Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways.

Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca(2+)]i increase elicited by extracellularly applying an IP3-generating molecule (ATP), via σ1Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca(2+) elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine co-injection. The cocaine-triggered augmentation was σ1R-dependent, TRPC-mediated and contingent on [Ca(2+)]i elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D1-expressing nAcc neurons: enhancement of IP3R-mediated responses via σ1R activation at the endoplasmic reticulum, resulting in augmented Ca(2+) release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of σ1R or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway identified in vitro

Asthma Phenotypes in Childhood

INTRODUCTION: Asthma is no longer thought of as a single disease, but rather a collection of varying symptoms expressing different disease patterns. One of the ongoing challenges is understanding the underlying pathophysiological mechanisms that may be responsible for the varying responses to treatment. Areas Covered: This review provides an overview of our current understanding of the asthma phenotype concept in childhood and describes key findings from both conventional and data-driven methods. Expert Commentary: With the vast amounts of data generated from cohorts, there is hope that we can elucidate distinct pathophysiological mechanisms, or endotypes. In return, this would lead to better patient stratification and disease management, thereby providing true personalised medicine

Carnitine palmitoyl transferase type 2 defi ciency -case report and review of the literature

ABSTRACT -Carnitine palmitoyl transferase (CPT) defi ciency is a relatively rare disease of fatty acid oxidation inherited autosomal recessively. CPT2 defi ciency presents frequently in adults with rhabdomyolysis and myoglobinuria triggered most oft en by prolonged exercise. Carnitine is required for the transfer of longchain fatty acids from the cytoplasm to the mitochondrial matrix for their oxidation. Strenuous exercise is known to increase serum creatine kinase (CK) in nearly all healthy people and can be elevated oft en over ten times the upper limit of normal. Rhabdomyolysis can be of inherited etiology (disorders of glycogenolysis, fatty acid oxidation, mitochondrial respiratory chain pathways) or acquired (trauma, compartment syndrome, drugs, caff eine, toxins, infections, infl ammatory muscle diseases, and exertion). Here we present a female patient with CPT2 defi ciency diagnosed aft er recurrent rhabdomyolysis upon physical exertion and carbohydrate-restrictive diet. With the implementation of dietary measures and lifestyle changes that included more frequent but shorter interval exercise and avoidance of inappropriate physical exertion, the patient had a normal neurological status with only slightly elevated CK levels. Th is example illustrates the importance of careful monitoring of patients with increased levels of CK, even when there are no evident clinical, histopathologic or electromyoneurography (EMNG) indicators of myopathy