Dopamine D1/D2 receptor interaction.
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Animals↗
Biomedical subjects
A Akaike
Publications and source records attributed to A Akaike.
Inhibition of hippocampal CA1 neurons by 5-hydroxytryptamine, derived from the dorsal raphe nucleus and the 5-hydroxytryptamine1A agonist SM-3997.
Electrophysiological studies, using chloral hydrate-anesthetized rats, were undertaken to determine whether hippocampal pyramidal neurons, receiving input from the medial septal nucleus, were affected by 5-hydroxytryptamine (5-HT) derived from the dorsal raphe nucleus. The pyramidal neurons in the CA1 region of the hippocampus were classified into short- and long-latency neurons, based on their response to stimulation of the medial septal nucleus. Microiontophoretically applied atropine inhibited the generation of spikes upon stimulation of the medial septal nucleus in short-latency neurons, but had no effect on long-latency neurons. In the short-latency neurons, the stimulation-induced spikes of the medial septal nucleus were inhibited by conditioning stimuli applied to the dorsal raphe nucleus and iontophoretic application of 5-HT and the 5-HT1A agonists, SM-3997 (3 a alpha,4 beta,7 beta,7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate) and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin). The conditioning effect of the dorsal raphe nucleus was antagonized by methysergide. However, in the long-latency neurons, the spikes elicited by stimulation of the medial septal nucleus were not affected by the conditioning stimulation of the dorsal raphe nucleus, or iontophoretically applied 5-HT. These results indicate that 5-HT, originating in the dorsal raphe nucleus inhibited hippocampal pyramidal neurons receiving cholinergic input from the medial septal nucleus, but not those receiving non-cholinergic input from the medial septal nucleus. The drug SM-3997 inhibited the activity of hippocampal pyramidal neurons, that receive excitatory cholinergic input from the medial septal nucleus by acting on 5-HT1A receptors.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Voltage and current clamp studies of muscarinic and nicotinic excitation of the rat adrenal chromaffin cells.
Characteristics of the muscarinic and nicotinic excitation of chromaffin cells that had been freshly isolated from the rat adrenal medullae were analyzed using voltage and current clamp techniques. A dose-dependent increase in the extracellularly recorded firing of cells was observed when 10(-6) to 10(-4) M acetylcholine (ACh) were locally applied to the cells in the vicinity of the target cell being recorded using a microinflow method. During voltage clamp recording at the resting membrane potential, ACh induced two different sequential inward currents: a transient current with a rapid rising phase (fast response) and an apparent inward current with a slow rising phase (slow response). The membrane conductance increased during the ACh-induced fast response, and it subsequently decreased during the slow response. The amplitude of the fast response decreased when the holding potential was shifted to depolarized levels, whereas the amplitude of the slow response increased with depolarization. Nicotine produced fast depolarization and a transient inward current that was reduced by the membrane depolarization. In contrast, muscarine induced a slow depolarization and an apparent inward current that increased with depolarization. Muscarine also reduced the inward K+ current that had been induced by the application of a high K+ medium to the outside of the cell at the resting membrane potential. It is suggested that muscarinic excitation is triggered by the suppression of K+ channels that are open at potentials near the resting membrane potential. The present results indicate that ACh-induced excitation of adrenal chromaffin cells involves two separate mechanisms mediated by nicotinic and muscarinic receptors.
Acetylcholine↗
A patch clamp study of muscarinic excitation of the rat adrenal chromaffin cells.
