Effect of stretching on the action potentials of the human and rabbit ventricular myocardium

The effect of stretching from L0 to Lmax on the electrical activity was studied on human myocardial preparations from patients with heart disease and on strips of rabbit ventricular myocardium. Muscular deformation was shown to decrease the amplitude and velocity of depolarization in slow action potentials. The action potentials (AP) possessing a fast depolarization phase were not sensitive to physiological stretching. Antiarrhythmic drugs--ethmozin (2 X 10(-5) M) and ethacizin (2 X 10(-6) M)--caused a decrease in the rate of AP depolarization, thus increasing AP sensitivity to deformation. It is suggested that stretching under the action of ethmozin and ethacizin reduced cardiomyocyte excitability due to suppression of slow Ca-current.     

Intracellular and voltage clamp studies of capsaicin induced effects on a sensory neuron model

The acute effects of capsaicin (CAP) were studied on membrane properties, the action potential (AP) and the membrane ionic currents in the giant serotoninergic neuron of the cerebral ganglion (MCC) in the snail of Helix pomatia L. CAP (30-300 microM) depolarized the MCC, decreased the amplitude, the rate of rise and the rate of fall of the action potential. CAP prolonged the AP-duration, increased the membrane slope resistance, decreased the hyperpolarizing afterpotential and the posttetanic hyperpolarization both in normal and Na-free media. All the effects were reversible and could be evoked repeatedly. CAP attenuated the outward membrane currents with decreasing potency in the sequence of the transient potassium (IA) voltage-dependent potassium (IK), Ca-dependent potassium (IC) and leakage currents (IL). CAP decreased or increased the peak amplitude of the Ca-current (ICa), depending on the extracellular Ca concentration. CAP increased the inactivation of the ICa, decreased the Ca-conductance (GCa) in normal and high Ca solutions and shifted the Ca-equilibrium potential (VCa) to more positive voltage in 30 mM Ca-solution. CAP decreased the electrically activated Na-current and blocked the acetylcholine (ACh) activated increase in Na-K conductances. It is concluded that CAP profoundly affects the electrically and some transmitter-activated cationic conductances. Further studies are needed to clarify the significance of these changes with respect to the mechanism of the selective neurotoxic effects of CAP.     

The blocking action of platelet-activating factor (PAF) on the calcium currents of the atrial fibers in the frog and guinea pig

The effects of platelet-activating factor (PAF) on the myocardial cell membrane Ca-current (ICa) and Ca-action potential (Ca-AP) were investigated. In double sucrose-gap voltage-clamped frog atrial trabeculae PAF (2 X 10(-7) M) reduced ICa-amplitude to 40-50%; at the same time the IK-amplitude was increased to the same value. These changes of ICa and IK amplitudes were protected by simultaneous action of PAF and PAF antagonist BN 52021 (4 X 10(-6) M). In the partially depolarized (K+0 = 15-20 mM) of the guinea pig myocardial auricles PAF decreased Ca-AP amplitude and Vmax of its upstroke and shortened the Ca-AP duration (intracellular microelectrodes) like the isometric tension responses. These effects were prevented by PAF antagonist U-66985. Histamine was also able to protect from the PAF-induced changes of Ca-AP and tension responses. Our data demonstrated both by direct and by indirect methods of ICa registration in myocardia membrane that PAF induces reversed blocking of ICa. Because the blocking effects of PAF on frog and guinea pig myocardium are identical, these results imply that the mechanisms of PAF action on cold- and warm-blooded animals are similar in principle. The coupling of ICa and IK changes confirm our earlier supposition that PAF-induced Ca-AP shorting can be explained by IK augmentation.     

Dopamine transporter is essential for the maintenance of spontaneous activity of auditory nerve neurones and their responsiveness to sound stimulation

Dopamine, a neurotransmitter released by the lateral olivocochlear efferents, has been shown tonically to inhibit the spontaneous and sound-evoked activity of auditory nerve fibres. This permanent inhibition probably requires the presence of an efficient transporter to remove dopamine from the synaptic cleft. Here, we report that the dopamine transporter is located in the lateral efferent fibres both below the inner hair cells and in the inner spiral bundle. Perilymphatic perfusion of the dopamine transporter inhibitors nomifensine and N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine into the cochlea reduced the spontaneous neural noise and the sound-evoked compound action potential of the auditory nerve in a dose-dependent manner, leading to both neural responses being completely abolished. We observed no significant change in cochlear responses generated by sensory hair cells (cochlear microphonic, summating potential, distortion products otoacoustic emissions) or in the endocochlear potential reflecting the functional state of the stria vascularis. This is consistent with a selective action of dopamine transporter inhibitors on auditory nerve activity. Capillary electrophoresis with laser-induced fluorescence (EC-LIF) measurements showed that nomifensine-induced inhibition of auditory nerve responses was due to increased extracellular dopamine levels in the cochlea. Altogether, these results show that the dopamine transporter is essential for maintaining the spontaneous activity of auditory nerve neurones and their responsiveness to sound stimulation.     

