicotine reward, the contribution of other nicotinic subtypes to varenicline's effects on nicotine reward is currently unknown. Therefore, we examined the role of α5 and α7 nAChR subunits in the effects of varenicline on nicotine reward using the conditioned place preference (CPP) test in mice. Moreover, the effects of varenicline on nicotine withdrawal-induced hyperalgesia and aversion are unknown. We also examined the reversal of nicotine withdrawal in mouse models of dependence by varenicline.Varenicline dose-dependently blocked the development and expression of nicotine reward in the CPP test. The blockade of nicotine reward by varenicline (0.1 mg/kg) was preserved in α7 knockout mice but reduced in α5 knockout mice. Administration of varenicline at high dose of 2.5 mg/kg resulted in a place aversion that was dependent on α5 nAChRs but not β2 nAChRs. Furthermore, varenicline (0.1 and 0.5 mg/kg) reversed nicotine withdrawal signs such as hyperalgesia and somatic signs and withdrawal-induced aversion in a dose-related manner.Our results indicate that the α5 nAChR subunit plays a role in the effects of varenicline on nicotine reward in mice. Moreover, the mediation of α5 nAChRs, but not β2 nAChRs are probably needed for aversive properties of varenicline at high dose. Varenicline was also shown to reduce several nicotine withdrawal signs.

Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal.

Cannabidiol (CBD) represents a promising therapeutic tool for treating cannabis use disorder (CUD). This study aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous cannabinoid withdrawal. Spontaneous cannabinoid withdrawal was evaluated 12h after cessation of CP-55,940 treatment (0.5mg·kg-1 every 12h, i.p.; 7days) in C57BL/6J mice. The effects of CBD (5, 10 and 20mg·kg-1 , i.p.) on withdrawal-related behavioural signs were evaluated by measuring motor activity, somatic signs and anxiety-like behaviour. Furthermore, gene expression changes in TH in the ventral tegmental area, and in the opioid μ receptor (Oprm1), cannabinoid CB1 receptor (Cnr1) and CB2 receptor (Cnr2) in the nucleus accumbens, were also evaluated using the real-time PCR technique. The administration of CBD significantly blocked the increase in motor activity and the increased number of rearings, rubbings and jumpings associated with cannabinoid withdrawal, and it normalized the decrease in the number of groomings. However, CBD did not change somatic signs in vehicle-treated animals. In addition, the anxiogenic-like effect observed in abstinent mice disappeared with CBD administration, whereas CBD induced an anxiolytic-like effect in non-abstinent animals. Moreover, CBD normalized gene expression changes induced by CP-55,940-mediated spontaneous withdrawal. The results suggest that CBD alleviates spontaneous cannabinoid withdrawal and normalizes associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for treating CUD.

Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats.

GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior.

Hippocampal glial cells modulate morphine-induced behavioral responses

Drugs of abuse cause persistent alterations in synaptic plasticity that is thought to underlie addictive-like behaviors. Although, the perisynaptic glial cells are implicated in metabolic maintenance and support of the nervous systems, accumulating evidence suggests that glial cells exert a modulatory action on synaptic functions and participate in synaptic plasticity. However, it is well-documented that glial cells are associated with the acquisition of rewarding effects of abused drugs. The role of hippocampal glial cells in addictive-like behaviors remains poorly understood. In this study, we investigated the role of hippocampal glial cells in morphine-induced behavioral responses including morphine dependence, tolerance to the antinociceptive properties of morphine, and conditioned place preference (CPP). Male rats received subcutaneous (s.c.) morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. To suppress glial cells activity, the animals received microinjection of fluorocitrate (FC, a metabolic inhibitor of glial cells) into the CA1 region before each morphine administration. The animals were assessed for morphine dependence by monitoring naloxone hydrochloride-induced precipitation of somatic signs of morphine withdrawal. The tolerance to the antinociceptive effects of morphine and morphine-induced CPP were measured in a separate set of experimental groups. We found animals receiving FC before morphine injection demonstrated a significant reduction in several signs of morphine withdrawal such as freezing, defecation, chewing, explosive running, ptosis, activity, scratching, wet dog shake, and writhing. Inhibition of glial cells caused a significant reduction of tolerance to the antinociceptive effect of morphine. Finally, intra-CA1 administration of FC decreased morphine-induced CPP. Our findings suggest that hippocampal glial cells may be involved in morphine-induced behavioral responses.

Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal.

