Oxytocin Reduces Cocaine Seeking and Reverses Chronic Cocaine-Induced Changes in Glutamate Receptor Function

Background:

Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown.

Methods:

In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level.

Results:

Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner.

Conclusions:

These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions.     

High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations

Type 1 citrullinemia (CTLN1) often presents as a hyperammonemic encephalopathy in the neonatal period, but it can also develop in the late-infantile period and in adults. In addition, some patients can be identified in the presymptomatic period by neonatal or family member screening. In this study, twenty Korean patients with CTLN1 (19 families) were examined; fourteen patients with neonatal-onset, three with late-onset, and three that were identified presymptomatically. The 13 patients with hyperammonemic encephalopathy received continuous venovenous hemofiltration (CVVH) or peritoneal dialysis (PD). Although the hyperammonemia was relieved more effectively in the six patients on CVVH than the seven on PD, most of these patients suffered from severe neurologic deficits. Recurrent hyperammonemic episodes (7 pts, 35%), recurrent and reversible acute hepatic dysfunction (5 pts, 25%), and focal cerebral infarction (2 pts, 10%) were noted. The neonates with hyperammonemic encephalopathy had extensive brain injuries at the onset of hyperammonemia, followed by encephalomalacia and brain atrophy at quite an early age. Genetic testing for the ASS1 gene revealed a different mutation spectrum from those of other ethnicities; Three common mutations, c.421-2A > G (37.8%), c.1128-6_1188dup67 (18.9%), and p.Gly324Ser (16.2%), accounted for 73% of the mutations. The poor outcome was expected in patients with the peak ammonia level at onset over 600 μmol/L, whose proportion was higher in the neonatal presentation group than in the presymptomatic/late presentation group. Our findings add to the current understanding of the ethnic diversity of CTLN1 from both clinical and genetic perspectives.     

Wireless sensor networks for indoor air quality monitoring

The purpose of this study is to build an indoor air quality monitoring system based on wireless sensor networks (WSNs) technology. The main functions of the system include (1) remote parameter adjustment and firmware update mechanism for the sensors to enhance the flexibility and convenience of the system, (2) sensor nodes are designed by referring to the IEEE 1451.4 standard. This way, sensor nodes can automatically adjust and be plug and play, and (3) calibration method to strength the measurement value's sensitivity and accuracy. The experimental results show that transmission speed improves 30% than Trickle, transmission volume reduced to 42% of the original volume, updating task in 5*5 network topology can be executed 1.79 times and power consumption reduced to 30%. When baseline drifts, we can use the firmware update mechanism to adjust the reference value. The way can reduce error percentage from 15% to 7%.     

Possible pathophysiology of ketamine‐related cystitis and associated treatment strategies

Ketamine‐related cystitis is characterized by ketamine‐induced urinary frequency and bladder pain. It has become a serious problem in recent years. The most typical grossly pathological bladder change with ketamine related cystitis is a contracted bladder and bladder wall thickening. Ulcerative cystitis with an easily bleeding mucosa is a common cystoscopic finding. Microscopically, the urothelium is denuded and is infiltrated by inflammatory cells, such as mast cells and eosinophils. The pathogenesis of ketamine‐related cystitis is complicated and involves many different pathways. Past evidence suggests a direct toxic effect, bladder barrier dysfunction, neurogenic inflammation, immunoglobulin‐E‐mediated inflammation, overexpression of carcinogenic genes, abnormal apoptosis and nitric oxide synthase‐mediated inflammation contribute to the pathogenesis of ketamine‐related cystitis. The first step to managing ketamine‐related cystitis is always asking patients to cease ketamine. Medical treatment might be helpful in patients with early ketamine‐related cystitis and abstinence from ketamine. Several case studies showed that the intravesical installation of hyaluronic acid and intravesical injection of botulinum toxin type A were effective for symptom relief in selected patients. For patients with irreversible pathological change, such as contracted bladder, augmentation enterocystoplasty might be the only solution to increase bladder capacity and relieve intractable bladder pain.     

Composition of common bile duct stones in Chinese patients during and after endoscopic sphincterotomy

AIM: Endoscopic sphincterotomy (ES) is a well-established therapeutic modality for the removal of common bile duct (CBD) stones. After ES there are still around 10% of patients that experience recurrent CBD stones. The aim of this study is to investigate the composition of CBD stones before and after ES and its clinical significance in Chinese patients. METHODS: From January 1996 to December 2003, 735 patients with CBD stones received ES at Kaohsiung Veterans General Hospital and stone specimens from 266 patients were sent for analysis. Seventy-five patients had recurrent CBD stones and stone specimens from 44 patients were sent for analysis. The composition of the stones was analyzed by infrared (IR) spectrometry and they were classified as cholesterol or bilirubinate stones according to the predominant composition. Clinical data were analyzed. RESULTS: In the initial 266 stone samples, 217 (82%) were bilirubinate stones, 42 (16%) were cholesterol stones, 3 were calcium carbonate stones, 4 were mixed cholesterol and bilirubinate stones. Patients with bilirubinate stones were significantly older than patients with cholesterol stones (66±13 years vs56±17 years, P= 0.001). In the 44 recurrent stone samples, 38 (86%) were bilirubinate stones, 3 (7%) were cholesterol stones, and 3 were mixed cholesterol and bilirubinate stones. In 27 patients, both initial and recurrent stone specimens can be obtained, 23 patients had bilirubinate stones initially and 2 became cholesterol stones in the recurrent attack. In the four patients with initial cholesterol stones, three patients had bilirubinate stones and one patient had a cholesterol stone in the recurrent attack. CONCLUSION: Bilirubinate stone is the predominant composition of initial or recurrent CBD stone in Chinese patients. The composition of CBD stones may be different from initial stones after ES.     

A novel mutation of KCNJ11 gene in a patient with permanent neonatal diabetes mellitus

A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167 (aTC → tTC) in a region that corresponds to a predicted intracellular gate of the ATP-sensitive potassium channel.     

Norepinephrine provides short-term neuroprotection against Aβ1–42 by reducing oxidative stress independent of Nrf2 activation

Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-β (Aβ)1-42–induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Aβ1-42–induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Aβ1-42–induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Aβ1-42–mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Aβ1-42–induced activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch-like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Aβ1-42–induced ROS generation and elicited no protection against Aβ1–42. Taken together, these findings suggest that NE could exert neuroprotective function against Aβ1–42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway.