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)

1. Whole-cell recordings were made from striatal neurones obtained from neonatal rats and maintained in primary cultures. The effects of dopamine D1 receptor activation were studied on the voltage-gated sodium current. 2. Bath application of a specific D1 agonist, SKF38393 (1 microM), reduced the neuronal excitability recorded in current-clamp by increasing the threshold for generation of action potentials. 3. In voltage-clamp recordings, SKF38393 (1 microM) reversibly reduced the peak amplitude of the sodium current by 37.8 +/- 4.95%. This effect was reversed by the D1 antagonist SCH23390 and was blocked by the intracellular loading of GDP-beta-S (2 mM) suggesting GTP-binding protein involvement. 4. The D1 agonist reduced the peak amplitude of the sodium current without significantly affecting (i) the voltage dependence of the current-voltage relationship, (ii) the voltage dependence of the steady-state activation and inactivation, (iii) the kinetics of the time-dependent inactivation, and (iv) the kinetics of recovery from inactivation. 5. The peak amplitude of the sodium current was progressively reduced by intracellular loading of cyclic AMP-dependent protein kinase (100 U ml-1). 6. Diffusion of a specific peptide inhibitor of the cyclic AMP-dependent protein kinase (PKI; 10 microM) into the cytosol of neurones blocked the effect of the D1 agonist on the sodium current amplitude. 7. These results demonstrate that dopamine acting at the D1 receptor reduces the amplitude of the sodium current without modifying its voltage- and time-dependent properties. This effect involves activation of the cyclic AMP-dependent protein kinase and results in a depression of the striatal neuronal excitability by increasing the threshold for generation of action potentials.
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PMID:Dopamine D1 receptor modulates the voltage-gated sodium current in rat striatal neurones through a protein kinase A. 777 43

In order to study the possible contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, the effect of the D1 agonist, SKF 38393, was studied in combination with intranigral infusions of glutamate antagonists of the NMDA (MK 801, CPP) or AMPA (NBQX) type of receptor. Local infusion into the SN of the 6-OHDA lesioned side of MK 801, CPP or NBQX at doses inducing no or minimal behavioral effects significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. The same result was obtained after intra-SN infusion of the GABA agonist, muscimol. High doses of MK 801, CPP or muscimol infused into the SN produced intense contralateral turning per se and induced a sparse c-fos expression in the lesioned CPu which was antagonized by parenteral administration of MK 801. The results indicate that a depression of SN pars reticulata efferent neurons potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.
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PMID:Modulation of dopamine D1-mediated turning behavior and striatal c-fos expression by the substantia nigra. 779 18

We compared the effect of two selective dopamine D1 receptor agonists, SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl) and A68930 ((1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman.HCl), and that of imipramine in the behavioural despair model of depression. The dopamine D1 receptor agonists and imipramine showed an anti-immobility effect. Moreover we found that the 'antidepressant' effect of imipramine in the behavioural despair test was antagonized by SCH 23390, a selective dopamine D1 receptor blocker. The results further support the hypothesis that dopamine D1 receptor stimulation plays an important role in the mechanism of action of antidepressants and suggest that dopamine D1 receptor agonists might be considered as potential antidepressant drugs.
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PMID:Antidepressant-like effect of selective dopamine D1 receptor agonists in the behavioural despair animal model of depression. 781 61

The locomotor stimulatory effects of the dopamine D1 receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3-300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100-300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D1 receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D1 receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D1 agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D1 receptor subtype.
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PMID:Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice. 787 Sep 1

The effects of dopamine D1 and dopamine D2 receptor agonists and of subconvulsant doses of N-methyl-D-aspartate (NMDA) and the non-competitive NMDA receptor antagonist, dizocilpine (MK-801), alone and in combination, on the motor activity of short- and long-term reserpinized mice (mice pretreated with 5 mg/kg reserpine 4 h or 20 h before, respectively) were analyzed. With short-term reserpinization, the dopamine D2 receptor agonist, quinpirole (1.5 mg/kg), but not the dopamine D1 receptor agonist, SKF-38393 (15 mg/kg), increased motor activity. The effect of quinpirole in short-term reserpinized mice was potentiated by the simultaneous administration of SKF-38393 (15 mg/kg) and was counteracted by the previous administration of the dopamine D2 receptor antagonist, raclopride (1 mg/kg), or by the simultaneous administration of NMDA (25 mg/kg) or MK-801 (0.5 mg/kg). Neither NMDA (25-100 mg/kg) nor MK-801 (0.5-3 mg/kg) induced motor activation in short-term reserpinized mice. With long-term reserpinization, either quinpirole (1.5 mg/kg) or SKF-38393 (15 mg/kg) increased motor activity. The effect of quinpirole in long-term reserpinized mice was not potentiated by the concurrent administration of SKF-38393 (15 mg/kg), was inhibited by the simultaneous administration of MK-801 (0.5 mg/kg) and was not modified by NMDA (25 mg/kg). The effect of SKF-38393 (15 mg/kg) in long-term reserpinized mice was inhibited by the concomitant administration of MK-801 (0.5 mg/kg) and was slightly antagonized by NMDA (25 mg/kg). NMDA induced motor activation in long-term reserpinized mice at doses which were similar to those causing motor activation in non-reserpinized mice (75 and 100 mg/kg), while MK-801 induced motor activation at a dose which was associated with motor depression in non-reserpinized mice (2 mg/kg). The NMDA-induced motor activation in long-term reserpinized mice was counteracted by the previous administration of a low dose of MK-801 (0.5 mg/kg) and was still present when a stronger dopamine-depleting pretreatment was used. These results are interpreted on the basis of changes in sensitivity of the direct striatal efferent pathway after long-term reserpinization.
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PMID:Motor activation in short- and long-term reserpinized mice: role of N-methyl-D-aspartate, dopamine D1 and dopamine D2 receptors. 791 43

