Antagonist for atrial natriuretic peptide receptors ameliorates glomerular hyperfiltration in diabetic rats

To evaluate the possible contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration, we examined the effect of non-peptide competitive antagonist for biological receptors of ANP, HS-142-1, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in diabetic rats. Increased GFR and RPF in diabetic rats were significantly ameliorated by the injection of HS-142-1, while blood pressure remained unchanged. Urinary cyclic GMP excretion was significantly higher in diabetic rats than in control rats and HS-142-1 decreased urinary cGMP excretion significantly. These results indicate that atrial natriuretic peptide contributes to the development of glomerular hyperfiltration and hyperperfusion in diabetes and HS-142-1 might be useful in the treatment of them.     

Dopamine D2 receptors quantified in vivo in human narcolepsy

The correlation of clinical with psychological and social data is an attempt to find predictors of the definite long-term outcome after brain injury. 34 patients were reexamined 3 to 8 years after the accident using a number of psychological tests. Additionally, life quality was defined and evaluated. Only patients with an initial Glasgow Coma Scale-Score of 3-12, an intracranial traumatic lesion on computertomography and age 16-65 years at the time of accident were included in this study. Patients exhibited a uniform pattern of disturbances in psychosocial long-term outcome. These disturbances were compared with initial clinical data: memory, attention and learning were significantly correlated with the duration of coma and the presence of additional extracerebral injuries. From the initial computerized tomography, the findings 'compression of basal cisterns' and 'intracerebral contusion' showed to be predictors of the cerebral function. Late social status and behavior, defined as quality of life, were clearly related with initial clinical findings. In conclusion, there are early clinical predictors of the long term social and psychological outcome after brain injury.     

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.     

Dopamine D2-like receptors in the rat kidney: effect of denervation

A new method for estimation of agonist-affinity (KA) and relative efficacy was introduced. This method afforded a procedure by which relative efficacy may be estimated while the actual KA values of agonist-receptor complexes are unknown. The relative efficacy may be estimated by employing a newly defined drug parameter, namely the eES value. The eES value is related to drug efficacy and is defined in such a manner that an isolated eES is a meaningful quantity which may indicate whether or not spare receptors are present in an agonist-effector system. The estimation of eES was based on the fact that fixed agonist-competitive antagonist combinations mimic partial agonists and mediate submaximal concentration-effect curves. However, for the practical estimation of eES one may employ data acquired from agonistic concentration-effect curves determined in the absence and presence of increasing concentrations of a competitive antagonist. This procedure was illustrated by utilizing theoretical concentration-effect curves and applied practically by estimating eES and KA values acquired from sets of carbachol and salbutamol curves. The sets of carbachol and salbutamol concentration-effect curves were determined in the absence and presence of their respective competitive antagonists, namely tripitramine and pindolol.     

Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2

Several G(i)-linked neurotransmitter receptors, including dopamine D2 receptors, act synergistically with Ca(2+)-mobilizing stimuli to potentiate release of arachidonic acid (AA) from membrane phospholipids. In brain, AA and its metabolites are thought to act as intracellular second messengers, suggesting that receptor-dependent potentiation of AA release may participate in neuronal transmembrane signaling. To study the molecular mechanisms underlying this modulatory response, we have now used Chinese hamster ovary cells transfected with rat D2-receptor cDNA, CHO(D2). Two antisense oligodeoxynucleotides corresponding to distinct cDNA sequences of cytosolic, AA-specific phospholipase A2 (cPLA2) were synthesized and added to cultures of CHO(D2) cells. Incubation with antisense oligodeoxynucleotides inhibited D2 receptor-dependent release of AA but had no effect on D2-receptor binding or D2 inhibition of cyclic AMP accumulation. In addition, pharmacological experiments showed that D2 receptor-dependent AA release was prevented by nonselective phospholipase inhibitors (such as mepacrine) but not by inhibitors of membrane-bound, non-AA-specific PLA2 (such as p-bromophenacyl bromide). cPLA2 is expressed in brain tissue. The results, showing that cPLA2 participates in receptor-dependent potentiation of AA release in CHO(D2) cells, suggest that this phospholipase may serve a similar signaling function in brain.     

Dopamine activity in the lateral anterior hypothalamus modulates AAS-induced aggression through D2 but not D5 receptors.