A patch clamp study was performed to determine the ionic mechanisms underlying the muscarinic excitation of rat adrenal chromaffin cells. Burst-like, single-channel currents with brief openings were recorded during cell-attached or cell-free patch recording when the pipette solution contained high K+ media (70-140 mM), and the currents were recorded at potentials near the resting membrane potential. The amplitude and frequency of channel openings were dependent on the membrane potential and the K+ concentration of the external medium. Moreover, the single-channel currents observed with high K+ outside the membrane during inside-out recording were suppressed by the addition of a K+ channel blocker, tetraethylammonium, inside the membrane. These results suggest that the single K+ currents recorded in the present study had properties similar to those of the resting or muscarine-activated K+ currents in atrioventricular cells of the rabbit heart. During cell-attached patch recording with the high K+ medium in the recording pipette, muscarine at concentrations of 10(-5) to 10(-4) M dose dependently decreased the frequency of the channel openings but did not affect the current-voltage relationship or the time constants of open and close time histograms. These results indicate that muscarinic-induced suppression of K+ currents is caused by a decrease in the number of active K+ channels at the resting membrane potential.
Animals↗
Muscarinic regulation of spontaneously active medial vestibular neurons in vitro.
We examined the effects of cholinergic agonists and antagonists on spontaneously occurring action potentials extracellularly recorded from medial vestibular nucleus (MVN) neurons in rat brainstem slice preparation to elucidate the cholinergic mechanism involved in excitation. Addition of carbachol (10(-6)-10(-5) M) and muscarine (10(-6)-10(-5) M) into the bath dose-dependently increased the spontaneous firing rate, while nicotine (10(-5)-10(-4) M) had no effects. Acetylcholine (10(-6)-10(-5) M) in the presence of physostigmine (10(-7) M) also increased the firing rate in a dose-dependent manner. Conversely, atropine (10(-8)-3 x 10(-7) M) slightly decreased the firing and dose-dependently inhibited the carbachol-induced increase in the firing rate. These results suggest that the firing rate of spontaneously active MVN neurons are regulated by acetylcholine via muscarinic receptors.
Acetylcholine↗
[Electroencephalographic study on the central action of a new anxiolytic: 3a alpha, 4 beta, 7 beta, 7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4, 7-methano-1H-isoindole-1, 3(2H)-dione dihydrogen citrate (SM-3997)].
Electroencephalographic (EEG) studies were performed to examine the effects of SM-3997 on the spontaneous EEG, EEG arousal responses, recruiting responses and hippocampal afterdischarges in rabbits and the spontaneous EEG in chronically electrode-implanted rats. In acute experiments using rabbits, SM-3997 at doses of 1-3 mg/kg, i.v., produced low-voltage fast waves in cortical EEG and slow waves with reduction of the amplitude in hippocampal EEG. The drug at doses of 1-3 mg/kg, i.v., dose-dependently inhibited the threshold stimulus voltages in EEG arousal responses induced by stimulation of the midbrain reticular formation and slightly inhibited the threshold in recruiting responses by stimulation of the centromedian nucleus of the thalamus. However, the cortical and hippocampal afterdischarges induced by hippocampal stimulation remained unaffected by SM-3997 at doses up to 3 mg/kg, i.v., while they were inhibited by diazepam of 1 mg/kg, i.v. In the study using rats in which electrodes were chronically implanted, SM-3997 at doses of 10-30 mg/kg, i.p., also produced low voltage fast waves in cortical EEG and slow waves of reduced amplitude in hippocampal EEG; and it simultaneously caused flat body posture. These results suggest that SM-3997 acts on both the cerebral cortex and hippocampus, inducing much more pronounced inhibition on the midbrain reticular formation-hippocampal system
Animals↗
Electrophysiological evidence for cholinoceptive neurons in the medial vestibular nucleus: studies on rat brain stem in vitro.