1. Whole-cell patch clamp recordings were made from nucleus accumbens neurones in slices of rat ventral forebrain. In the presence of picrotoxin (50 microM), the amplitude of 6-cyano-7-nitroquinoxaline-2, 3-dione-sensitive glutamate EPSCs, recorded at holding potentials between -80 and -90 mV, was reversibly reduced by 56 +/- 11% (n = 6) by dopamine (30 microM). The selective dopamine D1 receptor agonists SKF 38393 (10 microM) and SKF 81297A (10 microM), but not the selective D2 receptor agonist quinpirole (10 microM), also reversibly depressed the EPSC by 36-48%. The depression of the EPSC by dopamine was completely blocked by the D1 receptor antagonist SCH 23390 (1 microM), whereas the D2 antagonist (-)-sulpiride (1 microM) was without effect. 2. EPSCs were reversibly depressed by the dopamine mimetic psychostimulants cocaine (1-20 microM) and amphetamine (10-30 microM) by 40 +/- 16 and 62 +/- 9%, respectively, but only in about half of the cells tested (11/23 and 6/13, respectively). Their actions were completely reversed by SCH 23390 (1 microM), indicating that endogenous dopamine can also depress the EPSC via D1 receptors. 3. No discernable effects of dopamine, SKF 81297A, SKF 38393, quinpirole, cocaine or amphetamine were observed on membrane conductance or holding current (at holding potentials of -80 to -90 mV), suggesting that the depression of the EPSC was solely due to an action on presynaptic D1 receptors. 4. In contrast, agents that elevate intracellular levels of adenosine-3':5'-cyclic monophosphate (cAMP) (forskolin (1-10 microM), 3-isobutyl-1-methylxanthine (0.1-1 mM), rolipram (10 microM), and dibutyryl cAMP (0.5-1 mM)) caused a reversible increase in the EPSC amplitude (by 21-150%). Furthermore, in the presence of forskolin (10 microM), the ability of dopamine to depress synaptic transmission was unaffected. 5. Together these data suggest that both exogenous dopamine and dopamine released from intrinsic nerve terminals attenuate glutamate receptor-mediated synaptic transmission in the nucleus accumbens by presynaptic D1 receptor activation. The transduction mechanism underlying this effect does not appear to involve the formation of cAMP.
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PMID:Endogenous and exogenous dopamine depress EPSCs in rat nucleus accumbens in vitro via D1 receptors activation. 873 May 90

Flinders Sensitive Line hypercholinergic rats, which exhibit augmented hypothermic responses to the cholinesterase inhibitor physostigmine and to the muscarinic agonist oxotremorine, have been proposed to represent a useful animal model for some aspects of human depression. With disturbance of reward processes considered to be a core feature of depression, the present studies were designed to investigate the neuropharmacology of brain stimulation-reward (BSR) in Flinders Sensitive Line (FSL) rats, Flinders Resistant Line (FRL) rats, and outbred control Sprague-Dawley rats. All animals were tested in a rate-free, current-threshold brain stimulation-reward paradigm, following acute challenges with the monoamine reuptake inhibitor cocaine, the dopamine D1 receptor antagonist SCH-23390, the cholinergic muscarinic antagonist scopolamine, and the serotonin reuptake inhibitor fluoxetine. Baseline BSR thresholds did not differ across the three groups. For all groups, cocaine lowered thresholds, SCH-23390 and scopolamine-elevated thresholds, while fluoxetine had no significant effect. Thresholds for the three groups were not differentially affected by pharmacological locomotor activity relative to outbred Sprague-Dawley controls. These results suggest that both Flinders lines exhibit behavioral differences from outbred control rats, but not with regard to reward processes as assessed by rewarding electrical stimulation of the lateral hypothalamus.
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PMID:Rewarding electrical brain stimulation: similar thresholds for Flinders Sensitive Line Hypercholinergic and Flinders Resistant Line Hypocholinergic rats. 873 6

