In vivo measurements by differential pulse voltammetry of extra-cellular 5-hydroxyindoleacetic acid in the rat brain

The use of differential pulse voltammetry, performed with electrochemically treated carbon fiber electrodes, enables us to detect in vitro or in vivo, in the striatum of anaesthetized rats, an oxidation peak (3) at a potential of + 300 mV. Electrolytic or 5-7-dihydroxytryptamine lesions of the medial forebrain bundle are followed by a decrease of 59 and 62% respectively of this peak. Biochemical measurements are significantly correlated with the measured peak (3) and decreases. Thus, peak (3) increases obtained after injection of L-tryptophan and/or Reserpine, as well as the decreases observed after injection of Clorgyline or 3-hydroxybenzylhydrazine, confirm that peak (3) is dependent upon 5-hydroxyindoleacetic acid concentration. The detection of a peak (3) in the cerebrospinal fluid and its increase after injection of Probenecid reinforce this conclusion.     

Influence of dieldrin on serotonin turnover and 5-hydroxyindole acetic acid efflux in mouse brain

Chronic administration of dieldrin failed to produce any alteration of brain serotonin, norepinephrine or dopamine in mice, but caused an increase in 5-hydroxyindole acetic acid levels. The turnover rate of serotonin was unaffected by dieldrin. The probenecid induced accumulation rate of 5-hydroxyindole acetic acid was considerably lowered in dieldrin-treated mice. The results suggested a possible influence of dieldrin on 5-hydroxyindole acetic acid efflux from mouse brain.     

The maturation of 5-hydroxytryptamine and 5-hydroxyindole acetic acid in the gerbil (Meriones unguiculatus) brain

5-Hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) stores have been estimated in gerbil cerebral hemispheres and brainstem between one day postpartum and adulthood. Although patterns of 5-HT and 5-HIAA maturation were similar in part to those of the rat and mouse, there was significant difference in the pattern of postnatal 5-HIAA.     

Diazepam increases 5-hydroxyindole concentrations in rat brain and spinal cord

Diazepam elevates serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) concentrations in rat brain and spinal cord. The maximal effect occurs 1–2 hrs after drug injection and is dose related between 5–20 mg/kg (intraperitoneal). The action of diazepam on brain 5HT and 5HIAA concentrations is modified by previous food consumption: the ingestion of a diet that raises brain 5HT and 5HIAA one hour before drug injection enhances the diazepam-induced increase in brain indoles; consumption of a diet that lowers brain 5HT and 5HIAA partially blocks the elevation in brain indoles that follows diazepam injection.     

Changes with darkness in regional brain 5-hydroxytryptamine and 5-hydroxyindole acetic acid: Local differences with pinealectomy,sham surgery,and melatonin

Brain regional 5-HT (5-hydroxytryptamine) and 5-HIAA (5-hydroxyindole-3-acetic acid) concentrations in male LE rats at three times were measured by a fluorescence method, to evaluate effects of intracranial surgery and administration of melatonin on the changes in these compounds during the first part of the dark phase of the daily cycle in a fixed 12:12 L:D photoperiod. Early surgical pinealectomy or a similar but sham intracranial surgery, led to delay in darkness-associated fall in frontal cortical and striatal 5-HT. A single melatonin injection two hours before darkness, reversed this effect in frontal cortex but not striatum. Melatonin's specification of action in this experiment is interpreted as residing in specific timing of release and/or administration, rather than in either a fixed or general basis neurochemically.I dedicate with pleasure this work to Professor Paola S. Timiras, outstanding researcher, scholar and teacher, and constant friend.     

Serotonin catabolism and the formation and fate of 5-hydroxyindole thiazolidine carboxylic acid

Serotonin (5-HT) functions as a neurotransmitter and neuromodulator in both the central and enteric nervous systems of mammals. The dynamic degradation of 5-HT metabolites in 5-HT-containing nervous system tissues is monitored by capillary electrophoresis with wavelength-resolved laser-induced native fluorescence detection in an effort to investigate known and novel 5-HT catabolic pathways. Tissue samples from wild type mice, genetically altered mice, Long Evans rats, and cultured differentiated rat pheochromocytoma PC-12 cells, are analyzed before and after incubation with excess 5-HT. From these experiments, several new compounds are detected. One metabolite, identified as 5-hydroxyindole thiazoladine carboxylic acid (5-HITCA), has been selected for further study. In 5-HT-incubated central and enteric nervous system tissue samples and differentiated PC-12 cells, 5-HITCA forms at levels equivalent to 5-hydroxyindole acetic acid, via a condensation reaction between L-cysteine and 5-hydroxyindole acetaldehyde. In the enteric nervous system, 5-HITCA is detected without the addition of 5-HT. The levels of L-cysteine and homocysteine in rat brain mitochondria are measured between 80 and 140 microm and 1.9 and 3.4 microm, respectively, demonstrating that 5-HITCA can be formed using available, free L-cysteine in these tissues. The lack of significant accumulation of 5-HITCA in the central and enteric nervous systems, along with data showing the degradation of 5-HITCA into 5-hydroxyindole acetaldehyde, suggests that an equilibrium coupled to the enzyme, aldehyde dehydrogenase type 2, prevents the accumulation of 5-HITCA. Even so, the formation of 5-HITCA represents a catabolic pathway of 5-HT that can affect the levels of 5-HT-derived compounds in the body.     