Electrophysiological studies were performed to determine whether or not cholinoceptive neurons are present in the rat medial vestibular nucleus (MVN) using brainstem slice preparations. Fifty-three MVN neurons, whose activities were extracellularly recorded, fired spikes spontaneously and regularly with an interspike interval of 180 +/- 27 ms (mean +/- S.E.M.) and a coefficient of variation of 0.11 +/- 0.02. Intracellularly recorded neurons also exhibited similar spontaneous and regular generation of action potentials. Carbachol dose-dependently increased the spontaneous firing, although the firing rate was decreased in a few neurons. The addition of atropine reduced the firing rate, and dose-dependently attenuated the carbachol-induced excitation of the neurons. In a low Ca2+ and high Mg2+ medium, carbachol also increased the firing rate. These results indicate that the MVN contains neurons with spontaneous and regular firing, and that the excitability of these neurons is regulated by a cholinergic muscarinic mechanism.
Animals↗
Muscarinic inhibition as a dominant role in cholinergic regulation of transmission in the caudate nucleus.
The effects of cholinergic agonists and antagonists were investigated using slice preparations of the rat caudate nucleus (CN) to elucidate the role of the cholinergic system in the CN. Either carbachol (10(-7) to 10(-5) M) or muscarine (10(-7) to 10(-5) M) dose-dependently inhibited extracellular action potentials orthodromically elicited by local stimulation in the CN. A combination of acetylcholine (10(-6) to 10(-4) M) with physostigmine (10(-6) M) also inhibited the orthodromic response of CN neuron, but nicotine (10(-6) to 10(-3) M) had no effects on the neuronal activity. Atropine (10(-8) to 10(-6) M) antagonized the carbachol-induced inhibition of CN neuron with pA2 of 7.58. Carbachol (10(-5) M) or muscarine (10(-5) M) decreased the amplitude of excitatory postsynaptic potential (EPSP) without altering the resting membrane potential or input impedance of the CN neuron, whereas nicotine (10(-5) M) did not affect either the resting membrane potential or amplitude of EPSP. When carbachol (10(-5) M) was added to the bath, the number of action potentials elicited by applying a depolarizing current into the cell was increased, whereas action potentials transsynaptically elicited by local stimulation were inhibited conversely. The excitatory effects of carbachol on the postsynaptic site of the neuron were also blocked by atropine (3 x 10(-7) M). Carbachol (10(-5) M) did not affect the time courses of the rise and decay phases of EPSP induced by the local stimulation, but did reduce the amplitude of the EPSP.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Excitatory and inhibitory effects of dopamine on neuronal activity of the caudate nucleus neurons in vitro.
Effects of dopamine on the rat caudate nucleus neurons were examined in a slice preparation using an intracellular recording technique. Perfusion of the bath with a low concentration (1 microM) of dopamine produced a depolarization concomitant with an increase in the spontaneous firing and the number of action potentials evoked by a depolarizing pulse applied into the cells. In contrast, higher concentrations (100-500 microM) of dopamine inhibited the spontaneous and current-induced firings without apparent effects on the resting membrane potential. In addition, during application of a high concentration (100 microM) of dopamine there was a marked elevation of the threshold potential of the action potential elicited by a higher depolarizing current. Simultaneous application of haloperidol (0.5-5 microM) antagonized both excitatory and inhibitory effects induced by the low and high concentrations of dopamine, respectively. In addition, the excitatory effect induced by a low concentration (1 microM) of dopamine was antagonized by domperidone (0.5 microM), a selective D2 receptor antagonist, while the inhibitory effect by a high concentration (100 microM) was blocked by SCH 23390, a selective D1 receptor antagonist. These results strongly suggest that the postsynaptic sites of caudate nucleus neurons have at least two subtypes of dopamine receptors (D1 and D2 receptors) that mediate inhibitory and excitatory responses of the neuron to dopamine, respectively.
Action Potentials↗
Inhibitory effects of thyrotropin-releasing hormone on neuronal activity in the nucleus accumbens.
