(1/1654) Plasticity of first-order sensory synapses: interactions between homosynaptic long-term potentiation and heterosynaptically evoked dopaminergic potentiation.
Persistent potentiations of the chemical and electrotonic components of the eighth nerve (NVIII) EPSP recorded in vivo in the goldfish reticulospinal neuron, the Mauthner cell, can be evoked by afferent tetanization or local dendritic application of an endogenous transmitter, dopamine (3-hydroxytyramine). These modifications are attributable to the activation of distinct intracellular kinase cascades. Although dopamine-evoked potentiation (DEP) is mediated by the cAMP-dependent protein kinase (PKA), tetanization most likely activates a Ca2+-dependent protein kinase via an increased intracellular Ca2+ concentration. We present evidence that the eighth nerve tetanus that induces LTP does not act by triggering dopamine release, because it is evoked in the presence of a broad spectrum of dopamine antagonists. To test for interactions between these pathways, we applied the potentiating paradigms sequentially. When dopamine was applied first, tetanization produced additional potentiation of the mixed synaptic response, but when the sequence was reversed, DEP was occluded, indicating that the synapses potentiated by the two procedures belong to the same or overlapping populations. Experiments were conducted to determine interactions between the underlying regulatory mechanisms and the level of their convergence. Inhibiting PKA does not impede tetanus-induced LTP, and chelating postsynaptic Ca2+ with BAPTA does not block DEP, indicating that the initial steps of the induction processes are independent. Pharmacological and voltage-clamp analyses indicate that the two pathways converge on functional AMPA/kainate receptors for the chemically mediated EPSP and gap junctions for the electrotonic component or at intermediaries common to both pathways. A cellular model incorporating these interactions is proposed on the basis of differential modulation of synaptic responses via receptor-protein phosphorylation. (+info)
(2/1654) Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: a test-retest analysis.
Subacute and long-term stability of measurements of D2 dopamine receptor density (Bmax), affinity (Kd) was studied with positron emission tomography in eight healthy male volunteers. [11C]-Raclopride and the transient equilibrium method were used to measure D2 receptor characteristics. The interval between measurements (scan pairs) was 3 to 7 weeks (subacute) for four subjects and 6 to 11 months (long-term) for four subjects. A test-retest analysis of quantitative measurements of D2 receptor Bmax and Kd was compared with that done on binding potential (BP, Bmax/Kd) measures. In addition, the effect of error in defining the transient equilibrium time (tmax) in the parameter estimation procedure was explored with simulations. The subacute test-retest indicates good reproducibility of D2 receptor density, affinity, and BP ratio measurements with intraclass correlation coefficients of 0.90, 0.96, and 0.86, respectively. The variability of the measurements after 6 to 11 months was slightly higher than that seen in a subacute testing for Kd and more clearly so for binding potential and Bmax. The absolute variability in Bmax (14.5%) measurements was consistently higher than that of Kd (8.4%) or BP (7.9%) both in subacute and long-term measurements. Simulations indicated that the Bmax and Kd estimation procedure is more sensitive to error in the tmax than that for the BP. The results indicate a good overall stability of the equilibrium method with [11C]raclopride for measuring dopamine D2 receptor binding characteristics in the striatum. The BP approach is more stable than Kd and especially Bmax measurements. Error in defining the tmax in particular in the low specific radioactivity scan may be one source of greater variability in Bmax versus BP. However, a higher intraindividual variability in measurements of the D2 receptor Bmax also may include a component of continuous regulation of this parameter over time. These methodologic aspects should be considered in the design and interpretation of longitudinal studies on D2 dopamine receptor characteristics with [11C]-raclopride. (+info)
(3/1654) Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.