The effects of haloperidol and amphetamine on ascorbic acid and uric acid in caudate and nucleus accumbens of rats as measured by voltammetry in vivo

The ability of haloperidol (0.1 mg/kg) to reduce the amphetamine-induced (2 and 5 mg/kg) increase in ascorbic and uric acid in anterior caudate and in nucleus accumbens was tested using voltammetry in vivo. In both areas, haloperidol reduced the amphetamine-induced increase in uric acid. In both areas, haloperidol only marginally affected the amphetamine-induced increase in ascorbic acid. Amphetamine-induced increases in uric acid were more nearly dose-related than changes in ascorbic acid. Of the two compounds, uric acid seems more likely to be associated with dopamine.     

Electrochemical determination of indole butyric acid by differential pulse voltammetry on hanging mercury drops electrode

A voltammetric method for the determination of trace amounts of indole butyric acid was developed. DP voltammetry of indole butyric acid exhibits tensammetric peak at the adsorption and desorption potential of indole butyric acid. In the potential range where adsorption occurs, the base current is depressed. The determination method is based on the adsorption of indole butyric acid on a hanging mercury drop electrode and desorption of indole butyric acid at negative tensammetric peak. The system showed no positive tensammetric peak on hanging mercury drop electrode under the experimental conditions. The tensammetric peak potential of indole butyric acid was between ?500 and ?600 mV (versus Ag/AgCl), depending on pH, accumulation potential, accumulation time, sweep rate, pulse amplitude and so on. Variation of the sweep rate between 40 and 140 mV/s caused a linear increase in the tensammetric peak height. The peak current was proportional to the concentration of IBA over the range 40–320 μg/L under optimum experimental conditions (pH?=?3.5, accumulation potential of ?1.2 V and accumulation time of 120 s).     

Circadian periodicity of urinary volume, creatinine and 5-hydroxyindole acetic acid excretion in healthy Indians

The circadian periodicity of urinary output, creatinine (Cr) and 5-hydroxyindole acetic acid (5-HIAA) excretion was studied under near-tropical conditions in 130 healthy volunteers (65 men and 65 women, 16-75 years of age) with a diurnal activity from about 06:30 to about 22:00 and nocturnal rest. These volunteers were divided into 4 groups, 16-30, 31-45, 46-60 and 61-75 years of age, comprising 20, 20, 15 and 10 participants of each gender, respectively. A marked circadian rhythm was recorded for urine volume, Cr and 5-HIAA excretion in healthy Indians of different ages. The acrophase tended to be delayed in the older age group. The relative amplitude decreased with advancing age, notably in women. Overall, men produced a larger urine volume as compared to women. Excretions of Cr and 5-HIAA in healthy Indian volunteers of different ages may be influenced by diet, societal relations, climate and/or geographic location. The contribution of such factors in metabolism and degradation warrants further study.     

Acetaminophen inhibits liver trytophan-2,3-dioxygenase activity with a concomitant rise in brain serotonin levels and a reduction in urinary 5-hydroxyindole acetic acid

The effect of the analgesic agent, acetaminophen was determined on rat forebrain serotonin levels as well as hepatic tryptophan-2,3-dioxygenase (TDO) activity and urinary 5-hydroxyindole acetic acid (5-HIAA). The results show that acetaminophen administration (100mg/kg) over three hours does not affect the holoenzyme of tryptophan-2,3-dioxygenase but significantly inhibits the apoenzyme. This inhibition is accompanied by a concomitant rise in forebrain serotonin levels. This phenomenon is also accompanied by a reduction in urinary 5-HIAA levels. These results suggest that acetaminophen use is accompanied by changes in brain serotonin levels due to inhibition of hepatic tryptophan-2,3-dioxygenase activity. This in turn could explain the possible abuse potential of acetaminophen and its effects on mood at high doses.     

Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds

Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (K(d)s) for nine new antipsychotic drugs (iloperidone, melperone, olanzapine, ORG 5222, quetiapine, risperidone, sertindole, ziprasidone, and zotepine), one metabolite of a new drug (9-OH-risperidone), and three older antipsychotics (clozapine, haloperidol, and pimozide) at nine different receptors (alpha1-adrenergic, alpha2-adrenergic, dopamine D2, histamine H1, muscarinic, and serotonin 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2C receptors). Iloperidone was the most potent drug at the two adrenergic receptors. ORG 5222 was the most potent drug at dopamine D2 and 5-HT2c receptors, while ziprasidone was the most potent compound at three serotonergic receptors (5-HT1A, 5-HT1D, and 5-HT2A). At the remaining two receptors, olanzapine was the most potent drug at the histamine H1 receptor (Kd=0.087 nM); clozapine at the muscarinic receptor (Kd=9 nM). Certain therapeutic and adverse effects, as well as certain drug interactions can be predicted from a drug's potency for blocking a specific receptor. These data can provide guidelines for the clinician in the choice of antipsychotic drug.