Differentiating the rapid actions of cocaine

The subjective effects of intravenous cocaine are felt almost immediately, and this immediacy plays an important part in the drug's rewarding impact. The primary rewarding effect of cocaine involves blockade of dopamine reuptake; however, the onset of this action is too late to account for the drug's initial effects. Recent studies suggest that cocaine-predictive cues--including peripheral interoceptive cues generated by cocaine itself--come to cause more direct and earlier reward signalling by activating excitatory inputs to the dopamine system. The conditioned activation of the dopamine system by cocaine-predictive cues offers a new target for potential addiction therapies.     

Mechanisms of the stimulating effect of brain antibodies on the Ca2 current in the neuron membrane

Antibodies against rat brain microsomes induce a 16 +/- 3% increase in the amplitude of Ca-current (ICa) in snail neurons. Ca-ions block ICa in dose-dependent and potential-dependent manner. Antibodies against microsomes decrease the effectiveness of ICa blockade by Ca-ions: a 85 +/- 10% increase in ICa is observed and I-V curve is normalized. It is suggested that an enhancing effect of antibodies on ICa and the elimination of blocking Ca-effect on ICa are connected with the weakening of divalent cations binding by the anionic groups of calcium channels.     

小鼠大脑纹状体诱发多巴胺信号分析——Monte Carlo模拟

突触前释放的多巴胺以容积式释放（volume transmission）来传递多巴胺信号,而碳纤电极（carbon fiber electrode,CFE）所记录的胞外电化学信号是大量多巴胺分子氧化电流的平均统计结果。这些特征为使用Monte Carlo方法来直观而细致地描述多巴胺在胞外“自由行走”的行为提供了可能。作者尝试使用Monte Carlo建模的方法来研究动作电位（AP）刺激的频率对纹状体内多巴胺浓度（[DA]）变化的影响。结果显示,与实验记录多巴胺信号相比,在生理强度（低频≤20 Hz,或≤12个 APs高频 80 Hz）刺激模式下,基于单一囊泡库的突触模型可以较好地模拟实验结果。此外,作者还分析了大脑神经网络结构等对实验数据的影响。研究说明,Monte Carlo模拟为研究大脑内多巴胺信号的产生机制提供了一种有效的辅助研究方法。     

Aminergic modulation of the myogenic heart in the branchiopod crustacean Triops longicaudatus

Although crustaceans typically have a neurogenic heart, the primitive crustacean Triops longicaudatus has a myogenic heart with the heartbeat arising from the endogenous rhythmic activity of the myocardium. In the present investigation, the effects of six biogenic amines, epinephrine, norepinephrine, dopamine, octopamine, serotonin and histamine, on the myogenic heart of T. longicaudatus were examined. Epinephrine, norepinephrine, dopamine and octopamine accelerated the heartbeat, increasing both the frequency and amplitude of the action potential of the myocardium in a concentration dependent manner. The ability of epinephrine and norepinephrine to produce the acceleratory effects was more potent than that of dopamine and octopamine; the threshold concentrations of epinephrine and norepinephrine were approximately 10(-10) M and those of dopamine and octopamine approximately 10(-7) M. Serotonin weakly inhibited the heartbeat, decreasing both the frequency and amplitude of the myocardial action potential in a concentration dependent manner with a threshold concentration of approximately 10(-6) M. Histamine exhibited no effect on the heartbeat. The results provide the first evidence for direct effects of amines on the crustacean myocardium and suggest neurohormonal regulation of the myogenic heart in T. longicaudatus.     