Sydnocarb (3-(beta-phenylisopropyl)-N-phenylcarbamoylsydnonimine) is a psychostimulant in clinical practice in Russia as a primary and adjunct therapy for a host of psychiatric disorders, including schizophrenia and depression. It has been described as a stimulant with an addiction liability and toxicity less than that of amphetamines. The present study undertook to evaluate the psychomotor stimulant effects of sydnocarb in comparison to those of methamphetamine. Sydnocarb increased locomotor activity of mice with reduced potency (approximately 10-fold) and efficacy compared with methamphetamine. Sydnocarb blocked the locomotor depressant effects of haloperidol at doses that were inactive when given alone. The locomotor stimulant effects of both methamphetamine and sydnocarb were dose-dependently blocked by the dopamine D1 and D2 antagonists SCH 39166 and spiperone, respectively; blockade generally occurred at doses of the antagonists that did not depress locomotor activity when given alone. In mice trained to discriminate methamphetamine from saline, sydnocarb fully substituted for methamphetamine with a 9-fold lower potency. When substituted for methamphetamine under self-administration experiments in rats, 10-fold higher concentrations of sydnocarb maintained responding by its i.v. presentation. Sydnocarb engendered stereotypy in high doses with approximately a 2-fold lower potency than methamphetamine. However, sydnocarb was much less efficacious than methamphetamine in inducing stereotyped behavior. Both sydnocarb and methamphetamine increased dialysate levels of dopamine in mouse striatum; however, the potency and efficacy of sydnocarb was less than methamphetamine. The convulsive effects of cocaine were significantly enhanced by the coadministration of nontoxic doses of methamphetamine but not of sydnocarb. Taken together, the present findings indicate that sydnocarb has psychomotor stimulant effects that are shared by methamphetamine while demonstrating a reduced behavioral toxicity. (+info)
(4/1654) Depression of peripheral chemosensitivity by a dopaminergic mechanism in patients with obstructive sleep apnoea syndrome.
In the present study, respiratory drives to chemical stimuli and peripheral chemosensitivity were evaluated in patients with obstructive sleep apnoea (OSAS). The effects of oral administration of domperidone, a selective dopamine D2-receptor antagonist, were also examined, to study the respiratory effects of endogenous dopamine on peripheral chemoreceptors. Sixteen patients with OSAS and nine normal control subjects were studied. Respiratory responses to hypercapnia and hypoxia were measured using the rebreathing method and isocapnic progressive hypoxia method, respectively. The hypoxic withdrawal test, which measures the decrease in ventilation caused by two breaths of 100% O2 under mild hypercapnic hypoxic conditions (end-tidal oxygen and carbon dioxide tensions approximately 8.0 kPa and 5.3-6.7 kPa, respectively), was used to evaluate peripheral chemosensitivity. In the patients with OSAS, ventilatory responses to hypercapnia and hypoxia were significantly decreased compared with those of control subjects. Hypoxic withdrawal tests showed that peripheral chemosensitivity was significantly lower in patients with OSAS than in normal subjects. Hypercapnic ventilatory response and peripheral chemosensitivity were enhanced by administration of domperidone in the patients with OSAS, although no changes in either of these were observed in the control subjects. The hypoxic ventilatory response and peripheral chemosensitivity in the patients with OSAS were each significantly correlated with severity of hypoxia during sleep. These findings suggest that peripheral chemosensitivity in patients with obstructive sleep apnoea syndrome may be decreased as a result of abnormality in dopaminergic mechanisms and that the reduced chemosensitivity observed in patients with obstructive sleep apnoea syndrome may affect the severity of hypoxia during sleep. (+info)
(5/1654) (-)-Stepholidine enhances K+ depolarization-induced activation of synaptosomal tyrosine 3-monooxygenase from rat striatum.
AIM: To study the mechanism of K+ depolarization-induced activation of synaptosomal tyrosine 3-monooxygenase (TM) in rat striatum and the effect of (-)-stepholidine (SPD) on this activation. METHODS: The TM was assayed for DOPA by HPLC-ECD; the activities of Ca2+/calmodulin (CaM)-dependent protein kinase (PK II) and Ca2+/phosphoinositide-dependent protein kinase (PKC) were assayed using histidine as substrate. RESULTS: The incubation of striatal synaptosomes in K(+)-riched (60 mmol.L-1) medium resulted in a marked activation of TM. PKC inhibitor polymyxin B (PMB) completely blocked the activation of K+ 60 mmol.L-1 on TM. Selective D2 receptor agonist quinpirole (QP), Ca2+ removal from incubation medium and CaM antagonist W7 failed to affect the activation. However, SPD enhanced the activation of K+ 60 mmol.L-1 on TM. Meanwhile, the incubation in K+ 60 mmol.L-1 also activated PKC. Neither QP nor SPD affected K+ depolarization-induced activation of PKC. CONCLUSION: The activation of K+ depolarization on synaptosomal TM is enhanced by SPD and this activation is mediated by PKC rather than by PK II. (+info)
(6/1654) Preproopiomelanocortin and preprodynorphin mRNA expressions in rat brain after electroacupuncture + droperidol.
