5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride.
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The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states. (+info)
Studies on the role of dopamine in the degeneration of 5-HT nerve endings in the brain of Dark Agouti rats following 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration.
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1. We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') administration. 2. Haloperidol (2 mg kg(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA + haloperidol treated rats was kept elevated, this protective effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) failed to induce neurodegeneration. 4. The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3- and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5. The neuroprotective drug clomethiazole (50 mg kg(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings. (+info)
Effect of low-dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine-induced dopamine release in vivo.
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1. Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. 2. Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg(-1), i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [3H]-dopamine was determined in synaptosomes from selegiline-treated animals. 3. Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg(-1), s.c.). 4. Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. 5. The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [3H]-dopamine uptake in synaptosomes of selegiline-treated animals. 6. The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active. (+info)
Dopamine depolarizes podocytes via a D1-like receptor.
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BACKGROUND: Dopamine influences glomerular haemodynamics and dopamine receptors have been demonstrated in the glomerulus, but little is known about the cellular effects of dopamine in glomerular cells. The aim of this study was to investigate the influence of dopamine on the cellular functions of podocytes. METHODS: The effect of dopamine on membrane voltage was investigated in differentiated mouse podocytes. The membrane voltage was measured using the patch clamp technique. Reverse transcribed-polymerase chain reaction (RT-PCR) studies were performed to investigate the expression of dopamine receptor mRNA in mouse glomeruli and podocytes. RESULTS: The addition of dopamine (100 nM-1000 microM) caused a concentration-dependent depolarization of podocytes (EC50 is approximate to 10 microM). Like dopamine, the selective agonist of the D1-like receptor, SKF 82958, depolarized podocytes in a concentration-dependent manner. (EC50 is approximate to 50 microM). SKF 82958 stimulated a time-and concentration-dependent accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in podocytes (EC50 is approximate to microM). RT-PCR studies with primers derived from mouse sequences amplified mouse mRNA for the D1-like and the D2-like receptor in glomeruli, which were obtained by the sieve technique, whereas only mRNA for the D1-like receptor was detected in cultured mouse podocytes. CONCLUSION: The data indicate that dopamine induces a cAMP-dependent depolarization via a D1-like receptor in podocytes. (+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)
Oxygen-wasting effect of inotropy in the "virtual work model".
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In the "virtual work model," left ventricular total mechanical energy (TME) is linearly related to myocardial oxygen consumption (MVO2). This relationship (MVO2-TME) is supposedly independent of inotropic stimulation, vascular loading, and heart rate variations. We reexamined the effect of inotropic stimulation (dopamine) on the metabolic to mechanical energy transfer in nine open-chest anesthetized pigs. Left ventricular mechanical energy was calculated using TME (mean ejection pressure x end-diastolic volume + stroke work), TMEW (end-diastolic volume reduced by unstressed ventricular volume), and the pressure-volume area (PVA). A highly linear relationship between MVO2 and mechanical energy was found for all three indexes during control and dopamine runs (r = 0.87-0.99). The slopes were unaltered by dopamine. y-Axis intercepts were (control vs. dopamine) as follows (in J. beat-1. 100 mg-1; means +/- SD): TME, 0.36 +/- 0.12 vs. 0.61 +/- 0.30 (P < 0.02); TMEW, 0.43 +/- 0.16 vs. 0.72 +/- 0.32 (P < 0.02); and PVA, 0.34 +/- 0.13 vs. 0.60 +/- 0.30 (P < 0.02). We conclude that the virtual work model is dependent on inotropic stimulation and that new insight into myocardial chemomechanical coupling is not added by this concept. (+info)
Dopaminergic synapses mediate neuronal changes in an analogue of operant conditioning.
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Feeding behavior in Aplysia can be modified by operant conditioning in which contingent reinforcement is conveyed by the esophageal nerve (E n.). A neuronal analogue of this conditioning in the isolated buccal ganglia was developed by using stimulation of E n. as an analogue of contingent reinforcement. Previous studies indicated that E n. may release dopamine. We used a dopamine antagonist (methylergonovine) to investigate whether dopamine mediated the enhancement of motor patterns in the analogue of operant conditioning. Methylergonovine blocked synaptic connections from the reinforcement pathway and the contingent-dependent enhancement of the reinforced pattern. These results suggest that dopamine mediates at least part of the neuronal modifications induced by contingent reinforcement. (+info)
Incremental conductance levels of GABAA receptors in dopaminergic neurones of the rat substantia nigra pars compacta.
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1. Molecular and biophysical properties of GABAA receptors of dopaminergic (DA) neurones of the pars compacta of the rat substantia nigra were studied in slices and after acute dissociation. 2. Single-cell reverse transcriptase-multiplex polymerase chain reaction confirmed that DA neurones contained mRNAs encoding for the alpha3 subunit of the GABAA receptor, but further showed the presence of alpha4 subunit mRNAs. alpha2, beta1 and gamma1 subunit mRNAs were never detected. Overall, DA neurones present a pattern of expression of GABAA receptor subunit mRNAs containing mainly alpha3/4beta2/3gamma3. 3. Outside-out patches were excised from DA neurones and GABAA single-channel patch-clamp currents were recorded under low doses (1-5 microM) of GABA or isoguvacine, a selective GABAA agonist. Recordings presented several conductance levels which appeared to be integer multiples of an elementary conductance of 4-5 pS. This property was shared by GABAA receptors of cerebellar Purkinje neurones recorded in slices (however, with an elementary conductance of 3 pS). Only the 5-6 lowest levels were analysed. 4. A progressive change in the distribution of occupancy of these levels was observed when increasing the isoguvacine concentration (up to 10 microM) as well as when adding zolpidem (20-200 nM), a drug acting at the benzodiazepine binding site: both treatments enlarged the occupancy of the highest conductance levels, while decreasing that of the smallest ones. Conversely, Zn2+ (10 microM), a negative allosteric modulator of GABAA receptor channels, decreased the occupancy of the highest levels in favour of the lowest ones. 5. These properties of alpha3/4beta2/3gamma3-containing GABAA receptors would support the hypothesis of either single GABAA receptor channels with multiple open states or that of a synchronous recruitment of GABAA receptor channels that could involve their clustering in the membranes of DA neurones. (+info)