Treatment with anabolic-androgenic steroids (AAS) throughout adolescence facilitates offensive aggression in Syrian hamsters. In the anterior hypothalamus (AH), the dopaminergic neural system undergoes alterations after repeated exposure to AAS, producing elevated aggression. Previously, systemic administration of selective dopamine receptor antagonists has been shown to reduce aggression in various species and animal models. However, these reductions in aggression occur with concomitant alterations in general arousal and mobility. Therefore, to control for these systemic effects, the current studies utilized microinjection techniques to determine the effects of local antagonism of D2 and D5 receptors in the AH on adolescent AAS-induced aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the D2 antagonist eticlopride, or the D5 antagonist SCH-23390, into the AH. Treatment with eticlopride showed dose-dependent suppression of aggressive behavior in the absence of changes in mobility. Conversely, while injection of SCH-23390 suppressed aggressive behavior, these reductions were met with alterations in social interest and locomotor behavior. To elucidate a plausible mechanism for the observed D5 receptor mediation of AAS-induced aggression, brains of AAS and sesame oil-treated animals were processed for double-label immunofluorescence of GAD?? (a marker for GABA production) and D5 receptors in the lateral subdivision of the AH (LAH). Results indicate a sparse distribution of GAD?? neurons colocalized with D5 receptors in the LAH. Together, these results indicate that D5 receptors in the LAH modulate non-GABAergic pathways that indirectly influence aggression control, while D2 receptors have a direct influence on AAS-induced aggression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine D4 receptors: a new opportunity for research on schizophrenia

Classically, the D2 receptors formed the core of the dopamine hypothesis for schizophrenia. Recently, the dopamine D4 receptors have received particular attention in this context. This is due to the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, and displays a ten-fold higher affinity for D4 compared to D2 or D3 receptors. Following various reports presenting the interest of D4 receptors in treating schizophrenia, multiple chemical developments were made. During the last five years, various structures were described with a high selectivity for D4 receptor subtype. Currently, although the first clinical report was very disappointing, the observation which support the idea that D4 might serve as a target for clozapine have significantly modified and extended the understanding of mechanism underlying atypical antipsychotic treatment of schizophrenia.     

pH dependence of ligand binding to D2 dopamine receptors

The binding of a range of ligands to D2 dopamine receptors in bovine caudate nucleus and recombinant CHO cells expressing the receptor has been determined at different pH values between 4.5 and 8.5. The maximum number of D2 dopamine receptor binding sites in each tissue was not affected by the change in pH, but the affinity of ligands for binding to the receptors was decreased as the pH was decreased. For classical dopamine antagonists, e.g. spiperone and haloperidol, the data on pH dependence of the dissociation constant for receptor binding indicated that the protonation of a single ionizing group on the receptor (pKa approximately 6) influenced the binding process. For antagonists of the substituted benzamide class, the data indicated that the protonation of two ionizing groups (pKa between 6 and 7) influenced the ligand binding process. These ionizing residues may correspond to Asp 114 for the classical antagonists and Asp 114 and Asp 80 for the substituted benzamide antagonists. Further evidence for the participation of carboxyl residues in the ligand binding process was obtained from the inhibition by N,N'-dicyclohexylcarbodiimide of the binding of [3H]spiperone and [3H]YM 09151-2 to D2 receptors in the recombinant CHO cells.     

Renal prostaglandins and thromboxane A2 lack a functional significance in the genesis of protein-induced glomerular hyperfiltration in human renal disease

Ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) was purified from an obligately autotrophic hydrogen-oxidizing bacterium, Hydrogenovibrio marinus MH-110. The protein has a M(r) value of approximately 110,000, and is composed of two identical subunits of 55,000. To our knowledge, the existence of L2-form RubisCO in a chemolithoautotrophic bacterium is first reported in this paper. The N-terminal amino acid sequence determination of the purified enzyme showed high homology with those of the L2-form RubisCO of Rhodospirillum rubrum and the Lx-form RubisCO from Rhodobacter sphaeroides.     

Acoustic absorption due to proton transfer in solutions of proteins, peptides and amino acids at neutral pH

Measurements of ultrasonic absorption in the frequency range 2 to 60 MHz have been made on solutions of the amino acid histidine, dipeptides glycyl tyrosine and histidyl tyrosine, and proteins lysozyme and bovine serum albumin. Measurements were carried out at 37 degrees C and covered the pH range 6.8 to 7.7. Mechanisms for the observed excess acoustic absorption involving bimolecular and intramolecular proton transfer are considered.     

Dopamine D1 and D2 antagonist effects on response likelihood and duration.

Experimentally induced and parkinsonian disruptions in dopamine (DA) transmission are associated with motor abnormalities that include a reduced likelihood of behavioral response initiation and an increased duration of executed responses. Here we investigated the dopamine receptor subtypes involved in regulating these two aspects of behavior. We examined the effects of D1 family (D1/D5) antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; 0, 0.04, 0.08, or 0.16 mg/kg) and D2/D3 antagonist 3,5-dichloro-N-(1-ethylpyrrolidin-2-ylmethyl)-2-hydroxy-6-methoxybenzamide (+)-tartrate salt (raclopride; 0, 0.2, or 0.4 mg/kg) on the likelihood and duration of a cued Pavlovian approach and a cued operant lever-press response. While the high doses of the D1 and D2 antagonists produced similar levels of overall locomotor suppression, only the D2 antagonist increased the duration of time that animals’ heads remained in the food compartment during both Pavlovian and operant task performance. In contrast, D1 antagonist SCH23390 decreased the proportion of trials in which animals executed both the Pavlovian approach and operant lever-press, while raclopride did not. The results suggest that D2 receptor blockade preferentially increases response duration, and, under the simple discrete-trial procedures employed here, D1 receptor blockade preferential reduces Pavlovian and operant response likelihood. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.     