Kinetic Evaluation of the Commonality Between the Site(s) of Action of Cocaine and Some Other Structurally Similar and Dissimilar Inhibitors of the Striatal Transporter for Dopamine

Abstract: The inhibition by cocaine of the apparent initial rate of the transport of striatal dopamine was compared with inhibitions produced by cocaethylene, benztropine, GBR-12909, mazindol, and nomifensine. Rotating disk electrode voltammetry was used to measure the kinetically resolved, inwardly directed transport of dopamine in striatal suspensions. Evidence is presented that the primary site of action of cocaine may be at the external face of the transporter. Experiments to determine whether or not the other inhibitors bind to the same site as cocaine were conducted by comparing the inhibitions observed for each of the inhibitors alone with that observed when paired with cocaine. The resulting changes in the velocity of the transport of dopamine induced by the inhibitors were then fit to one of the previously developed models of inhibition by pairs of inhibitors affecting the kinetics of actively transporting systems: a single-site model, a two-site model in which the two binding sites for the inhibitors interact, and a two-site model in which the two binding sites for the two inhibitors act independently. Cocaine inhibited the transport of dopamine competitively with its structural analogues, cocaethylene and benztropine. The structurally dissimilar inhibitor, GBR-12909, was found also to be competitive with cocaine. In contrast, mazindol and nomifensine were found to bind to separate interactive sites when individually paired with cocaine. These results suggest that mazindol and nomifensine may interact with the kinetically active transporter for dopamine in a manner different from that of cocaine. Mazindol was tested and found to inhibit competitively the inward transport of dopamine into striatal suspensions. In contrast, our previous published findings show cocaine to be an uncompetitive inhibitor of the transport of striatal dopamine. These results suggest that cocaine inhibits inward transport of dopamine by reducing the intramembrane turnover of the transporter, whereas mazindol alters the kinetics of the recognition of dopamine by the transporter. Finally, the potential effects of these binding modes of inhibitors on synaptic chemical communication in dopaminergic systems were analyzed. The results of these analyses suggest that different effects on the extracellular concentrations of dopamine can result from the different patterns of inhibition, suggesting that different modulatory influences on pre- and postsynaptic receptor occupation can result from inhibition of the transport of dopamine.     

Dopaminergic modulation of axon initial segment calcium channels regulates action potential initiation

Action potentials initiate in the axon initial segment (AIS), a specialized compartment enriched with Na(+) and K(+) channels. Recently, we found that T- and R-type Ca(2+) channels are concentrated in the AIS, where they contribute to local subthreshold membrane depolarization and thereby influence action potential initiation. While periods of high-frequency activity can alter availability of AIS voltage-gated channels, mechanisms for long-term modulation of AIS channel function remain unknown. Here, we examined the regulatory pathways that control AIS Ca(2+) channel activity in brainstem interneurons. T-type Ca(2+) channels were downregulated by dopamine receptor activation acting via protein kinase C, which in turn reduced neuronal output. These effects occurred without altering AIS Na(+) or somatodendritic T-type channel activity and could be mediated by endogenous dopamine sources present in the auditory brainstem. This pathway represents a new mechanism to inhibit neurons by specifically regulating Ca(2+) channels directly involved in action potential initiation.     

Atrial natriuretic factor inhibits the sympathetic nervous activity in one-kidney, one-clip hypertension in the rat

The one-kidney, one-clip model of rat hypertension was found to have an increased natriuresis following chronic infusion of atrial natriuretic factor (ANF). We have now found that this natriuretic effect of ANF is associated with a suppression of the initially elevated urinary excretion of norepinephrine and epinephrine and increase of the excretion of the main dopamine metabolite-dihydroxyphenylacetic acid as well as of the urinary dopamine to norepinephrine ratio. These data are compatible with the hypothesis that ANF suppresses the increased sympathetic activity in this model of hypertension and this action combined with opposite changes of dopamine may contribute to the natriuretic effect of ANF.     

Effect of butaclamol enantiomers on hypothalamic tyrosine hydroxylase in the rat brain

The authors demonstrate stereospecificity of the action of butaclamol enantiomers on substrate inhibition of hypothalamic tyrosine hydroxylase (TH) and regulation of the tyrosine hydroxylase response by the presynaptic membrane (presynaptic receptors) of rat hypothalamus synaptosomes under membrane activation with dopamine. The effect of (+)-butaclamol on the substrate inhibition of TH was noticeable at a concentration of 10(-8)M, reaching a maximum at 10(-5)M. (-)-Butaclamol administered at the same concentrations did not influence the substrate inhibition of the enzyme. (+)-Butaclamol added to the incubation medium containing hypothalamic synaptosomes concurrently with dopamine (10(-5)M) completely blocked the regulatory action of the latter on TH, with this action mediated via presynaptic receptors. (-)-Butaclamol (10(-5)M) antagonized the action of dopamine under the same conditions. The data obtained indicate high stereo-specificity of butaclamol enantiomers as regards their effect on presynaptic regulation of TH, suggesting that elimination of the substrate inhibition of hypothalamic TH is a stereoselective effect of neuroleptics and can be a prognostically important criterion in the appraisal of compounds with potential neuroleptic activity.     

