Plasticity of first-order sensory synapses: interactions between homosynaptic long-term potentiation and heterosynaptically evoked dopaminergic potentiation.
(1/1467)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)
Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine.
(2/1467)LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia. (+info)
Behavioral, toxic, and neurochemical effects of sydnocarb, a novel psychomotor stimulant: comparisons with methamphetamine.
(3/1467)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)
Electrical and mechanical responses to diltiazem in potassium depolarized myocardium of the guinea pig.
(4/1467)Effects of diltiazem on the electrical and mechanical activities of guinea pig papillary muscle were investigated in K-rich Tyrode's solution (Kc1 12.7 mM). The electrical properties of cell membrane in K-rich solution were also examined in the ventricular muscle fibers. It was found that the overshoot as well as the maximum rate of rise (Vmax) of the action potential were highly sensitive to the extracellular concentration of CaC12 in K-rich solution. Vmax was also affected by NaC1. Diltiazem at a lower concentration (1.1 X 10(-7) M) caused a reduction in the contractile force of K-depolarized papillary muscle without producing significant changes in the resting and action potentials. In the presence of a higher concentration of diltiazem (1.1 X 10(-5) M), the contractile force decreased concurrently with the change in the action potential. Addition of CaC12 restored the original strength of contraction in parallel to the recovery of the action potential, especially in its overshoot and Vmax. From these results, it is inferred that diltiazem may decrease the contractile force of guinea pig papillary muscle either by interfering with the intrasmembrane calcium influx or by intracellularly reducing the free calcium ion concentration in the myoplasm. (+info)
Vasopressin V2 receptor enhances gain of baroreflex in conscious spontaneously hypertensive rats.
(5/1467)The aim of the present study was to determine the receptor subtype involved in arginine vasopressin (AVP)-induced modulation of baroreflex function in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using novel nonpeptide AVP V1- and V2-receptor antagonists. Baroreceptor heart rate (HR) reflex was investigated in both SHR and WKY rats which were intravenously administered the selective V1- and V2-receptor antagonists OPC-21268 and OPC-31260, respectively. Baroreflex function was assessed by obtaining alternate pressor and depressor responses to phenylephrine and sodium nitroprusside, respectively, to construct baroreflex curves. In both SHR and WKY rats baroreflex activity was tested before and after intravenous administration of vehicle (20% DMSO), OPC-21268 (10 mg/kg), and OPC-31260 (1 and 10 mg/kg). Vehicle did not significantly alter basal mean arterial pressure (MAP) and HR values or baroreflex function in SHR or WKY rats. The V1-receptor antagonist had no significant effect on resting MAP or HR values or on baroreflex parameters in both groups of rats, although this dose was shown to significantly inhibit the pressor response to AVP (5 ng iv; ANOVA, P < 0.05). In SHR but not WKY rats the V2-receptor antagonist significantly attenuated the gain (or slope) of the baroreflex curve (to 73 +/- 3 and 79 +/- 7% of control for 1 and 10 mg/kg, respectively), although AVP-induced pressor responses were also attenuated with the higher dose of the V2-receptor antagonist. These findings suggest that AVP tonically enhances baroreflex function through a V2 receptor in the SHR. (+info)
Characteristics of tetrahydroprotoberberines on dopamine D1 and D2 receptors in calf striatum.
(6/1467)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)
Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.
(7/1467)kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention. (+info)
G-protein activation by putative antagonists at mutant Thr373Lys alpha2A adrenergic receptors.
(8/1467)1. Replacement of a threonine by a lysine at position 373 in the C-terminal portion of the third intracellular loop of the human alpha2A-adrenergic receptor (alpha2A AR) has been reported to generate a constitutively active mutant receptor in analogy with similar mutations in the alpha1B and beta2 AR (Ren et al., 1993). In the present study, the mutant Thr373Lys alpha2A AR receptor was investigated by measuring the formation of inositol phosphates in either the absence or presence of mouse G(alpha)15 protein in Cos-7 cells. 2. Increased affinity, potency and/or efficacy for the agonists [(-)-adrenaline, UK 14304, clonidine, guanabenz and oxymetazoline] was observed, consistent with a precoupled mutant alpha2A AR: G-protein state. The basal inositol phosphates response was similar at the wild-type (wt) and mutant alpha2A AR, but was enhanced at the mutant alpha2A AR upon co-expression with the mouse G(alpha)15 protein. This enhanced response could not be attenuated in the presence of any of the tested alpha2 AR antagonists (10 microM), suggesting that inverse agonist activity did not occur at the mutant alpha2A AR. 3. Ligands that so far have been identified as antagonists at the wt alpha2A AR demonstrated either no intrinsic activity (MK 912, WB 4101, RS 15385, RX 811059 and RX 821002) or positive efficacy [Emax, % vs. 1 microM UK 14304: dexefaroxan (27+/-7), idazoxan (34+/-9), atipamezole (27+/-4), BRL 44408 (59+/-5) and SKF 86466 (54+/-9)] at the mutant alpha2A AR, but only in the presence of the mouse G(alpha)15 protein. The ligand potencies corresponded with their respective pKi values at the mutant alpha2A AR receptor. 4. The partial agonist effect of SKF 86466 was resistant to pertussis toxin treatment (100 ng ml(-1)) and not affected by co-expression of the rat G(alpha)i1 protein. It was virtually absent in the presence of 10 microM RS 15385. SKF 86466 was without intrinsic activity upon co-expression of the mouse G(alpha)q protein. 5. Some putative alpha2 AR antagonists exerted a partial agonist activity that was highly dependent on the presence of specific G-protein alpha-subunits, suggesting that these ligands cause selective G-protein activation at the mutant alpha2A AR. (+info)