Receptor Hypersensitivity Research Articles

Postural Orthostatic Tachycardia Syndrome (POTS) of Autoimmune Origin - Case and Review

Introduction: Postural Orthostatic Tachycardia Syndrome (POTS) belongs to a group of orthostatic intolerance syndromes. It is defined by the increase in heart rate ≥30 bpm or heart rate higher than 120/min during first 10 minutes after standing, without significant decrease in blood pressure. It is a rare disease, typically affecting younger females. The dysregulation of autonomic nervous system plays a key role in the pathogenesis. The autonomic dysbalance can be caused by various neurohumoral mechanisms, receptor hypersensitivity, hypovolemia, mast cell dysregulation and last but not least, autoimmunity. The presence of autoantibodies targeted against various adrenergic and muscarinic receptors, as well, as angiotensin or endothelin receptors, has been identified in some but not all patients with POTS. Case Description: We present a case of a young patient with an overlap syndrome of POTS and vasovagal vasodepressoric syncope diagnosed with the head up tilt test, without any identified trigger. The laboratory investigation documented the presence of anti-alpha-1, beta-1 and beta-2 adrenergic receptor antibodies, antimuscarinic receptor 3 antibodies and antibodies against angiotensin II type 1 receptor. MIBG (metaiodobenzylguanidine) scan has not revealed any changes in the sympathetic inervation of the heart. The initial treatment by betablockers, as well as by ivabradine failed. On midodrine medication, the symptoms of postural tachycardia and the reflex syncope improved. Conclusion: The role of autoimmunity in POTS is currently studied, though the role of autoantibodies against autonomic nervous system in the pathogenesis of vasovagal syncope remains unclear.

Haloperidol induced Pisa syndrome in a patient with treatment resistant schizophrenia

IntroductionAcute dystonia, an adverse effect of neuroleptics, is linked to D2 neuronal receptor hypersensitivity or neurotoxicity due to oxidative stress mechanisms. Pisa syndrome (PS) or Pleurothotonus, a relatively uncommon condition, manifests as dystonia of the trunk and is potentially reversible with early intervention.ObjectivesTo describe PS following haloperidol decanoate injection in a treatment-resistant schizophrenia (TRS) patient, identify associated risk factors, and present therapeutic options.MethodsWe provide a comprehensive case description and perform a PubMed database search using the following keywords: “Pisa syndrome,” “dystonia,” “schizophrenia,” and “antipsychotic”.ResultsA 54-year-old man with TRS, previously treated with 100 mg of haloperidol decanoate and 10 mg of olanzapine due to clozapine-induced myocarditis, exhibited hallucinatory delusional syndrome and behavioral disturbances. Neurological examination, lab tests, and brain imaging confirmed a psychotic relapse. Haloperidol decanoate dosage was increased to 150 mg. Four days later, the patient developed a trunk tilt that resolved after receiving anticholinergic treatment.Despite PS being more common in females and associated with brain conditions, this patient presented multiple risk factors, including prolonged typical antipsychotic treatment, advanced age, and an increase in antipsychotic doses. Discontinuing the causative antipsychotic or adding synthetic anticholinergics led to symptom reversibility.ConclusionsPS is a rare occurrence. Understanding associated risk factors and frequently implicated medications is crucial for elucidating the phenomenon and managing the disorderDisclosure of InterestNone Declared

Parkinson’s New Advancements in Diagnosis and Treatment: A Review

Parkinsonism Disease (PD) is a progressive neurological disorder. Although PD is associated with a variety of Non-motor symptoms (NMS) in virtually all patients including hyposmia, constipation, pain and sleep disturbances. It is age related disorder and affects more than 6 million population every year. It is associated with neuronal degeneration in substantia nigra and to lesser extent, in the globus pallidus, putamen and caudate nucleus. The degeneration of the neurons of the substantia nigra that send their axons to the corpus striatum results in reduction in the release of neurotransmitter dopamine with in corpus striatum. This leads to hypersensitivity of the dopamine receptors in the post synaptic neurons in the striatum. Individuals have characteristics signs and symptoms tremors, bradykinesia, postural instabilities, rigidity. Neither loss of sense nor muscle power is usually seen in such cases. Deep tendon, Superficial and Abdominal reflexes are well retained on evaluation. There has been various types of classification in Parkinsonism which are described later. Together with aging, genetics, environment and the role of biological sex as important factor in development of PD has been widely discussed in the past decade. Investigations in PD remains a challenge, recent studies included 7 Tesla MRI, PET and SPECT have proved to be confirmatory in diagnosis of PD. Parkinsonism disease treatment includes increasing the levels of dopamine in brain by giving its immediate precursor L-dopa which can easily cross blood brain barrier unlike dopamine. Evidence of slowing the process of degeneration has been seen with drug selegiline. Other than drugs surgical options include pallidotomy

