Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term changes of synaptic transmission following brief trains of high-frequency stimulation of excitatory pathways in the brain have attracted attention as a possible correlate of memory. In the cerebellum, concurrent activation of parallel fibers and climbing fibers leads to a long-term depression (LTD) of synaptic transmission, which may be the cellular substrate of motor learning in this structure. We report here for the first time that high-frequency stimulation of corticostriatal glutamatergic fibers in the striatum, another brain structure strongly involved in motor control, also induces LTD of synaptic transmission. Induction of striatal LTD is blocked either by SCH 23390, a D1 dopamine (DA) receptor antagonist or by L-sulpiride, a D2 DA receptor antagonist. The lesion of the nigrostriatal DAergic pathway abolishes LTD. After DA depletion, LTD can be restored by the application of exogenous DA. LTD can also be restored by coadministration of D1 and D2 DA receptor agonists, but not by the application of a single class of DA agonists alone. Our data show that coactivation of D1 and D2 DA receptors is required for LTD in the striatum. D1/D2 receptor cooperation in the induction of LTD may play a crucial role in the behavioural function of DA and in the therapeutic effects of DA agonists in Parkinson's disease.
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PMID:Coactivation of D1 and D2 dopamine receptors is required for long-term synaptic depression in the striatum. 135 11

The effect of tetanic activation of corticostriatal glutamatergic fibers was studied in striatal slices by utilizing extracellular and intracellular recording techniques. Tetanic stimulation produced a long-term synaptic depression (LTD) (> 2 h) of both extracellularly recorded field potentials and intracellularly recorded EPSPs. LTD was not coupled with changes of intrinsic membrane properties of the recorded neurons. In some neurons, repetitive cortical activation produced a short-term posttetanic potentiation (1-3 min). Subthreshold tetanic stimulation, which under control condition did not cause LTD, induced LTD when associated with membrane depolarization. Moreover, LTD was not expressed in cells in which the conditioning tetanus was coupled with hyperpolarization of the membrane. Bath application of aminophosphonovalerate (30-50 microM), an antagonist of NMDA receptors, did not affect the amplitude of the synaptic potentials and the expression of LTD. Striatal LTD was significantly reduced by the pretreatment of the slices with 30 microM 2-amino-3-phosphonopropionic acid, an antagonist of glutamate metabotropic receptors. LTD was not blocked by bicuculline (30 microM), a GABA(A) receptor antagonist. Scopolamine (3 microM), an antagonist of muscarinic receptors, induced a slight, but significant, increase of the amplitude of LTD. Both SCH 23390 (3 microM), an antagonist of D1 dopamine (DA) receptors, and I-sulpiride (1 microM), an antagonist of D2 DA receptors, blocked LTD. LTD was also absent in slices obtained from rats in which the nigrostriatal DA system was lesioned by unilateral nigral injection of 6-hydroxydopamine. In DA-depleted slices, LTD could be restored by applying exogenous DA (30 microM) before the conditioning tetanus. In DA-depleted slices, LTD could also be restored by coadministration of SKF 38393 (3-10 microM), a D1 receptor agonist, and of LY 171555 (1-3 microM), a D2 receptor agonist. Application of a single class of DA receptor agonists failed to restore LTD. These data show that striatal LTD requires three main physiological and pharmacological conditions: (1) membrane depolarization and action potential discharge of the postsynaptic cell during the conditioning tetanus, (2) activation of glutamate metabotropic receptors, and (3) coactivation of D1 and D2 DA receptors. Striatal LTD may alter the output signals from the striatum to the other structures of the basal ganglia. This form of synaptic plasticity can influence the striatal control of motor activity.
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PMID:Long-term synaptic depression in the striatum: physiological and pharmacological characterization. 135 31