Recent preclinical data has implicated the α7 nicotinic acetylcholine receptor (nAChR) as a target in modulating nicotine reward. However, the role of the channel properties of the α7 nAChR in nicotine withdrawal is unknown. This study aimed to investigate the impact of α7 nAChR pharmacological modulation on mecamylamine-precipitated nicotine withdrawal behaviors in mice by using positive allosteric modulators (PAMs). The effect of the orthosteric α7 nAChR full agonist PNU282987 (1, 3, 9mg/kg, s.c.), type I α7 PAM NS1738 (1 and 10mg/kg; i.p.) and the type II α7 PAM PNU120596 (3 and 9mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured in mice undergoing mecamylamine-precipitated nicotine withdrawal. Mice were infused with 24mg/kg/day nicotine or saline for 14days using s.c. osmotic minipumps. Nicotine withdrawal signs were precipitated upon administration of the non-selective nAChR antagonist mecamylamine (3.5mg/kg, i.p.). Anxiety-like behavior in nicotine withdrawn mice was only attenuated by PNU282987 in a dose-related fashion. Somatic signs were reduced by PNU282987 and NS1738. PNU120596 was the only compound that reversed precipitated nicotine withdrawal-induced hyperalgesia. Taken together, our results suggest that modulation of the α7 nAChR can play important roles in mecamylamine-precipitated nicotine withdrawal behaviors in mice. In addition, the effects of PAMs in this study suggest that endogenous acetylcholine/choline tone is sufficient to attenuate some aspects of precipitated nicotine withdrawal. These findings highlight a beneficial effect of using α7 nAChR PAMs in some aspects of precipitated nicotine withdrawal.

Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study

BackgroundOsteogenesis Imperfecta (OI) is characterized by a number of deviations in the orofacial region. The aims of the present study were to investigate the occurrence of temporomandibular disorders, to evaluate the psychosocial status, and to assess the dental occlusion in a population of adult OI patients.MethodsParticipants (n = 75) were classified with mild OI, type I (n = 56), or moderate-severe OI, type III and IV (n = 19). OI patients were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders (axis I and II).ResultsTemporomandibular disorders and functional limitations in the orofacial region were rare and did not differ between patients with mild and moderate-severe OI (P > 0.050). No significant differences between Graded Chronic Pain Scale grades 0, 1, and 2 were found in mild OI vs. moderate-severe OI (P > 0.160). Few patients (16%) had signs of depression, but close to half (48%) had signs of somatization. Patients with moderate-severe OI had a lower mean number of teeth compared to patients with mild OI (P < 0.050). In general, malocclusions were prevalent, and mandibular overjet and posterior cross-bite were found more often in moderate-severe OI compared with mild (P < 0.050).ConclusionsPatients with moderate-severe OI had more malocclusions than patients with mild OI. The psychosocial status of OI patients was remarkably healthy considering the severity of this disabling systemic disorder. The bodily pain complaints frequently reported in OI patients were not largely reflected in the orofacial area as painful temporomandibular disorders.

Origin and development of the book Medical Semiology

Semiotics and Semiology share a similar etymology and meaning: the study of signs. In Medicine, signs are objective manifestations of disease, as opposed to the subjective nature of symptoms. Medical semiology comprises the study of symptoms, somatic signs and laboratory signs, history taking and physical examination (in English-speaking countries is known as Bedside diagnostic examination or Physical diagnosis). The first edition of Medical Semiology dates from 1987, and new editions appeared in 1999, 2010, and 2017. The book is devoted to semiology proper with clinical orientation. Its origin, however, dates back to 1937, when the University of Chile appointed Dr. Hernán Alessandri (1900-1981), the eminent Chilean medical educator, Professor in Semiology at the Internal Medicine Section of the Hospital del Salvador in Santiago. The authors of the present book served as Dr. Alessandri's teaching assistants for decades. The two-semester course in semiology had a tutorial character: each teaching assistant was assigned five students whom engaged daily in practical activities in the hospital wards for a total of four hours, in addition to a 45- minute lecture on the theoretical aspects of the subject. The 720-page fourth edition of the book brings together teaching method and clinical experience of more than 50 years. The book consists of six Sections: "Cardinal manifestations of disease", "Major clinical syndromes", "History taking and Physical examination", "Clinical diagnosis and the patient-physician relationship", "Laboratory clinical tests and Instrumental exploration of the body," and "Glossary of diseases." In its forty Chapters, a total of 207 issues are described in detail.

Quantitative neuroimaging in mucopolysaccharidoses clinical trials.

The mucopolysaccharidosis (MPS) disorders are rare lysosomal storage disorders caused by mutations in lysosomal enzymes involved in glycosaminoglycan (GAG) degradation. The resulting intracellular accumulation of GAGs leads to widespread tissue and organ dysfunction. In addition to somatic signs and symptoms, patients with MPS can present with neurological manifestations such as cognitive decline, behavioral problems (e.g. hyperactivity and aggressiveness), sleep disturbances, and/or epilepsy. These are associated with significant abnormalities of the central nervous system (CNS), including white and gray matter lesions, brain atrophy, ventriculomegaly, and spinal cord compression. In order to effectively manage and develop therapies for MPS that target neurological disease, it is important to visualize and quantify these CNS abnormalities. This review describes optimal approaches for conducting magnetic resonance imaging assessments in multi-center clinical studies, and summarizes current knowledge from neuroimaging studies in MPS disorders. The content of the review is based on presentations and discussions on these topics that were held during a meeting of an international group of experts.

