Concentrations of 5-hydroxyindolylacetic acid and homovanillic acid in the cerebrospinal fluid of the dog before and during treatment with probenecid

Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of transient receptor potential vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2^−/− mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca^2 + handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca^2 +.

Although the cardinal manifestations of Parkinson's disease (PD) are attributed to a decline in dopamine levels in the striatum, a breadth of non-motor features and treatment-related complications in which the serotonergic system plays a pivotal role are increasingly recognised. Serotonin (5-HT)-mediated neurotransmission is altered in PD and the roles of the different 5-HT receptor subtypes in disease manifestations have been investigated. The aims of this article are to summarise and discuss all published preclinical and clinical studies that have investigated the serotonergic system in PD and related animal models, in order to recapitulate the state of the current knowledge and to identify areas that need further research and understanding.

Lumbar puncture at the L4–5 level was performed on 12 healthy male and 12 healthy female volunteers. Confirming previous results, we found pronounced gradients in cerebrospinal fluid (CSF) 5-HIAA and HVA (5-hydroxyindoleacetic acid and homovanillic acid). We also found a gradient in 4-hydroxy-3-methoxyphenylglycol (HMPG), but only in the male volunteers. We also found that tapping-time was significantly longer in females than in males. One reason for this discrepancy may be that an estimate of the spinal distance was greater in males, which might indicate that a hydrodynamic factor plays a role. On taking tapping-time into consideration, the 5-HIAA and HMPG concentrations were significantly higher in males than in females.

After application of [³H]benzylpenicillin ([³H]BP) in lateral brain ventricle in dogs, the distribution of [³H]BP to contralateral ventricle and cisterna magna was much higher when its active transport from cerebrospinal fluid (CSF) was blocked by probenecid than under control conditions. Analysis of [³H]BP concentrations in both lateral ventricles and cisterna magna over time indicates that active transport restricts distribution of substances along CSF spaces and contributes to the maintenance of their concentration gradients between CSF compartments. This suggests that biochemical changes in a part of the brain and the adjacent CSF compartment may not be reflected into remote compartments of CSF such as lumbar CSF if substances in question are removed from CSF by active transport.

The present study examined immunoreactive prolactin (ir-PRL) access into the cerebrospinal fluid (CSF) by monitoring ir-PRL levels in the blood and cerebroventricular perfusates of ovariectomized (ovx) rats treated with the dopamine antagonist, domperidone (DOMP). In Expt. 1 PRL plasma levels were measured in rats treated with DOMP i.p. (2.5, 5.0 and 10.0 mg/kg). All doses of DOMP significantly increased PRL plasma levels. In Expt. 2 animals were treated i.p. with DOMP (10 mg/kg) or DOMP plus the active transport blocking agent, probenecid (PROB; 250 mg/kg). Plasma PRL and ir-PRL in cerebroventricular perfusates were measured in separate sets of animals using catheters and a push-pull perfusion system, respectively. DOMP induced an increase in plasma PRL that was followed 30–40 min later by a rise in ventricular perfusates ir-PRL levels. PROB treatment induced a greater increase in plasma PRL levels in DOMP-treated animals, but delayed the DOMP-induced increase in ir-PRL ventricular perfusate ir-PRL levels. The delay in the rise of ir-PRL in ventricular perfusates observed in rats treated with DOMP plus PROB may be due to a PROB's interference with the transport of PRL from the blood into CSF. These results suggest that under some conditions ir-PRL in CSF originates from the pituitary.

The effect of the membrane potential on the efflux of 5-HIAA from 5-HT neurons was studied in anesthetized (halothane: 1% in gas mixture of N₂O: 70% and O₂: 30%) cats. The endogenous 5-HT and its metabolite 5-HIAA were measured continuously from the cortex, the thalamus, the hypothalamus and the raphe nuclei using brain microdialysis technique combined with HPLC-ED monoamine measurements. Membrane potential variations were induced by changing the extracellular concentration of potassium through the microdialysis membrane. The levels of the extracellular 5-HIAA varied according to the different regions of the brain, being highest in the hypothalamus and lowest in the cerebral cortex. Increases in the extracellular potassium from 4 to 120 mM invariably produced a decrease of the extracellular 5-HIAA in all the tested brain regions. This decrease was inversely proportional to the logarithm of extracellular potassium concentration. Thus, it is postulated that the 5-HIAA is moved from inside the cell to extracellular space by an active mechanism of transport electrically coupled to the membrane potential.