Effects of the dopamine (DA) D1 antagonist SCH 23390 and the DA D2 antagonist (-)-sulpiride on apomorphine-induced characteristic changes in spontaneous motor activity were investigated in mice using the system we have devised for automatically analyzing animal behaviors in mice. Apomorphine (3 mg/kg, SC) markedly increased parameters of spontaneous motor activity such as locomotor activity and rearing time. Apomorphine-induced increase in locomotor activity had peaks at 5-20 and 30-50 min after administration, and its trough was closely related to the marked increase in rearing time induced by this agonist. Apomorphine-induced locomotor activity accumulated over a 40-min period from 5 to 45 min after apomorphine injection, during which apomorphine-induced increase in rearing time peaked, was significantly increased by intraperitoneal administration of 0.03 and 0.1 but not 0.01 mg/kg SCH 23390. Apomorphine-induced increase in rearing time was dose-dependently depressed by this antagonist. In contrast, (-)-sulpiride (10-40 mg/kg, IP) decreased apomorphine-induced increases in rearing time and locomotor activity rather than enhancing the latter parameter. These data suggest that the apparent enhancement by SCH 23390 of apomorphine-induced locomotor activity is mediated through DA D1 receptors and does not always correlate with depression of apomorphine-induced rearing behavior in mice.
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PMID:Apparent enhancement by SCH 23390 of apomorphine-induced locomotor activity in mice. 178 98

In hippocampal pyramidal cells (HPCs), Dopamine (DA) application (1 microM) produced, in 50% of recorded cells, an hyperpolarization of the resting membrane potential (r.m.p.) and an increase of the afterhyperpolarization (AHP) amplitude and duration in 79% of recorded cells. DA-induced effects on both the r.m.p. and AHP were mimicked by bath application of a D-1 selective agonist, SKF 38393 (20 microM). In addition, we have observed that a D-1 selective antagonist such as SCH 23390 (1 microM) abolished the action of both DA and SKF 38393. In contrast, the activation of D-2 receptors through LY 171555 (10 microns) produced, in 50% of cells, a depolarization of the r.m.p. and a depression of the AHP in 67% of recorded cells. These results suggest that the effects observed in hippocampal pyramidal neurons after DA application of micromolar concentration are mediated by D-1 subtype of receptors.
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PMID:Effects of dopamine, D-1 and D-2 dopaminergic agonists on the excitability of hippocampal CA1 pyramidal cells in guinea pig. 198 61

The analgesic and acute central nervous system (CNS) side effect potential of the enkephalinase inhibitor SCH 32615 (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenyl-alanine-beta-alanine) were evaluated after IV administration to mice, rats and squirrel monkeys. In mice, SCH 32615 caused dose-related suppression of acetic acid-induced writhing (minimal effective dose, MED = 3 mg/kg IV). In rats, SCH 32615 produced dose-related increases in the response latencies in the yeast inflamed-paw test (MED = 10 mg/kg IV). In squirrel monkeys, using a new hot-water bath tail-flick test, SCH 32615 significantly prolonged the escape latencies (MED = 100 mg/kg IV). These results in primates are the first data showing an analgesic action of an enkephalinase inhibitor in a reflex model of pain. When measured for its CNS side effect potential, SCH 32615 had no significant effects in rats (up to 100 times its analgesically active doses) or in monkeys (up to three times). In the mouse, at doses 100 times its minimal effective dose, SCH 32615 produced brief convulsions; these lasted only a minute, resolved quickly, and did not cause lethality. In contrast, in rats and squirrel monkeys, the standard opioid analgesic morphine produced profound CNS side effects; this was particularly notable in monkeys, in which morphine's maximal analgesic effects were associated with near lethal respiratory depression. These data demonstrate that SCH 32615 produces selective analgesic actions and that its acute side effect liability is less than that seen with a clinically used standard.
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PMID:Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615. 201 47