Dopamine D2 receptor-mediated modulation of rod-cone coupling in the Xenopus retina

Lectins are able to bind to cholecystokinin (CCK) receptors and other glycosylated membrane proteins. The lectins wheat germ agglutinin (WGA) and Ulex europaeus agglutinin (UEA-I) are used for affinity chromatography to isolate the highly glycosylated CCK-A receptor of pancreatic acinar cells. According to the working hypothesis that lectin binding to the CCK receptor should alter the ligand-receptor interaction, the effect of WGA and UEA-I on CCK-8-induced enzyme secretion was studied on isolated rat pancreatic acini in vitro. In vitro both lectins showed a dosage-dependent inhibition of CCK-8-induced alpha-amylase secretion of acini over 60 min. WGA showed a strong inhibitory effect on amylase secretion, approximately 40%, in vitro. UEA-I caused a smaller, but significant decrease, approximately 20%, in enzyme secretion of isolated acini. Additionally, both lectins inhibited cerulein/secretin- or cerulein-induced pancreatic secretion of rats in vivo, but not after secretin alone. The results are discussed with respect to a possible influence of both lectins on the interaction of CCK or cerulein with the CCK-A receptor.     

Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster).

The prairie vole (Microtus ochrogaster), a monogamous rodent that forms long-lasting pair bonds, has proven useful for the neurobiological study of social attachment. In the laboratory, pair bonds can be assessed by testing for a partner preference, a choice test in which pair-bonded voles regularly prefer their partner to a conspecific stranger. Studies reported here investigate the role of dopamine D2-like receptors (i.e., D2, D3, and D4 receptors) in the nucleus accumbens (NAcc) for the formation of a partner preference in female voles. Mating facilitated partner preference formation and associated with an approximately 50% increase in extracellular dopamine in the NAcc. Microinjection of the D2 antagonist eticlopride into the NAcc (but not the prelimbic cortex) blocked the formation of a partner preference in mating voles, whereas the D2 agonist quinpirole facilitated formation of a partner preference in the absence of mating. Taken together, these results suggest that D2-like receptors in the NAcc are important for the mediation of social attachments in female voles. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Left-right asymmetry of striatal dopamine D2 receptors

Brain functions may be lateralized to the right or the left hemisphere. However, the biochemical characteristics accompanying these functions are largely unknown. To test possible lateralization of striatal dopamine D2 receptors, we examined 18 volunteers using 123I-iodobenzamide and single photon emission tomography. The striatum-to-cerebellum D2 binding ratio was 1.93 +/- 0.22 (mean +/- S.D.) on the right side and 1.85 +/- 0.19 on the left side. In 14 subjects, D2 binding was higher in the right compared to the left striatum (P < 0.05). These results are supported by a meta-analysis performed on 15 studies reported in the literature. We conclude that side differences of striatal dopamine D2 receptors exist. We propose that motor activity could be responsible for our findings.     

Excitatory amino acid receptors in the paraventricular hypothalamic nucleus mediate pressor response induced by carotid body chemoreceptor stimulation in rats

In urethane-anesthetized rats with spinal transection, antagonists of excitatory amino acid receptors, P2 purinoceptors and adrenoceptors were microinjected into the paraventricular hypothalamic nucleus (PVN) and their effects on the pressor response evoked by carotid body chemoreceptor stimulation were examined. Microinjections of the non-selective excitatory amino acid antagonist kynurenate, the non-NMDA receptor antagonist CNQX and the NMDA antagonist 2-amino-5-phosphonovalerate (AP5) into the PVN inhibited the chemoreceptor reflex-induced pressor response. The excitatory amino acid agonist L-glutamate injected into the PVN produced an increase in blood pressure. The P2 purinoceptor antagonist suramin did not affect the pressor response and ATP did not affect basal blood pressure. The alpha adrenoceptor antagonist phentolamine, prazosin and yohimbine also inhibited the chemoreceptor-induced pressor response, while the beta antagonist propranolol did not affect it. These findings indicate that excitatory amino acid receptors and alpha adrenoceptors in the PVN are involved in mediating the pressor response induced by carotid body chemoreceptor stimulation in rats.