Differences in pharmacological properties of dopamine release between the substantia nigra and striatum: an in vivo electrochemical study.
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The properties of dopamine (DA) release in the rat substantia nigra (SN) and striatum were investigated using high-speed chronoamperometric recordings in brain slices. In both brain regions, a 2-min bath superfusion with 30 mM KCl produced robust DA-like electrochemical signals, with the mean amplitude of the signal being >10-fold greater in the striatum than the SN. The reproducibility of the response was confirmed by a second stimulus (S2)/first-stimulus (S1) ratio of >0.8 in both regions. The bath application of tetrodotoxin significantly reduced the S2/S1 ratio in both the striatum and SN, implicating the requirement for voltage-sensitive sodium channels in the DA-release process. However, the application of cadmium chloride, a nonselective blocker of voltage-sensitive calcium channels, reduced the S2/S1 ratio only in the striatum and not within the SN. Moreover, removal of Ca2+ from the buffer did not significantly affect release within the SN, despite a >85% reduction in release within the striatum. In addition, although the D2 receptor antagonist sulpiride enhanced the S2/S1 ratio in the striatum, no effect of this agent was seen in the SN. Finally, the application of d-amphetamine produced DA-like electrochemical signals in both the striatum and SN. However, the amplitude of the d-amphetamine-evoked response, relative to the KCl-evoked release, was much smaller in the striatum than in the SN. Taken together, these data support the hypothesis that differences in the mechanism or mechanisms of release exist between somatodendritic and axonal elements within the nigrostriatal pathway. (+info)
Sequestration of dopamine D2 receptors depends on coexpression of G-protein-coupled receptor kinases 2 or 5.
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We examined the agonist-dependent sequestration/internalization of dopamine D2 receptor (the long form D2L and short form D2S), which were transiently expressed in COS-7 and HEK 293 cells with or without G-protein-coupled receptor kinases (GRK2 or GRK5). Sequestration was assessed quantitatively by loss of [3H] sulpiride-binding activity from the cell surface and by transfer of [3H] spiperone-binding activity from the membrane fraction to the light vesicle fraction in sucrose-density gradients. In COS-7 cells expressing D2 receptors alone, virtually no sequestration was observed with or without dopamine (< 4%). When GRK2 was coexpressed, 50% of D2S receptors and 36% of D2L receptors were sequestered by treatment with 10(-4) M dopamine for 2 h, whereas no sequestration was observed in cells expressing the dominant negative form of GRK2 (DN-GRK2). When GRK5 was coexpressed, 36% of D2S receptors were sequestered following the same treatment. The agonist-dependent and GRK2-dependent sequestration of D2S receptors was reduced markedly in the presence of hypertonic medium containing 0.45 M sucrose, suggesting that the sequestration follows the clathrin pathway. Internalization of D2S receptors was also assessed by immunofluorescence confocal microscopy. Translocation of D2 receptors from the cell membrane to intracellular vesicles was observed following the treatment with dopamine from HEK 293 cells only when GRK2 was coexpressed. D2S receptors expressed in HEK 293 cells were shown to be phosphorylated by GRK2 in an agonist-dependent manner. These results indicate that the sequestration of D2 receptors occurs only through a GRK-mediated pathway. (+info)
Glutamatergic and dopaminergic contributions to rat bladder hyperactivity after cerebral artery occlusion.
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The contribution of glutamatergic and dopaminergic mechanisms to bladder hyperactivity after left middle cerebral artery occlusion was evaluated by determining the effects of intravenous cumulative doses of an N-methyl-D-aspartate (NMDA) glutamatergic antagonist (MK-801) and D1-selective (Sch-23390), D2-selective (sulpiride), or nonselective (haloperidol) dopaminergic antagonists on bladder activity in sham-operated (SO) and cerebral-infarcted (CI) rats. MK-801 (1 and 10 mg/kg) or sulpiride (3-30 mg/kg) significantly increased bladder capacity (BC) in CI but decreased or had no effect, respectively, on BC in SO. Sch-23390 (0.1-3 mg/kg) decreased BC in both SO and CI. In both CI and SO, low doses of haloperidol (0.1-1 mg/kg) increased BC, but a higher dose (3 mg/kg) reversed this effect. Administration of haloperidol (0.3 mg/kg) or sulpiride (10 mg/kg) in combination with MK-801 (0.01-10 mg/kg) markedly increased BC in CI but produced small decreases or increases in BC depending on the dose of MK-801 in SO. These results indicate that the bladder hyperactivity induced by cerebral infarction is mediated in part by NMDA glutamatergic and D2 dopaminergic excitatory mechanisms. (+info)
Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord.
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The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.), in RCS-loaded mice, and it was eliminated by both an electric lesion of the hypothalamic arcuate nucleus (HARN) and a highly selective dopamine D2 antagonist, eticlopride (0.05 microg), administered into the HARN in RCS-loaded rats. These results suggest that the analgesic effect of processed Aconiti tuber was produced via the stimulation of kappa-opioid receptors by dynorphin released in the spinal cord. It was also shown that dopamine D2 receptors in the HARN were involved in the expression of the analgesic activity of processed Aconiti tuber. (+info)
Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons. (+info)
Toxicological analysis of sulpiride in a lethal poisoning case.
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A fatality following ingestion of sulpiride is presented. The drug was identified and quantitated in postmortem blood by gas chromatography-mass spectrometry and high-performance liquid chromatography with diode-array detection. The concentration was 38 microg/mL, which was in excess of 34 times the therapeutic concentration of sulpiride. For other associated drugs, their concentrations were in their therapeutic ranges. (+info)
Dihydroetorphine-induced place preference was mediated by dopamine D1 receptors in rats.
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AIM: To study the influence of dopamine (DA) receptor antagonists upon the rewarding property of dihydroetorphine (DHE). METHODS: Conditioned place preference (CPP) paradigm was used to characterize the rewarding effect of DHE. DA receptor antagonists were injected administered subcutaneously or peritoneally and microinjected into nucleus accumbens (NAcc). RESULTS: DHE (0.05, 0.5, and 5.0 micrograms.kg-1, s.c.) produced place preference (P < 0.01). Both the DA receptor antagonist haloperidol and the selective D1 receptor antagonist Sch-23390 attenuated the place preference produced by DHE (0.5 microgram.kg-1, s.c.). l-Sulpiride and spiperone, selective D2 receptor antagonists, had no such effects. CONCLUSION: The D1 (but not D2) receptors in NAcc are crucial in the mediation of the rewarding effect of DHE. (+info)
Amphetamine depresses excitatory synaptic transmission via serotonin receptors in the ventral tegmental area.
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The ventral tegmental area (VTA) is the origination zone for dopaminergic neurons involved in reward and addictive properties of a variety of abused substances. A major excitatory projection to VTA neurons originates in the medial prefrontal cortex, and several lines of evidence suggest that glutamatergic synapses on VTA neurons are activated and modified during exposure to psychostimulant drugs. Here, we report for the first time that amphetamine depresses excitatory glutamatergic synaptic transmission onto VTA neurons in the midbrain slice preparation. Unexpectedly, this depression is mediated not by activation of dopamine receptors, but instead by activation of serotonin receptors. Our findings suggest that an acute effect of amphetamine exposure is the release of serotonin in the VTA, which in turn modulates excitation of VTA neurons. This process may be an important early component of permanent changes occurring in the reward pathway that contribute to drug addiction. (+info)