The contribution of the substantia nigra (SN) in the positive interaction between dopamine D1 receptor agonists and glutamate antagonists was studied in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopaminergic nigro-striatal pathway. Local infusion into the SN of the 6-OHDA lesioned side of NMDA glutamate antagonists MK 801 and CPP or the AMPA antagonist NBQX at doses inducing none or minimal behavioral effects, significantly increased the turning behavior and the expression of c-fos induced, in the lesioned caudate-putamen (CPu), by a parenteral administration of SKF 38393. High doses of MK 801 or CPP infused into the SN produced intense contralateral turning per-se but induced only sparse c-fos expression in the lesioned CPu. The results show that a depression of SN pars reticulata efferent neurons, potentiates D1-mediated responses and suggest that this area may play a role in the positive interaction between glutamate antagonists and D1 receptor agonists.
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PMID:Intranigral injections of glutamate antagonists modulate dopamine D1-mediated turning behavior and striatal c-fos expression. 874 12

Methylenedioxymethamphetamine (MDMA, Ecstasy) is a popular recreationally used drug among young people in Europe and North America. The recent surge in use of MDMA and increasing concerns about possible toxic effects of the drug have inspired a great deal of research into the mechanisms by which the drug may affect the central nervous system. This paper reviews studies on the neurochemical, behavioral and neurophysiological effects of MDMA, with emphasis on MDMA effects in regions of the brain that have been implicated in reward. Experiments in awake, behaving laboratory animals have demonstrated that single injections of MDMA increase extracellular levels of the neurotransmitters dopamine (DA) and serotonin (5HT) in the nucleus accumbens and in several other brain regions that are important for reward. Most of the behavioral and electrophysiological changes that have been reported to date for single doses of MDMA appear to be mediated by this MDMA-induced increase in extracellular DA and 5HT. As an example, MDMA-induced hyperthermia and locomotor hyperactivity in laboratory animals can be blocked by administering drugs that prevent MDMA-induced 5HT release and can be attenuated by administering 5HT receptor antagonists, whereas effects of MDMA on delayed reinforcement tasks appear to be mediated by MDMA-induced increases in extracellular DA. Similarly, the effects of MDMA on neuronal excitability in the nucleus accumbens and in several other brain regions can be prevented by administering drugs that block MDMA-induced 5HT release and can be attenuated by depleting brain DA levels or by administering either DA D1 receptor antagonists or 5HT receptor antagonists. In addition to the acute effects of MDMA, it is now well established that repeated or high-dose administration of MDMA is neurotoxic to a subpopulation of 5HT-containing axons that project to the forebrain in laboratory animals. Recent studies have shown that this neurotoxic effect of MDMA is associated with long-duration changes in both DA and 5HT neurotransmission in the nucleus accumbens. Whether these long-duration changes in neurotransmission might be related to reports of depression and other psychopathologies by some frequent users of MDMA remains to be determined. Methylene-dioxymethamphetamine has been found to increase extracellular levels of norepinephrine and to alter brain levels of several neuropeptides as well as altering levels of DA and 5HT. Much additional research is required to understand the multiple ways in which this complex drug may alter neurotransmission in the brain, both acutely and in the long term.
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PMID:The effects of methylenedioxymethamphetamine (MDMA, "Ecstasy") on monoaminergic neurotransmission in the central nervous system. 889 96

The effect of L-deprenyl (selegiline) on the excitatory synaptic transmission was characterized in the CA1 neurons of rat hippocampal slices by using a intracellular recording technique. Superfusion of L-deprenyl (0.1-10 microM) reversibly decreased the EPSP, which was evoked by orthodromic stimulation of the Schaffer collateral-commissural afferent pathway in a concentration-dependent manner. The sensitivity of postsynaptic neurons to the glutamate receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate, was not affected by L-deprenyl (1 microM) pretreatment. In addition, L-deprenyl (1 microM) clearly increased the magnitude of paired-pulse facilitation regardless of the interstimulus intervals of 20 to 300 msec used. The ability of L-deprenyl to decrease the EPSP amplitude was not observed in the dopamine-depleted rats. Pargyline and 4-phenylpyridine, the monoamine oxidase type B inhibitors, mimicked the depressant effect of L-deprenyl on the EPSP. Moreover, the reduction of L-deprenyl (1 microM) on the EPSP amplitude was specifically antagonized by sulpiride (0.01-0.1 microM), a selective dopamine D2 receptor antagonist. However, the dopamine D1 receptor antagonist, SKF-83566 (1-10 microM), did not significantly affect L-deprenyl's action. These results indicate that the monoamine oxidase type B inhibitory ability leading to an increase of the dopaminergic tonus in the hippocampus is involved in the L-deprenyl-induced depression of excitatory synaptic transmission in the CA1 region of the rat hippocampus. Moreover, application of L-deprenyl (1 and 10 microM) also reversibly suppressed the epileptiform activity evoked by picrotoxin.
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PMID:L-deprenyl (selegiline) decreases excitatory synaptic transmission in the rat hippocampus via a dopaminergic mechanism. 893 Jan 79


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