The effects of thyrotropin-releasing hormone (TRH) were examined on neuronal activity in the nucleus accumbens, receiving an input from the parafascicular nucleus of the thalamus or the hippocampus, in chloral hydrate-anesthetized rats, using a microiontophoretic technique. The spikes produced by stimulation of the parafascicular nucleus were predominantly and dose-dependently inhibited during iontophoretic application of TRH. When the effects of TRH and dopamine were tested on the same neurons of the nucleus accumbens, inhibition of the generation of spikes by both drugs was observed in most neurons. In contrast, spikes elicited by stimulation of the hippocampus in most neurons of the nucleus accumbens were not affected by TRH or dopamine. Both TRH- and dopamine-induced inhibition of the spikes induced by stimulation of the parafascicular nucleus was antagonized by simultaneous application of haloperidol. In animals treated with reserpine, inhibition of the generation of spikes upon stimulation of the parafascicular nucleus did not occur in any neurons in the nucleus accumbens during application of TRH, whereas the dopamine-induced inhibition was still observed. These results suggest that inhibitory effects of TRH on the neurons of the nucleus accumbens receiving an input from the parafascicular nucleus are mediated by dopamine released from the dopaminergic nerve terminals located in the nucleus accumbens.
Action Potentials↗
Acute effects of methamphetamine applied microiontophoretically to nucleus accumbens neurons in rats.
Microiontophoretic studies were performed to elucidate the acute effects of methamphetamine on the nucleus accumbens (Acc) neurons receiving input from the parafascicular nucleus (Pf) of the thalamus using rats anesthetized with chloral hydrate. Spike generation upon Pf stimulation was inhibited by conditioning stimuli applied to the ventral tegmental area (VTA), which is rich in dopamine-containing neurons, and by iontophoretic application of methamphetamine as well as dopamine. The VTA-, methamphetamine- and dopamine-induced inhibition of the spikes elicited by Pf stimulation was antagonized during simultaneous application of haloperidol. Glutamate-induced firing was also inhibited during iontophoretic application of methamphetamine and dopamine in neurons receiving input from the Pf, and the inhibition was blocked by simultaneously applied haloperidol. In the reserpine-treated animals, however, the Pf-induced spikes were not affected by methamphetamine, but inhibited by dopamine. These results indicate that methamphetamine inhibits the Acc neurons receiving input from the Pf, probably by releasing dopamine from dopaminergic nerve terminals from the VTA.
Action Potentials↗
[Central depressant effect of l-tetrahydroberberine-d-camphor sulfonate (THB-CS). Electroencephalographic study].
Effects of l-tetrahydroberberine-d-camphor sulfonate (THB-CS) on spontaneous EEG, arousal response and recruiting response were investigated in rabbits and rats in comparison with those of chlorpromazine. The spontaneous EEG recorded from the motor cortex and hippocampus showed a prominent resting pattern 3-5 min after intravenous administration of THB-CS in doses more than 0.01 mg/kg in rabbits and 30 min after oral administration of the drug in doses more than 1 mg/kg in rats. These effects lasted for 30-60 min after i.v. administration and 60-90 min after oral administration; however, the effects were not proportional to the doses up to 8 mg/kg (i.v.) and 12.5 mg/kg (p.o.). The abnormal characteristics of the EEG pattern such as seizure pattern and flattening were not observed. Chlorpromazine also produced the resting pattern in doses of 2 mg/kg (i.v.) in rabbits and 1 mg/kg (p.o.) in rats. THB-CS and chlorpromazine produced a slight elevation of threshold for the EEG arousal response elicited by high frequency stimulation of the midbrain reticular formation, but did not alter the recruiting response elicited by low frequency stimulation of the centromedian nucleus of the thalamus. These results suggest that the effects of THB-CS resemble those of chlorpromazine, but are different from those of barbiturates.
Administration, Oral↗
The reversible cholinesterase inhibitor physostigmine has channel-blocking and agonist effects on the acetylcholine receptor-ion channel complex.
The actions of the carbamate cholinesterase inhibitors, physostigmine (Phy) and physostigmine methiodide (MetPhy), were studied on the acetylcholine receptor-ion channel complex (AChR) of skeletal muscles. Low concentrations of these agents produced cholinesterase inhibition which resulted in potentiation of nerve-elicited muscle twitches and an increased peak amplitude and prolongation of the decay time constant (tau EPC) of endplate currents (EPCs) elicited in frog (Rana pipiens) sartorius muscles. However, increasing concentrations of Phy depressed the peak amplitude and shortened the decay phase of the EPC with an apparent loss in the voltage dependence of tau EPC. At higher concentrations and depolarized potentials, EPC decays were double exponential. The effects of both Phy and MetPhy on the postsynaptic AChR complex were also evident in preparations pretreated with diisopropylfluorophosphate. Under these conditions, a linear relationship between the reciprocal of tau EPC and the concentration of these agents was observed. Single channel studies revealed that Phy (20-600 microM) shortened channel lifetime and decreased channel conductance at very high concentrations. In addition, Phy (0.5 microM) induced the appearance of channel openings with conductance similar to that of acetylcholine. High concentrations (greater than 50 microM) of this agent activated channel openings with decreased conductance. Similar results were obtained with MetPhy. Thus, the reversible cholinesterase inhibitors Phy and MetPhy altered the properties of the AChR by interacting as agonists capable of inducing desensitization and blockade.
Acetylcholine↗
[Damage to the heart from tumor irradiation in the thorax--an echocardiographic study].
The authors give a review of 74 patients with radiation-induced heart disease which could be easily detected by echocardiography. In almost all of the patients a pericardial effusion (P.E.), with relative sinus tachycardia was found 3 to 4 weeks after onset of radiation and this was transient in some cases. This phenomenon was interpreted as an early radiation-induced reaction of the heart. 6 to 12 months after radiation, late damage of the heart occurred depending on field and total radiation dose. This manifested as massive P.E. with changes in ECG. Later there was damage to the myocardium caused by coronary sclerosis. The tendency to constrictive pericarditis was manifested not earlier than 3 years or later after radiation. The authors advise follow up of the irradiated patients case by case, checked by echocardiography, especially those who received more than 5000 rad to the heart area and therefore have high risk of late heart damage.
Aged↗
The interaction of anticholinesterase agents with the acetylcholine receptor-ionic channel complex.
The actions of pyridostigmine (Pyr), a quaternary carbamate compound, and physostigmine ( Phy ), a tertiary carbamate, both known for their reversible inhibition of acetylcholinesterase (AChE), were studied on the electrically excitable membrane and acetylcholine (ACh) receptor of the frog cutaneous pectoris, sartorius, and interosseal muscles, as well as the chronically denervated soleus muscle of the rat and myoballs from neonatal rats. Both Pyr and Phy first potentiated, then depressed and finally blocked the indirectly evoked muscle twitch. Pyr and Phy had negligible effects upon either membrane potential or muscle action potential. But at the synaptic junction, they decreased the peak amplitude of the endplate current (EPC) in a voltage- and concentration-dependent manner. Pyridostigmine produced a marked prolongation of the decay time constants of both the EPC and the miniature endplate current ( MEPC ), while maintaining a single exponential decay, and Phy decreased peak amplitude, while having little effect on its voltage dependence. Physostigmine also decreased the decay time constant, suggesting a channel block, presumably in open state. Single channel recordings using patch clamp techniques disclosed that Pyr interacts with the ACh receptor as a weak agonist capable of inducing desensitization, alone, and when combined with ACh. Physostigmine interacts directly with the ACh-ionic channel complex, blocking it in open conformation.
Action Potentials↗
The frog interosseal muscle fiber as a new model for patch clamp studies of chemosensitive- and voltage-sensitive ion channels: actions of acetylcholine and batrachotoxin.