Assessments of neurocognitive and behavioral function in the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders in which accumulation of glycosaminoglycans (GAGs) leads to progressive tissue and organ dysfunction. In addition to a variety of somatic signs and symptoms, patients with rapidly progressing MPS I (Hurler), II, III, and VII can present with significant neurological manifestations, including impaired cognitive abilities, difficulties in language and speech, behavioral abnormalities, sleep problems, and/or seizures. Neurological symptoms have a substantial impact on the quality of life of MPS patients and their families. Due to the progressive nature of cognitive impairment in these MPS patients, neurocognitive function is a sensitive indicator of disease progression, and a relevant outcome when testing efficacy of therapies for these disorders. In order to effectively manage and develop therapies that address neurological manifestations of MPS, it is important to use appropriate neurocognitive assessment tools that are sensitive to changes in neurocognitive function in MPS patients. This review discusses expert opinions on key issues and considerations for effective neurocognitive testing in MPS patients. In addition, it describes the neurocognitive assessment tools that have been used in clinical practice for these patients. The content of this review is based on existing literature and information from a meeting of international experts with extensive experience in managing and treating MPS disorders.

Developmental and behavioral aspects of mucopolysaccharidoses with brain manifestations - Neurological signs and symptoms.

The mucopolysaccharidoses (MPS) are a group of rare, inherited lysosomal storage disorders, caused by mutations in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). The resulting accumulation of GAGs in the body leads to widespread tissue and organ dysfunction. The spectrum, severity, and progression rate of clinical manifestations varies widely between and within the different MPS types. In addition to somatic signs and symptoms, which vary between the different MPS disorders, patients with MPS I, II, III, and VII present with significant neurological signs and symptoms, including impaired cognitive abilities, difficulties in language and speech, and/or behavioral and sleep problems. To effectively manage and develop therapies that target these neurological manifestations, it is of utmost importance to have a profound knowledge of their natural history and pathophysiology. This review describes the appearance and progression of neurological signs and symptoms in patients with MPS I, II, and III, based on presentations and discussions among an international group of experts during a meeting on the brain in MPS on April 28-30, 2016, and additional literature searches on this subject.

Reversal of Nicotine Withdrawal Signs Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Male Mice.

Nicotine withdrawal symptoms are important factors in determining the relapse rate to tobacco smoking and drugs that diminish these symptoms would potentially have a higher success rate as smoking cessation aids. Unlike US Food and Drug administration approved smoke cessation aids (nicotine and varenicline) which act as nicotinic acetylcholine receptors (nAChRs) agonists, desformylflustrabromine (dFBr) acts as a nAChR positive allosteric modulator with higher selectivity to the α4β2 nAChR. In animal studies, dFBr was well tolerated and reduced intravenous nicotine self-administration. In this study, we use behavioral test in mouse model of spontaneous nicotine withdrawal to assess the effect of dFBr on nicotine withdrawal symptoms. Spontaneous nicotine withdrawal in nicotine-dependent ICR male mice was established 18-24 h after termination (minipump removal) of 14 days infusion of nicotine. After that (day 15), spontaneous signs of nicotine withdrawal were examined in the following order: anxiety-like behaviors, somatic signs, and then hyperalgesia using previously published behavioral protocols. Fifteen minutes before withdrawal signs testing, mice received a subcutaneous acute injection of vehicle or dFBr at the doses of 0.02, 0.1, and 1 mg/kg to determine the effect of dFBr on nicotine withdrawal symptoms. dFBr produced dose-dependent reversal of nicotine withdrawal signs in mouse model of spontaneous nicotine withdrawal. Positive allosteric modulators of nAChR such as dFBr reduce nicotine withdrawal symptoms supporting the potential clinical use of this novel class of nAChR-based therapeutics as smoking cessation aid.

Src‐dependent phosphorylation of μ‐opioid receptor at Tyr336 modulates opiate withdrawal

Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ‐opioid receptor (MOR) at Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src‐mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (pY336) levels during naloxone‐precipitated withdrawal. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses attenuated pY336 levels, and several somatic withdrawal signs. This was also observed in Fyn−/− mice. The stereotaxic injection of wild‐type MOR, but not mutant (Y336F) MOR, lentiviruses into the locus coeruleus of MOR−/− mice restored somatic withdrawal jumping. Regulating pY336 levels during withdrawal might be a future target for drug development to prevent opiate addictive behaviors.