Glycyrrhizae Radix suppresses lipopolysaccharide- and diazepam-induced nerve inflammation in the hippocampus, and contracts the duration of pentobarbital- induced loss of righting reflex in a mouse model

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1β, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.

Delay in the formation of urination function in children

The control of urine retention and urination function in children is finally established by the age of 4–5 — it is at this age that the type of urination becomes adult. The stages of the formation of urination function are based on many factors — a decrease in the physiological hypersensitivity of the M-cholinergic receptors of the bladder to acetylcholine, an increase in inhibitory supraspinal effects on the parasympathetic reflex arc, which provides a level of intravesical pressure, on the process of myelination of the brain pathways, on the maturation of the higher cortical center of urination and strengthening of connections with subcortical structures. A tabular assessment of the manifestations of delay and impaired bladder function in children allows us to determine the level of maturity of the system responsible for the urination function. The development of control over the urination is greatly hindered by wearing diapers, failure to provide potty training, and improper water intake schedule in children. The authors of the article identified three age groups of children with enuresis and delayed formation of bladder function and determined at what age which disorders are most relevant. Assessment of the maturity of urination in children with enuresis allows us to analyze the stages of delayed bladder function. In the younger age group (6–7 years), the delay in the formation of self-service skills in the implementation of the act of urination prevailed, including the use of a gender-unreasonable posture. At the age of 8–11 years, there was a predominance of delayed formation of emptying reflexes. At the age of 12–14, there were signs of hypoactivity of the bladder.

Glucocorticoid receptor hypersensitivity enhances inflammatory signaling and inhibits cell cycle progression in porcine PBMCs.

The consequences of glucocorticoid receptor (GR) hypersensitivity during infection have so far received little attention. We previously discovered that a natural gain-of-function Ala610Val substitution in the porcine GR aggravates response of pigs to lipopolysaccharide (LPS)-induced endotoxemia, which can be alleviated by dexamethasone (DEX) pretreatment. In this work, we investigated the relevant molecular basis of these phenotypes by transcriptomic profiling of porcine peripheral blood mononuclear cells (PBMCs) carrying different GR genotypes, in unstimulated conditions or in response to DEX and/or LPS in vitro. The Val allele differentially regulated abunda+nt genes in an additive-genetic manner. A subset of more than 200 genes was consistently affected by the substitution across treatments. This was associated with upregulation of genes related i.a. to endo-lysosomal system, lipid and protein catabolism, and immune terms including platelet activation, and antigen presentation, while downregulated genes were mainly involved in cell cycle regulation. Most importantly, the set of genes constitutively upregulated by Val includes members of the TLR4/LPS signaling pathway, such as LY96. Consequently, when exposing PBMCs to LPS treatment, the Val variant upregulated a panel of additional genes related to TLR4 and several other pattern recognition receptors, as well as cell death and lymphocyte signaling, ultimately amplifying the inflammatory responses. In contrast, when stimulated by DEX treatment, the Val allele orchestrated several genes involved in anti-inflammatory responses during infection. This study provides novel insights into the impact of GR hypersensitivity on the fate and function of immune cells, which may be useful for endotoxemia therapy.

