Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases

Dopamine (DA) and other receptors physically interact in the plasma membrane of basal ganglia neurons forming receptor mosaics (RMs). Two types of RMs are discussed, homomers formed only by DA-receptor (DA-R) subtypes and heteromers formed by DA-R associated with other receptors, such as A2A, A1, mGluR5, N-methyl-d-aspartate (NMDA), γ-aminobutryic acid (GABA)-A, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. By being part of horizontal molecular networks, RMs tune multiple effector systems already at membrane level, such as G protein regulated inward rectifying potassium channels and dopamine transporter activity. Also, ligand-gated ion channels such as GABA-A and NMDA receptors are modulated by DA-R, e.g., in the striatal GABA output neurons through the formation of heteromeric complexes with these receptors. Thus, intramembrane DA-R-receptor interactions play an important role in the information handling in the basal ganglia. On this basis, functional implications of DA RM in physiological and pathological conditions are discussed. The effects of temperature on RM are discussed not only because receptor-decoding mechanisms are temperature sensitive, but also in view of the suggestion that possible ordering effects (i.e., changes in the entropy of a receptor complex) induced by a ligand are as a result of alterations in the receptor oligomerization (i.e., are related to rearrangements of the RM). Hence, brain temperature may have profound effects on brain integrative functions not only because its effects on the kinetics of biochemical reactions, but also for its effects on receptor geometry, building up of RM, and alterations in protein expression, as is the case of H-channels following febrile seizures. Note: This article is dedicated to Tullio Giacomini for his 70th birthday.     

Evaluation of Helicobacter pylori with a stool antigen assay in frail, elderly patients

OBJECTIVE: Helicobacter pylori infection has not been studied thoroughly in elderly patients. The aim of this study was to evaluate the reliability of stool antigen assay (HpSA) in the assessment of H. pylori infection in hospitalized, frail, elderly patients. MATERIALS AND METHODS: The study population consisted of 85 consecutively recruited elderly patients (> or =65 years old) hospitalized between May 1999 and December 2001 with diagnostic indications for upper gastrointestinal endoscopy. Twenty-nine subjects had been receiving treatment with proton-pump inhibitors (PPIs), such as omeprazole (10-20 mg/day) for 2-15 days, and 56 were not receiving treatment. HpSA was evaluated versus UBT (urea breath test), serology and histology: patients with at least two positive results out of the latter three tests were considered positive for H. pylori infection, while patients with at least two negative tests out of three were considered negative. RESULTS: The sensitivity and specificity of HpSA in the 56 untreated patients were, respectively, 76% (true positives TP = 22; false negatives FN = 7) and 93% (true negatives TN = 25; false positives FP = 2). The sensitivity and specificity of HpSA in the 29 patients on PPI treatment were, respectively, 82% (TP = 9; FN = 2) and 83% (TN = 15; FP = 3). CONCLUSIONS: HpSA is an accurate, non-invasive and easy method for diagnosing H. pylori infection in elderly patients.     

Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function

The existence of A2A-D2 heteromeric complexes is based on coimmunoprecipitation studies and on fluorescence resonance energy transfer and bioluminescence resonance energy transfer analyses. It has now become possible to show that A2A and D2 receptors also coimmunoprecipitate in striatal tissue, giving evidence for the existence of A2A-D2 heteromeric receptor complexes also in rat striatal tissue. The analysis gives evidence that these heteromers are constitutive, as they are observed in the absence of A2A and D2 agonists. The A2A-D2 heteromers could either be A2A-D2 heterodimers and/or higher-order A2A -D2 hetero-oligomers. In striatal neurons there are probably A2A-D2 heteromeric complexes, together with A2A-D2 homomeric complexes in the neuronal surface membrane. Their stoichiometry in various microdomains will have a major role in determining A2A and D2 signaling in the striatopallidal GABA neurons. Through the use of D2/D1 chimeras, evidence has been obtained that the fifth transmembrane (TM) domain and/or the I3 of the D2 receptor are part of the A2A-D2 receptor interface, where electrostatic epitope-epitope interactions involving the N-terminal part of I3 of the D2 receptor (arginine-rich epitope) play a major role, interacting with the carboxyl terminus of the A2A receptor. Computerized modeling of A2A-D2 heteromers are in line with these findings. It seems likely that A2A receptor-induced reduction of D2 receptor recognition, G protein coupling, and signaling, as well as the existence of A2A-D2 co-trafficking, are the consequence of the existence of an A2A-D2 receptor heteromer. The relevance of A2A-D2 heteromeric receptor complexes for Parkinson's disease and schizophrenia is emphasized as well as for the treatment of these diseases. Finally, recent evidence for the existence of antagonistic A2A-D3 heteromeric receptor complexes in cotransfected cell lines has been summarized.     