The effect of the D1 dopamine (DA) receptor agonist SKF 38393 was compared with that produced by the D1-receptor antagonist, SCH 23390, in rats implanted with electrodes for chronic sleep recordings. SKF 38393 (0.1 to 4.0 mg/kg) significantly suppressed rapid-eye-movement sleep (REMS) after the highest dose. SCH 23390 (0.1 to 2.0 mg/kg) increased slow-wave sleep (SWS), whereas wakefulness (W) and REMS were decreased. Pretreatment with SKF 38393 (0.5 mg/kg) prevented the effects of SCH 23390 (0.25 mg/kg) on W and SWS. However, REM sleep showed a further depression. Pretreatment with SKF 38393 (2.0 mg/kg) or SCH 23390 (0.25 mg/kg) failed to modify the increase of SWS and decrease of W induced by D2 receptor agonist bromocriptine (0.5 mg/kg) in a dose that selectively stimulates DA autoreceptors. On the other hand, SCH 23390 (0.25 mg/kg) failed to prevent REMS depression induced by bromocriptine (6.0 mg/kg) in a dose that preferentially acts at postsynaptic sites. Pretreatment with SCH 23390 (0.25 mg/kg) prevented the increase of W and decrease of SWS induced by the 5-HT2 receptor agonist DOI (0.25 mg/kg). Given the "fragility" of REMS in the rat, nonspecific factors could be contributing to its depression after SKF 38389 or SCH 23390 administration. Inhibition of D1 receptors could be responsible for SCH 23390-induced increase of SWS and decrease of W. However, a blockade of 5-HT2 receptors could be partly involved in these effects. Neither SKF 38393 nor SCH 23390 exerted activity on the sleep-wake cycle, which could be considered to reflect effects at DA autoreceptors.
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PMID:Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats. 214 85

The effects of dopamine (DA) on voltage-dependent Ca2+ currents were investigated in cultured rat lactotroph cells using the patch clamp recording technique. Each recorded cell was identified by the reverse hemolytic plaque assay. In the whole-cell configuration, two types of Ca2+ currents, L and T, were characterized on the basis of their kinetics, voltage sensitivity, and pharmacology. The L component had a threshold of -25 mV, showed little inactivation during a 150-msec voltage step, and was maximal at +10 mV. Cadmium ions (100 microM) significantly reduced its amplitude (75%). The T component was activated at a membrane potential close to -50 mV, was maximal at -10 mV, and showed a voltage-dependent inactivation between -90 and -30 mV. It was quickly inactivated during a maintained depolarization (time constant, 27 ms at -30 mV) and was strongly reduced (80%) by nickel ions (100 microM). Bath application of DA (10 nM) caused a markedly general depression of inward Ca2+ currents, acting differently on the T- and L-type currents. DA application shifted the voltage-dependence of the L-type current activation toward depolarization values (8 mV) without modifying its time- and voltage-dependent inactivation. In contrast, DA enhanced the inactivation of the T-type current by accelerating its time-dependent inactivation (25% decrease in the time constant of inactivation) and by shifting the voltage-dependence of the T-type current inactivation toward hyperpolarizing values (-63 mV in control vs. -77 mV in the presence of DA). These effects of DA were dose-dependent and involved the activation of a D2 receptor type. They were mimicked by bromocriptine application (10 nM), whereas sulpiride (100 nM) blocked the DA-evoked response. The D1 antagonist SCH 23390 was ineffective up to 100 microM. All of these DA-induced modifications in Ca2+ currents were abolished using a GTP-free pipette solution or after pretreatment of cells with pertussis toxin, suggesting that DA can regulate the function of Ca2+ channels through GTP-binding proteins (G-proteins). Our results show that DA acts simultaneously by reducing both voltage-dependent Ca2+ currents on lactotroph cells. Thus, DA reduces the entry of Ca2+ ions across the surface membrane and thereby influences electrical activity and the cytosolic free Ca2+ concentration involved in both basal and evoked PRL release.
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PMID:Dopamine inhibits two characterized voltage-dependent calcium currents in identified rat lactotroph cells. 216 20

Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mumol/l, SKF 38393 10 mumol/l, dopamine 10 mumol/l and clonidine 0.1 mumol/l depressed all e.j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mumol/l, domperidone 1 mumol/l, SCH 23390 1 mumol/l and rauwolscine 1 mumol/l did not change, or even depressed the first e.j.ps. Of these compounds only S- and R-sulpiride, 10 mumol/l and rauwolscine 1 mumol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 mumol/l had the largest effect. S- and R-sulpiride, 10 mumol/l, as well as domperidone 1 mumol/l antagonized the action of LY 171555 1 mumol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mumol/l and rauwolscine 1 mumol/l blunted the effect of SKF 38393 10 mumol/l. Rauwolscine 1 mumol/l slightly reduced the inhibition by dopamine 10 mumol/l; S-sulpiride 10 mumol/l was antagonistic only in the presence of rauwolscine 1 mumol/l. When rauwolscine 1 mumol/l, prazosin 0.1 mumol/l, propranolol 1 mumol/l and cocaine 10 mumol/l was added to the medium, dopamine 10 mumol/l continued to produce the same depression of e.j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mumol/l also counteracted dopamine 10 mumol/l. Rauwolscine 1 mumol/l prevented the effect of clonidine 0.1 mumol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA2- and postsynaptic DA1-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e.j.ps. Dopamine interferes with neuroeffector transmission due to alpha 2-adrenoceptor agonist properties; its DA2-effect is unmasked only after alpha 2-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine.
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PMID:Presynaptic dopamine DA2-receptors in rabbit jejunal arteries. An electrophysiological study. 257 71

SCH 23390, a D-1 dopaminergic antagonist, was examined for its effects on the cholinergic system in rat brain. The compound raised the content of acetylcholine selectively in striatum and not in other brain areas including the hippocampus, nucleus accumbens, hemispheric residuum and midbrain-hindbrain, mirroring the action of dopaminomimetic drugs. That the increase in acetylcholine content reflected a depression of striatal cholinergic neuronal activity was substantiated by the drug's ability to inhibit sodium-dependent high affinity choline uptake, to reduce the electrically evoked release of [3H]acetylcholine from striatal slices in vitro and to reduce acetylcholine release from striatum in freely moving rats in vivo. The increase in striatal acetylcholine was prevented by the D-1 dopaminergic agonist, SK 38393-A, but not by the D-2 agonist, LY 171555. Inhibition of dopamine synthesis by DL alpha-methyltyrosine methyl ester HCI or the selective degeneration of nigrostriatal dopaminergic terminals by the neurotoxin 6-hydroxydopamine HBr prevented the acetylcholine increasing effect of SCH 23390 completely, suggesting that presynaptic dopamine is important in the action of the dopaminergic antagonist. In agreement with these findings, SCH 23390 amplified the action of amphetamine, a dopamine releaser, on striatal cholinergic neurons. Furthermore, blockade of D-2 receptors by pimozide or sulpiride did not suppress the cholinergic effect of SCH 23390. When combined with a subthreshold dose of LY 171555, SCH 23390 did not potentiate the action of the D-2 dopaminergic agonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:D-1 receptor-linked mechanism modulates cholinergic neurotransmission in rat striatum. 288 38

As determined by autoradiographic techniques, multiple high doses of methamphetamine elicited a reduction in dopamine receptor population (both D1 and D2) in several areas of the rat central nervous system. D1 receptors were labeled with the D1-selective antagonist, [3H]SCH 23390, and D2 receptors were labeled with the D2-selective neuroleptic, [3H]sulpiride. Scatchard analysis, obtained from saturation data in caudate-putamen, indicated that the receptor alterations were due to a decrease in the number of receptors (Bmax) without an apparent change in affinity (Kd). A time course demonstrated that five doses of methamphetamine were required to elicit significant changes in receptors in most brain areas examined. The onset of the receptor alterations in various brain regions correlated with the development of methamphetamine-induced depression of striatal tyrosine hydroxylase activity. In most brain areas, the dopamine receptors returned to normal within 7 days following methamphetamine.
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PMID:Methamphetamine-induced reduction in D1 and D2 dopamine receptors as evidenced by autoradiography: comparison with tyrosine hydroxylase activity. 289 Oct 82


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