The patch clamp technique was used to record the currents flowing through single ion channels in isolated frog muscle fibers. The majority of the acetylcholine (ACh)-activated channels had a conductance of 32 pS, although 20 pS channels were also occasionally observed. Lifetimes of ACh-activated channels increased with the transmembrane potential in the range from - 30 mV to - 105 mV. In these same fibers we also observed channels which were activated by low concentrations of batrachotoxin (BTX; 10 nM). These channels, presumed to be Na channels, had a conductance of 19 pS and opened at potentials at which Na channels would not normally open. A notable feature of these BTX-activated channels was that they opened and closed repeatedly. Therefore, it appears that the toxin, in addition to activating Na channels, also blocks the inactivation process. The physiological properties of these channels reveal significant differences between the ion channels of tissue-cultured and mature tissues.
Acetylcholine↗
The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex. II. Patch clamp studies.
Patch clamping of myoballs to record single channels was performed to examine the interaction of the anticholinesterase agent pyridostigmine (Pyr) with the acetylcholine (ACh) receptor-ion channel complex. Single ACh channel currents were recorded from tissue-cultured muscle cells of neonatal rats (myoballs). Pyr (50-100 microM) decreased the frequency of channel-opening events activated by ACh, and induced a modified form of the ACh channel currents. Channel conductance was lower in the presence of Pyr, and channel lifetime remained unaltered or only slightly prolonged. In addition, channel openings were frequently interrupted by fast flickers in the presence of Pyr. Higher concentrations (200 microM-1 mM) of the drug induced irregular waves of bursting activity during the initial phase of the application, and, subsequently, significantly reduced the frequency of channel openings. Infrequent channel openings with low conductance were observed in the patch when the micropipette was filled with Pyr alone. These results suggest that, in addition to its anticholinesterase activity, Pyr reacts with the ACh receptor, and both alone or in combination with ACh induces an altered, desensitized species of the nicotinic receptor-ion channel complex.
Animals↗
The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex. I. Agonist, desensitizing, and binding properties.
The actions of pyridostigmine (Pyr), an anticholinesterase agent, were studied on the acetylcholine (ACh) receptor-ion channel complex and on the electrically excitable membrane of the frog cutaneous pectoris and sartorius muscles and the chronically denervated soleus muscle of the rat. Pyr at concentrations of 0.2-0.4 mM potentiated the indirect evoked muscle twitch and at concentrations greater than or equal to 0.8 mM depressed the indirect twitch with an IC50 of about 2 mM. Twitch depression produced by Pyr was reversed slowly, and after a 60-min wash only 59% of the control muscle twitch had returned. Pyr did not affect either the membrane potential or the muscle action potential. Pyr had several effects at the neuromuscular junction of the frog and rat. It decreased the peak amplitude of the end-plate current (EPC) in a voltage- and concentration-dependent manner. In contrast to diisopropylfluorophosphate, which depresses the EPC amplitude and induces a double exponential decay of the EPC and miniature end-plate current (MEPC), Pyr produced a marked prolongation of the time constants of EPC and MEPC decay while maintaining a single exponential decay. The decrease caused by Pyr of indirect twitch tension, EPC amplitude, and ACh sensitivity indicates mechanisms which limit the number and/or properties of conducting channels. The drug decreased channel conductance and prolonged channel lifetime as revealed by Fourier analysis of ACh-induced end-plate current fluctuations. An altered form of the conducting species induced by Pyr appears to be responsible for either the apparent agonist-induced depolarization or its ability to increase the affinity of ACh for its recognition site. Pyr was also found to inhibit the binding of ACh and alpha-bungarotoxin to receptor-rich membrane from the electric organ of Torpedo nobiliana, and to have a higher affinity for the receptor than for the ion channel binding sites. These actions are distinct from acetylcholinesterase inhibition caused by the agent. Strong evidence suggests that the direct influences of the agent on neuromuscular transmission involve at least three distinct, although possibly interacting, mechanisms: (a) a weak agonist action, (b) the formation of desensitized receptor-complex intermediates, and (c) the alteration of the conductance properties of active channels.
Animals↗