Cough: some aspects of pathogenesis and therapeutic approaches

This article is a literature review on the management of patients with acute cough. The classification of cough, the main causes of acute and subacute cough, the current view on the etiology and pathogenesis of chronic cough are presented. Cough is an important protective mechanism, but in acute and chronic diseases of the bronchopulmonary system cough significantly reduces the quality of life and causes numerous complications. The most common cause of acute and subacute cough is respiratory viruses. Chronic cough is currently explained by the theory of cough hypersensitivity, according to which chronic refractory cough is the result of hypersensitivity of the cough receptors. Before the cause of chronic cough is identified, and when treating patients with acute and subacute cough, symptomatic therapy with cough suppressants that eliminate increased cough reflex activity to normal levels regardless of cough etiology, although not affecting the pathophysiological mechanisms of cough, or with combined drugs with suppressant and expectorant effects, is often required. Peripheral suppressants reduce the activity of peripheral cough receptors of the upper airway mucosa by softening, moistening and enveloping. Central cough suppressants include butamirate. Central non-narcotic cough suppressants in various combinations with muco- and bronchodilators and antihistamines form part of many anti-cough medicines. Butamirate has a non-specific anticholinergic and therefore bronchodilator effect. This article presents a review of clinical studies on the efficacy of butamirate.

Targeted Treatment of Inappropriate Sinoatrial Node Tachycardia Based on Electrophysiological and Structural Mechanisms

The purpose of this review is to determine the causal mechanisms and treatment of inappropriate sinoatrial tachycardia (IST), defined as a non-physiological elevation in resting heart rate. IST is defined as a resting daytime sinus rate >100 beats/minute and an average 24-hour heart rate >90 beats/minute. Potential causal mechanisms include sympathetic receptor hypersensitivity, blunted parasympathetic tone, or enhanced intrinsic automaticity within the sinoatrial node (SAN) pacemaker-conduction complex. These anomalies may coexist in the same patient. Recent ex-vivo near-infrared transmural optical imaging of the SAN in human and animal hearts provides important insights into the functional and molecular features of this complex structure. In particular, it reveals the existence of preferential sinoatrial conduction pathways that ensure robust SAN activation with electrical conduction. The mechanism of IST is debated because even high-resolution electroanatomical mapping approaches cannot reveal intramural conduction in the 3-dimensional SAN complex. It may be secondary to enhanced automaticity, intranodal re-entry, or sinoatrial conduction pathway re-entry. Different pharmacological approaches can target these mechanisms. Long-acting β blockers in IST can act on both primarily increased automaticity and dysregulated autonomic system. Ivabradine targets sources of increased SAN automaticity. Conventional or hybrid ablation may target all the described abnormalities. This review provides a state-of-the-art overview of putative IST mechanisms. In conclusion, based on current knowledge, pharmacological and ablation approaches for IST, including the novel hybrid SAN sparing ablation, are discussed.

Molecular Mechanisms and Therapeutic Strategies for Levodopa-Induced Dyskinesia in Parkinson's Disease: A Perspective Through Preclinical and Clinical Evidence.

Parkinson’s disease (PD) is the second leading neurodegenerative disease that is characterized by severe locomotor abnormalities. Levodopa (L-DOPA) treatment has been considered a mainstay for the management of PD; however, its prolonged treatment is often associated with abnormal involuntary movements and results in L-DOPA-induced dyskinesia (LID). Although LID is encountered after chronic administration of L-DOPA, the appearance of dyskinesia after weeks or months of the L-DOPA treatment has complicated our understanding of its pathogenesis. Pathophysiology of LID is mainly associated with alteration of direct and indirect pathways of the cortico-basal ganglia-thalamic loop, which regulates normal fine motor movements. Hypersensitivity of dopamine receptors has been involved in the development of LID; moreover, these symptoms are worsened by concurrent non-dopaminergic innervations including glutamatergic, serotonergic, and peptidergic neurotransmission. The present study is focused on discussing the recent updates in molecular mechanisms and therapeutic approaches for the effective management of LID in PD patients.