AIM: To study the expression of preproopiomelanocortin (POMC) and preprodynorphin (PPD) mRNA following the combination of electroacupuncture (EA) with droperidol (Dro), a dopamine receptor antagonist. METHODS: The brains and spinal cords of Sprague-Dawley rats were sectioned after combination of EA with Dro, and the gene expression was investigated using nonradioactive in situ hybridization histochemistry (ISHH). RESULTS: Ten hours after EA, the POMC mRNA expression was enhanced; the expression was further enhanced when EA was combined with Dro. The expression of PPD mRNA showed regional difference in central nervous system (CNS): in spinal cord, EA enhanced the PPD mRNA expression and the combination of EA with Dro further promoted the expression; in the brain, the PPD mRNA expression after EA or combination of EA with Dro showed no obvious change in most regions (caudate-putamen, accumbens, arcuate nucleus of hypothalamus) or was decreased in supraoptic nucleus. CONCLUSION: Dro combined with EA promoted the expression of POMC mRNA in CNS and PPD mRNA in spinal cord, but reduced or had no effect on PPD mRNA expression in the brain. (+info)
(7/1654) Chimeric dopamine D2/angiotensin AT1 receptors: role of the length of third intracellular loop of D2 receptors in conferring specificity of receptor binding and G-protein coupling.
AIM: To define roles of the third intracellular loop (IL3) length of G-protein coupled receptors in conferring the specificity for receptor binding and G-protein coupling. METHODS: By polymerase chain reaction (PCR), the IL3 of D2 receptor was replaced with the counter part of AT1 receptor which has the shortest loop among all G-protein coupled receptors. D2/AT1 receptor cDNA was then stably transfected into Chinese hamster ovary cells and a clone with high level expression was obtained for receptor binding and agonist-induced phosphatidylinositols (PI) turnover experiments. RESULTS: Comparing to the D2 receptor, D2/AT1 chimeric receptor had lower affinities for all D2 receptor antagonists tested (spiperone, haloperidol, (+)-butaclamol, chlopromazine, clozapine, trifluoperdazine) and different affinity profiles to agonists (apomorphine, dopamine, quinpirole, bromocriptine). But the chimeric receptor failed to couple to G-protein and subsequent stimulation of PI turnover. CONCLUSION: The length of IL3 of D2 receptor participates defining recpetor binding sites conformation, and structure beyond IL3 may affect receptor G-protein coupling. (+info)
(8/1654) Characteristics of tetrahydroprotoberberines on dopamine D1 and D2 receptors in calf striatum.
AIM: To study the characteristics of tetrahydroprotoberberines (THPB) on dopamine D1 and D2 receptors and elucidate their structure-activity relationship. METHODS: Radioligand assay in vitro with a two-site model program analysis. RESULTS: Four THPB with two hydorxyl groups on C2 and C9 or C2 and C10 exhibited RH and RL two binding sites to D1 receptors and guanosine triphosphate regulated the RH binding site of SPD and THPB-132A in competition assay, while eleven THPB including nonhydroxy-THPB, monohydroxy-THPB, and THPB with two hydroxyl groups attaching to C3 and C10 showed one binding site to D1 receptors under the same conditions. However, the tested eleven THPB all manifested one binding site to D2 receptors in competition assay, and the 2-hydroxy-THPB had the most potent affinity for D2 receptors. CONCLUSION: Dihydroxy-THPB with two hydroxyl groups attaching to C2 and C9 or C2 and C10 possess the intrinsic activity of agonist to D1 receptors, while the other THPB do not. The tested eleven THPB all are the antagonists of D2 receptors. (+info)