Sensorimotor gating, orienting and social perception in schizophrenia

Basic neurocognition and social cognition appear to influence the social impairments of persons with schizophrenia. This study examined relationships between two very basic automatic processes (i.e., sensorimotor gating and orienting) and social perception in schizophrenic patients. Thirty outpatients with schizophrenia completed psychophysiological measures of sensorimotor gating (prepulse inhibition, PPI), orienting (prepulse facilitation, PPF), and social perception (the Half Profile of Nonverbal Sensitivity, Half PONS). A median split was used to divide patients into poor and good gaters and poor and good orienters. Analyses revealed that patients with good PPI scored significantly higher on the Half PONS than patients with poor PPI. PPI showed a significant correlation (r=-0.54) with Half PONS performance, indicating that schizophrenia patients who were better able to gate out competing stimuli (i.e., less startle) were also better at detecting relevant social cues. Orienting (PPF) and social perception were not related. This study is the first to our knowledge to demonstrate an association between sensorimotor gating and social perception. The findings are consistent with other studies that have demonstrated relationships between basic neurocognition and social cognition. By showing a link between sensorimotor gating and social perception, this study supports social cognition's potential role as a mediator of the relationship between neurocognition and social functioning in schizophrenia.     

Colobomas of the iris and choroid and high signal intensity cerebral foci on T2-weighted magnetic resonance images in Klinefelter's syndrome

A 5-year-old boy presented with ocular anomalies including microphthalmos, colobomas of the iris, choroid, and optic nerve head, and strabismus. Magnetic resonance imaging of the head showed multiple bilateral asymmetric high signal intensity foci in the subcortical and periventricular white matter. Genetic counseling disclosed a 47,XXY karyotype.     

The role of antioxidants in protection from ototoxic drugs

A number of studies have shown that cisplatin and gentamicin ototoxic effects may result from free radical-mediated damage due to the reduction of antioxidant substances and an increased lipid peroxidation. The authors summarize the results obtained evaluating the auditory and vestibular functions and the inner ear hair cell morphology and survival after administration of antioxidant agents against cisplatin and gentamicin. In the first experiment, albino guinea pigs were treated with gentamicin (100 mg/kg per day, i.m.) alone or gentamicin (100 mg/kg per day, i.m.) plus alpha-tocopherol (100 mg/kg per day, i.m.) for 2 weeks. In a second experiment, albino guinea pigs were injected with cisplatin (2.5 mg/kg per day) or cisplatin (2.5 mg/kg per day) plus tiopronin (300 mg/kg) for 6 days. Electrocochleographic recordings were made from an implanted round window electrode. In all experiments compound action potentials (CAPs) were measured at 2-16 kHz. Changes in cochlear function were characterized as CAP threshold shifts. To evaluate vestibular function, the animals underwent sinusoidal oscillations in the dark about their vertical and longitudinal axes to evoke horizontal and vertical vestibulo-ocular reflexes (VOR). Frequency stimulation parameters ranged from 0.02 to 0.4 Hz and peak-to-peak amplitude was 20 degrees. Morphological changes were analysed by light microscopy and scanning electron microscopy. Both hearing loss and vestibular dysfunction induced by gentamicin were significantly attenuated by alpha-tocopherol. However, tiopronin co-therapy slowed the progression of hearing loss in cisplatin-treated animals and significantly attenuated the final threshold shifts. Cisplatin had little effect on the hair cells of cristae ampullares and maculae. Vestibular function was completely preserved in tiopronin co-treated animals. In conclusion, antioxidants such as alpha-tocopherol or tiopronin interfere with gentamicin and cisplatin damage and this suggests that they may be useful in preventing oto-vestibulotoxicity. Therefore, it is important to develop protective strategies that permit the avoidance of the toxic side effects of these drugs without interfering with their therapeutic effects.     

The protective role of tiopronin in cisplatin ototoxicity in Wistar rats

The purpose of this study was to evaluate cisplatin-induced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls (p<0.05). When tiopronin was added, DPOAE responses were significantly increased compared to those obtained with the administration of cisplatin alone (p<0.05). The cochleogram showed that tiopronin had a significant protective effect in the basal half and in the lower half of the middle turn. We conclude that tiopronin, a drug effective in protecting against cisplatin nephrotoxicity, is also effective in protecting against cisplatin ototoxicity.     

Short-term effects of weight loss on the cardiovascular risk factors in morbidly obese patients

OBJECTIVE: To analyze the short-term effects of weight loss on the cardiovascular risk factors in morbidly obese patients. RESEARCH METHODS AND PROCEDURES: Five metabolic cardiovascular risk factors (blood glucose, blood pressure, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides) were determined before and 15.3 +/- 2.1 months after laparoscopic gastric banding in 650 morbidly obese patients. Global cardiovascular risk was calculated according to the Prospective Cardiovascular Münster (PROCAM) scoring system. RESULTS: Mean weight loss was 22.7 +/- 20.4 kg. Normalization of the metabolic alteration was observed in 67.3% of patients with diabetes, 38.3% of patients with hypercholesterolemia, 72.5% of patients with low HDL-cholesterol, 72.3% of patients with hypertriglyceridemia, and 46.7% of patients with hypertension. PROCAM score fell from 31.4 +/- 11.6 to 28.0 +/- 12.0 points (p < 0.001). The modifications of total cholesterol and blood pressure were unrelated to percentage weight loss. Percentage weight loss was significantly related to the reductions of fasting blood glucose, triglyceride level, and the PROCAM score and to the increase of HDL-cholesterol concentrations observed after surgery. However, the strength of these four relationships was generally low. The variations of HDL-cholesterol concentrations and blood pressure levels were more influenced by actual energy balance than by the extent of weight loss. DISCUSSION: Weight loss observed in the first 12 to 18 months after gastric banding was associated with a significant improvement of single cardiovascular risk factors and global risk. On the other hand, the extent of weight loss was poorly related to the magnitude of improvement in cardiovascular risk.