Clinico-pathophysiological considerations in coronary microvascular disorders

Around half of the patients undergoing an elective coronary angiogram to investigate typical stable angina symptoms are found to have non-obstructive coronary arteries (defined as < 50% stenosis). These patients are younger with a female predilection. While underlying mechanisms responsible for these presentations are heterogeneous, structural and functional abnormalities of the coronary microvasculature are highly prevalent. Thus, coronary microvascular dysfunction (CMD) is increasingly recognised as an important consideration in patients with non-obstructive coronary arteries. This review will focus on primary coronary microvascular disorders and summarise the four common clinical presentation pictures which can be considered as endotypes - Microvascular Ischaemia (formerly “Syndrome X”), Microvascular Angina, Microvascular Spasm, and Coronary Slow Flow. Furthermore, the pathophysiological mechanisms associated with CMD are also heterogenous. CMD may arise from an increased microvascular resistance, impaired microvascular dilation, and/or inducible microvascular spasm, ultimately causing myocardial ischaemia and angina. Alternatively, chest pain may arise from hypersensitivity of myocardial pain receptors rather than myocardial ischaemia. These two major abnormalities should be considered when assessing an individual clinical picture, and ultimately, the question arises whether to target the heart or the pain perception to treat the anginal symptoms.

Morphological and functional changes of striatal neurons with L‐dopa‐induced dyskinesia

AbstractPriming and expression of L‐dopa‐induced dyskinesia (LID) is associated with maladaptive plasticity of striatal spiny projection neurons (SPNs) in the direct pathway of the basal ganglia. The L‐dopa dosage threshold for dyskinesia decreases immediately after dopaminergic denervation, then gradually after repeated L‐dopa treatment. Dopaminergic denervation induces D1 receptor hypersensitivity in the soma and axon terminals and diminishes negative feedback from GABAB receptors in the direct pathway SPNs, resulting in neuronal hypersensitivity. After dopaminergic denervation, serotonergic neurons metabolize L‐dopa. Serotonergic neurons do not have D2 receptors or dopamine transporters, resulting in a non‐regulated release of dopamine, with subsequent pulsatile dopamine receptor stimulation. L‐dopa treatment post‐dopaminergic denervation induces LID in rat models. Dyskinetic rats show a lack of depotentiation at their corticostriatal synapses and enlargement of their dendritic spines within direct pathway SPNs, both of which account for strengthened corticostriatal synaptic transmission in LID models. Intra‐SPN signal transduction is activated, resulting in the hypersynthesis of GABA. The volume of the internal segment of the globus pallidus (GPi) increases alongside the enlargement of axon terminals with many synaptic vesicles containing GABA from direct pathway SPNs. When the model expresses LID, excessive GABA is released into the GPi. LID priming involves excessive GABA storage in GPi axon terminals, with LID triggered by enhanced GABA release into the GPi.

The phenomenon of rosacea-rushes (theoretical aspects)

According to the decisions of international scientific forums, the problem of phenomenon of rosacea (acne rosacea), a common dermatosis with numerous unexplained aspects of etiopathogenesis is a promising area of modern medical research. The aim of the study was theoretical substantiation of the essential features of the mechanisms of occurrence, development and clinical manifestations of the first signs of rosacea in women of reproductive age. The use of a systematic analytical methodical approach to assess the data of clinical and laboratory examinations of women with rosacea, conducted in different regions of the world, allowed to establish the originality of such manifestations of dermatosis as the appearance of unexpected rushes to limited areas of the face, accompanied by local redness and local heat areas of the skin differring significantly from similar rushes in other diseases or syndromes (menopause, migraine, etc.). It is established that the peculiarity of the relationship of these clinical characteristics (from English: rush, ruddy, redness, rosacea, reproductive age of women, reaction) allows to indicate the first signs of dermatosis as a phenomenon inherent in this disease Rush-Ruddy-Rosacea-Reproduce-Reaction (abbreviated – «5-R»), the key pathophysiological target of which (as well as the disease as a whole) is a disorder of a set of hierarchically dependent mechanisms of the evolutionarily determined motivational need to ensure reproductive function in women (both at the cellular level and extracellular structures of the ovaries, and at different levels of subcortical formations and centers of the cortex of the cerebral hemispheres). The phenomenon of rosacea rush is closely related to other phenomena of this dermatosis – hypersensitivity of bradykinin receptors, actinic elastosis, development of post erythematous telangiectasia. The prospect of further research on the problem of rosacea is to study the relationship of disorders in the functional systems of molecules of signaling compounds of different classes (hormones, eicosanoids, neuropeptides, kinins, cytokines and others) in the pathogenesis of the disease.

Preadolescent dopamine receptor antagonism increases postadolescent reward-related operant behaviors that may depend on dopamine receptor hypersensitivity

The dopaminergic system has a long history of being associated with reward-related activities but the developmental consequences of blocking dopamine receptor function on reward-based associative learning has been less studied. To this end, male, Long Evans rats were systemically (i.p.) treated with the dopamine receptor (DAr) antagonist, flupenthixol (0.25 mg/kg), or saline, from postnatal day (P)18 – 24 (preadolescence) then trained on an operant conditioning task from P41 – P45 (postadolescent) without drug treatment. The preadolescent flupenthixol group showed elevated active lever responses and locomotor activity during the drug-free test. Another group of rats was given flupenthixol prior to each acquisition session from P41 – 45 which significantly suppressed both active lever presses and locomotor activity. Separate groups of rats were treated with flupenthixol or saline from P18 – 24 then treated with apomorphine or saline on P41 followed by assessment of c-Fos labeling in the nucleus accumbens. Early flupenthixol treatment was associated with more apomorphine-induced c-Fos labeling in the nucleus accumbens shell than the early saline-apomorphine group, indicating a sensitized response. These findings suggest that preadolescent dopamine receptor blockade may lead to a sensitized postadolescent dopaminergic response that underlies enhanced behavioral responses in the presence of rewarding stimuli.

SELF HARM BEHAVOIR

In this study, it is aimed to examine this research from a wide perspective and to emphasize the importance of more specific studies on the subject.
 In this research, national and international studies on self-harm behavior were compiled.
 Self-injurious behavior is frequently encountered as an advanced behavioral problem. (Şipal, 2010) Self-injurious behavior is that a person can harm one's own tissues in such a way as to cause severe acts without the will to die consciously. Self-injurious behavior is associated with many psychiatric disorders. In addition, deliberate self-harm behavior should be separated from suicide attempts. Self-injurious behavior usually begins in adolescence. “In the community sample studies, it was found that self-injurious behavior was seen in 1/3 and 1/2 of adolescents (Lloyd-Richardson et al. 2007, Yates et al. 2008). self-injurious behavior typically begins in adolescence and often occurs impulsively; adolescents and young adulthood (Claassen et al. 2006) (Bildik, Somer, Basay, Basay, &Ozbaran, 2012). According to the results of the study, identity confusion and low self-esteem symptoms were found to be significantly more frequent in adolescents with self-injurious behavior (Akdemir, Zeki, Unal, Kara, & Cetin, 2013). It is observed that traumas experienced in the past are related to deliberate self-harm behavior. There are many reasons for self-harm behavior. One of them is abuse. If the trauma experienced is remembered, self-harm behavior arises in order to replace the high level of anxiety with physical pain. Miller and Favazza investigated the reasons for self-mutilation and listed the factors that caused self-mutilation as follows: To have a sense of relaxation; Suppressing emotional pain; Moving away from the feeling of emptiness to show their experiences.(Aksoy, Ögel, 2003). However, in individuals who frequently repeat the act of self-harm, feelings of embarrassment, guilt, regret, and desire for social isolation may also be exacerbated by the stimulation of other negative emotions. (Gratz, 2003) It has been suggested that there may be many biological factors under self-harm behavior. Some of them are opiate system disorder, hypersensitivity of dopamine receptors, decrease in the amount of serotonin. There are psychodynamic opinions about self-harm behavior. Emerson (1913) and Fenichel (1945) stated that self-harm behavior is a substitute for masturbation and is equivalent. Then, behaviorists related to self-harm behavior started to study. According to the behavioral approach, self-harm behavior was later learned and considered as a sense of self-protection against the difficulties of life.
 Intentional self-harm behavior is difficult to explain, but in recent years it has attracted attention by researchers (Chapman, Gratz, & Brown, 2006). In line with the literature review on the subject, it is seen that the studies on this subject need to be more detailed and more specialized case groups should be examined.