D2 Receptors May Modulate the Function of the Striatal Transporter for Dopamine: Kinetic Evidence from Studies In Vitro and In Vivo

Abstract: Recently it was hypothesized by others that the D₂dopamine receptor can regulate the uptake of dopamine. However, the evidence in support of this hypothesis, although compelling, was not based on observations related to direct measures of the kinetic activity of the transporter itself. Here kinetic evidence in support of this hypothesis is shown. The apparent time-resolved initial velocity of the transport of 1.0 μ M dopamine into striatal suspensions, measured using rotating disk electrode voltammetry, was found to increase in the presence of the D₂ receptor agonist, quinpirole, at 100 μ M . This effect was reversed by sulpiride. In separate studies it was shown that acute and chronic treatments with haloperidol at 0.5 mg/kg, i.p., reduced the reuptake transport of dopamine in vivo following intrastriatal stimulation of its release by K⁺. Thus, it appears that D₂ receptors may influence the functioning of the striatal transporter for dopamine. These results are consistent with a model in which presynaptically released dopamine may feed back onto the function of its transporter to increase the velocity of the clearance of synaptic dopamine following an action potential, suggesting the existence of a mechanism, in addition to release and synthesis modulation, for fine-tuning dopaminergic chemical signaling.     

The role of dopamine and serotonin in modulating the defensive behavior of the edible snail

Dopamine application in concentration of 10(-5)-10(-6) M into saline around the snail CNS leads to decrease of excitability of LPa7 neurone which is presynaptic in relation to defensive behaviour command neurones, and to decrease of amplitude of monosynaptic excitatory postsynaptic potential (EPSP) in the command neurones elicited by intracellular stimulation of LPa7 neurone. Besides, the dopamine causes a decrease of summated EPSP amplitude in the studied neurones in response to intestinal nerve stimulation (70% in average), a change of rest potential towards hyperpolarization for 6-8 mV, a reduction of the command neurones input resistance (20% in average). The described influences can lead to a general increase of the threshold of defensive system reaction to stimulation. Dopamine action on the defensive behaviour command neurones is significantly weakened in serotonine presence. Against the dopamine background, the efficiency of serotonine influence on the value of EPSP in command neurones in response to testing stimulus is reduced. According to the obtained data, a conclusion is made that interrelation of dopamine and serotonine concentrations can be a base for formation of behaviour choice in snail.     

Specificity of the dopamine sensitive adenylate cyclase for antipsychotic antagonists

Chlorpromazine, haloperidol and clozapine are approximately equipotent in antagonizing dopamine sensitive adenylate cyclase activity in homogenates of rat brain striatum, in contrast to the differences in clinical antipsychotic potencies reported by others. The antagonism appeared to occur at a structurally specific dopamine site, as inhibition by a series of chlorpromazine analogues of similar hydrophobicity exhibited a structural specificity similar to that found for their neuroleptic and cataleptic activities. Sulpiride, a dopamine antagonist with antipsychotic activity, and metoclopramide, a structurally related central dopamine antagonist, failed to inhibit the dopamine sensitive adenylate cyclase. Pre-treatment of rats with haloperidol (3 mg/kg per day) for 6 or 28 days did not induce a supersensitive response of the adenylate cyclase to stimulation by dopamine or apomorphine or inhibition by clozapine. It was concluded that the dopamine sensitive adenylate cyclase may not be the site of action of all anti-psychotic agents.     

Developmental changes in dopamine modulation of the heart in the isopod crustacean Ligia exotica: reversal of chronotropic effect

Developmental changes in dopamine modulation of the heart were examined in the isopod crustacean Ligia exotica. The Ligia cardiac pacemaker is transferred from the myocardium to the cardiac ganglion during juvenile development and the heartbeat changes from myogenic to neurogenic. In the myogenic heart of early juveniles, dopamine affected the myocardium and caused a decrease in the frequency and an increase in the duration of the myocardial action potential, resulting in negative chronotropic (decrease in beat frequency) and positive inotropic (increase in contractile force) effects on the heart. Contrastingly, in the heart of immature adults just after juvenile development, dopamine caused effects of adult type, positive chronotropic and positive inotropic effects on the heart affecting the cardiac ganglion and myocardium. During the middle and late juvenile stages, dopamine caused individually a negative or a positive chronotropic effect on the heart. These results suggest that the chronotropic effect of dopamine on the Ligia heart is reversed from negative to positive in association with the cardiac pacemaker transfer from the myocardium to the cardiac ganglion during juvenile development.     