THE MECHANISM OF ONCOGENIC MUTATIONS IN THE JUXTAMEMBRANE AND TRANSMEMBRANE REGION OF IL7RA AND TPOR/MPL

Mutations in the interleukin-7 receptor alpha chain (IL-7Ra), thymic stromal lymphopoietin protein receptor (TSLPR), and thrombopoietin receptor (TPOR/MPL) are common in the transmembrane and juxtamembrane region in leukaemia and myeloproliferative neoplasms. Our recent studies have recently defined the mechanism of how mutations in the IL-7RA that introduce positive charged amino acids at the extracellular transmembrane boundary contribute to enhanced JAK-STAT signalling and T-cell leukaemia (Campos et al., 2019). Our current studies have identified that the position of introduced cysteine and proline residues at the extracellular-transmembrane boundary in the IL7RA define the strength of constitutive signalling. We have also investigated signalling of clinical mutations of the TPOR/MPL in the transmembrane domain and identify that different mutations provide different strengths of signalling to specific pathways. In addition, we have experimentally identified novel mutations within the transmembrane of TPOR/MPL that result in constitutive activation. Together, these studies highly the important of the structure and function of the transmembrane and juxtamembrane sequences of cytokine receptors in activation of signalling pathways. Campos, L.W., Zenatti, P.P., Pissinato, L.G., Rodrigues, G.O.L., Artico, L.L., Guimaraes, T.R., Archangelo, L.F., Martinez, L., Brooks, A.J., and Yunes, J.A. (2019). Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7RA cause receptor hypersensitivity. Blood 133, 1259-1263.

Animal models of post-traumatic stress disorder and novel treatment targets.

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.

D1 receptor hypersensitivity in mice with low striatal D2 receptors facilitates select cocaine behaviors

Vulnerability for cocaine abuse in humans is associated with low dopamine D2 receptor (D2R) availability in the striatum. The mechanisms driving this vulnerability are poorly understood. In this study, we found that downregulating D2R expression selectively in striatal indirect-pathway neurons triggers a multitude of changes in D1 receptor (D1R)-expressing direct-pathway neurons, which comprise the other main subpopulation of striatal projection neurons. These changes include a leftward shift in the dose-response to a D1-like agonist that indicates a behavioral D1R hypersensitivity, a shift from PKA to ERK intracellular signaling cascades upon D1R activation, and a reduction in the density of bridging collaterals from D1R-expressing neurons to pallidal areas. We hypothesize that the D1R hypersensitivity underlies abuse vulnerability by facilitating the behavioral responses to repeated cocaine, such as locomotor sensitization and drug self-administration. We found evidence that littermate control mice develop D1R hypersensitivity after they are sensitized to cocaine. Indeed, D1-like agonist and cocaine cross-sensitize in control littermates and this effect was potentiated in mice lacking striatal D2Rs from indirect-pathway neurons. To our surprise, mice with low striatal D2Rs acquired cocaine self-administration similarly to littermate controls and showed no significant change in motivation to take cocaine but lower seeking. These findings indicate that downregulation of striatal D2Rs triggers D1R hypersensitivity to facilitate cocaine locomotor sensitization, which by itself was not associated with greater cocaine taking or seeking under the conditions tested.

Session 205 - On the Move: An Update on Tardive Dyskinesia

Abstract: Tardive dyskinesia (TD) affects 20–50% of patients treated with antipsychotic medications. The iatrogenic nature of TD was initially unrecognized when antipsychotics were first introduced in the 1950s. However, substantial research has since been conducted to elucidate the prevalence, risk factors, possible pathophysiology, and assessment of TD. Unfortunately, TD is potentially irreversible making prevention the primary mechanism for decreasing its prevalence. Extant literature suggests differences between races and genders in rates of TD. There also appears to be a dose (mean and cumulative)-response relationship between neuroleptics and development of TD as well as an increased risk with typical versus atypical antipsychotics. Other factors potentially impacting development of TD include Major Depressive Disorder, substance use disorders, movement disorder at baseline, history of ECT, diabetes, smoking, and genetic predisposition. While there is much yet to discover, proposed underlying mechanisms for the development of TD include hypersensitivity of nigrostriatal dopamine receptors after chronic blockade by neuroleptics, impaired synaptic plasticity, neurotoxicity due to oxidative stress, and genetic mutations. Subsequently, dopamine-depleting agents, benzodiazepines, anticholinergics, and antiepileptics have been researched as possible pharmacotherapies to ameliorate TD. Thus far, the benefits of these agents have not been robust. Recently, however, the FDA has improved the first medication for treatment of TD. Valbenazine inhibits vesicular monoamine transporter type 2 (VMAT2) which decreases monoamine uptake into synaptic vesicles and depletes monoamine stores. Because of its novelty, cost can be prohibitive for some patients; however, it may provide relief for some patients for whom other treatments have thus far failed. Because of the potential long term effects of TD on patients' overall well-being, it is important for clinicians to be vigilant regarding selection of antipsychotic medication, assessment of TD and available treatments for TD.

Hyperbaric medicine in Rijeka 25 years after the publication of the first Croatian list of indications for hyperbaric oxygenation

Argentina is facing an increase in cocaine use by adolescents and young adults from every socioeconomic background. It is calculated that up to 10% of all cocaine passing through this country is locally sold and consumed. Nevertheless, local information describing common cocaine-related neurological events is scarce. From August 1988 to March 1993, 13 patients were evaluated with neurological disease associated with cocaine abuse. Among these 13 patients (Table 1), the mean age was 29; 70% were men. Patients most commonly used the nasal route (snorting). Concomitant abuse of other intoxicants, especially alcohol, was frequent (85%). The major neurological complications included one or more seizures (n = 7), ischemic stroke (n = 2) (Fig. 1-2), hemorrhagic stroke (n = 2) associated with arteriovenous malformation (Fig. 3a-b), memory disturbances (n = 1) and paroxysmal dystonia (n = 1). Psychiatric complaints were present in all patients. Mortality was not observed. There was no correlation between the appearance of complications and the amount of cocaine used, or prior experience with this drug. Only one of the 7 patients with seizures had a previous history of seizures. All had generalized tonic-clonic seizures, and one had concomitant absence episodes. Cocaine modulates central neurotransmitters and has direct cerebrovascular effects. The neurological complications appear to be related to cocaine hyperadrenergic effects, striatal dopaminergic receptor hypersensitivity and perhaps vasculitis. Structural changes in the brain of long-term cocaine abusers could explain the persistence of neurologic symptoms after drug withdrawl.

Do neuroinflammatory pathways contribute to serotoninergic alterations in autism? p38alpha MAPK signaling drives perturbed serotonin clearance, receptor hypersensitivity, and social behavior deficits in the SERT Ala56 mouse

Autism Spectrum Disorder (ASD) is a prevalent neurodevelopmental disorder with no FDA approved medications that alleviate core symptoms. Aberrant proinflammatory cytokine signaling involving the interleukin-1 receptor and p38 MAPK have been reported in ASD, a disorder where 25% of subjects exhibit elevated serotonin (5-HT) blood levels (hyperserotonemia). In ASD subjects, we identified functional coding variation in the 5-HT transporter (SERT), mutations that elevate SERT activity and perturb p38 MAPK-dependent transporter regulation. Mice that express the most common of these variants, SERT Ala56, exhibit hyperserotonemia, elevated, p38 MAPK-dependent SERT phosphorylation, increased hippocampal 5-HT clearance, 5-HT receptor hypersensitivity, increased repetitive behavior and disrupted social interactions. Treatment of SERT Ala56 mice with the novel, selective, CNS penetrant, p38alpha MAPK inhibitor, MW150, or conditional elimination of p38alpha MAPK in 5-HT neurons, normalized 5-HT receptor hypersensitivity, elevated 5-HT clearance and social deficits. As p38alpha MAPK signaling supports the IL-1beta and TNF-alpha-induced activation of SERT, our findings suggest that proinflammatory, p38alpha MAPK activation may contribute to ASD risk via a perturbation of 5-HT signaling. Our studies also indicate that p38alpha MAPK may be a relevant target for the pharmacologic treatment of ASD. Funding: This work was supported by NIH grants MH078028, MH094527, NS007491 and U01AG043415. Additional support was provided by the Simons Foundation Autism Research Initiative and the PhRMA Foundation.