Inhibitory effect of dopamine on the transmission of excitation in isolated rat spinal cord

The effects of dopamine on ventral root potential produced by a single supramaximal dorsal root stimulation of the dorsal root was investigated during experiments on isolated superfused spinal cord segments from 10–16-day old rats. A reciprocal dose-dependent inhibition of the mono- and polysynaptic components of reflex response was also observed. Minimum effective concentration was 1×10^–8 M dopamine. Extent of reflex response increased in step with dopamine concentration, so that the amplitude of the monosynaptic component of ventral root potential was decreased by 20% and 87% of baseline level by the action of 10^–4 and 10^–3 M dopamine respectively on the cord. The amplitude of the polysynaptic component was thereby decreased by an average of 18% and 87%. Findings indicate that dopaminergic brainstem-spinal pathways contribute to the governing of impulse transmission in the segmental reflex arcs. Inhibition of dopaminergic synaptic transmission probably underlies the increase in latency already described in the literature, as well as the increase observed in the threshold of reflex motor response to nociceptive action following either stimulation of the dopaminergic brainstem structures or intravenous administration of dopamine agonists.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 5, pp. 616–621, September–October, 1986.     

Dual effects of dopamine on the adult heart of the isopod crustacean Ligia exotica

In the adult heart of the isopod crustacean Ligia exotica, the cardiac ganglion acts as the primary pacemaker with the myocardium having a latent pacemaker property. We show several lines of evidence that dopamine modulates the heartbeat of adult L. exotica affecting both pacemaker sites in the heart. Dopamine caused positive chronotropic (frequency increase) and inotropic (amplitude increase) effects on the heartbeat in a concentration dependent manner. The time courses of these effects were considerably different and the inotropic effect appeared later and lasted longer than the chronotropic effect. Dopamine rapidly increased the frequency of the bursting activity in the cardiac ganglion neurons and each impulse burst of the cardiac ganglion was always followed by a heartbeat. Moreover, dopamine slowly increased the amplitude and duration of the action potential plateau (plateau potential) of the myocardium. When the myocardial pacemaker activity was induced by application of tetrodotoxin, which suppresses cardiac ganglion activity, dopamine slowly increased the amplitude and duration of the myocardial plateau potential while decreasing its frequency. These results suggest that dopamine modulates the heartbeat in adult L. exotica producing a dual effect on the two pacemaker sites in the heart, the cardiac ganglion and myocardium.     

The Opioid Interactions of the Antipsychotic Medications Risperidone and Amisulpride in Mice and Their Potential Use in the Treatment of Other Non-Psychotic Medical Conditions

Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. The opioid epidemic in the USA has highlighted the need for alternative treatments for pain. Following reports on the opioid interactions of various antipsychotic medications, we speculated that the involvement of the opioid system in some of the antipsychotics’ mechanism of action may suggest their potential use in the treatment of pain. Risperidone is a neuroleptic with a potent dopamine D2 and serotonin 5-HT2 receptor-blocking activity as well as a high affinity for adrenergic and histamine H1 receptors. Amisulpride is a neuroleptic which selectively blocks dopamine D2 and D3 receptors. Both had a potent antinociceptive effect on ICR mice tested with a tail flick assay. That effect on both medications was antagonized by naloxone, indicating that at least some of the antinociceptive effects were mediated by an opioid mechanism of action. Further investigation found that β-Funaltrexamine hydrochloride (β-FNA), naloxonazine, and nor-Binaltorphimine dihydrochloride (nor-BNI) reversed the antinociceptive effect of both risperidone and amisulpride. Naltrindole at a dose that blocked [D-Pen2,D-Pen5]enkephalin (DPDPE, δ analgesia) blocked notably amisplride effect and only partially reversed that of risperidone. Risperidone induced an antinociceptive effect, implying involvement of μ and κ-opioid and δ-opioid mechanisms. Amisulpride-induced antinociception was mediated through selective involvement of all three opioid receptor subtypes. These findings emphasize the need for clinical trials to assess the possibility of extending the spectrum of medications available for the treatment of pain.

     

Research on the mechanism of the motor action of dopamine on in vitro isolated rat duodenum]

The study of the direct action of dopamine on the rat duodenum serotoninergic receptors and the parallelism of the results obtained with the motricity curves of this organ in vitro allows us to conclude that dopamine recognizes serotoninergic receptors : the excito- motor effect observed with certain dopamine concentrations on the isolated rat duodenum may be attributed to this action of dopamine on serotoninergic receptors. These results seem in agreement with the observations of other authors.