Simultaneous Determination of 5-Hydroxytryptophan and 3,4-Dihydroxyphenylalanine in Rat Brain by HPLC with Electrochemical Detection Following Electrical Stimulation of the Dorsal Raphe Nucleus

HPLC coupled with electrochemical detection was used to make concurrent measurements of the rate of accumulation of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine in selected brain regions (striatum, nucleus accumbens, septum, medial periventricular hypothalamus) and thoracic spinal cords of rats treated with NSD 1015, an inhibitor of aromatic-L-amino-acid decarboxylase. 5-Hydroxytryptophan and 3,4-dihydroxyphenylalanine accumulated in all brain regions 30 min after the intravenous infusion of various doses of NSD 1015; there were no significant differences in the responses to 12.5, 25, 50, and 100 mg/kg. After the intravenous administration of 25 mg/kg NSD 1015 the concentrations of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine increased linearly with time in all brain regions for at least 30 min. Electrical stimulation of 5-hydroxytryptamine neurons in the dorsal raphe nucleus for 30 min at 5 or 10 Hz increased 5-hydroxytryptophan accumulation in all brain regions but not in the spinal cord. Unexpectedly, this stimulation also increased the accumulation of 3,4-dihydroxyphenylalanine in the hypothalamus and spinal cord. These results suggest that 5-hydroxytryptophan accumulation following the administration of NSD 1015 is a valid index of 5-hydroxytryptamine neuronal activity in the brain.     

Monoamine Synthesis and Concentration in Neonatal Rat Brain During Hypercapnia and Recovery

One-day-old rats were exposed to a gas mixture of 15% CO2-21% O2-64% N2 for a 30-min period. Monoamine synthesis in whole brain was measured during, and at various intervals after, hypercapnia by estimating the accumulation of dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic L-amino-acid decarboxylase with NSD 1015. Endogenous concentrations of tyrosine, dopamine (DA), noradrenaline (NA), tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured at the same intervals. Exposure to CO2 induced an increased synthesis of catecholamines and 5-HT. Further, an increase in DA concentration was seen during hypercapnia, while NA and 5-HT were unchanged. After the CO2 exposure the increased in vivo synthesis rates of catecholamines and 5-HT were rapidly normalized, as was the endogenous DA concentration. A slight increase in 5-HT and 5-HIAA concentrations was seen immediately after CO2 exposure. These results indicate that in neonatal animals, hypercapnia induces changes in central monoamine neurons, primarily an increased synthesis. These alterations may be relevant to some physiological changes seen during CO2 exposure, such as the alteration in central respiratory performance.     

Metergoline,pirenperone and pizotifen alter dopamine and 5-hydroxytryptamine synthesis in discrete rat brain nuclei

The effects of the 5-hydroxytryptamine receptor antagonists metergoline, pirenperone and pizotifen on 5-hydroxytryptamine and dopamine synthesis were determined by measuring the rate of accumulation of 5-hydroxytryptamine and 3,4-dihydroxyphenylalanine, respectively, after administering l-tryptophan and m-hydroxybenzylhydrazine, an inhibitor of aromatic-l-amino acid decarboxylase. 5-Hydroxytryptophan, 3,4-dihydroxyphenylalanine and l-tryptophan were measured in four forebrain regions, the caudate putamen, nucleus accumbens, nucleus septi lateralis, and nucleus amygdaloideus centralis, which contain terminals of 5-hydroxytryptamine and dopamine neurons. Metergoline increased 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine accumulation, and decreased l-tryptophan concentration in a dose- and time-dependent manner. Pirenperone increased 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine accumulation, but had no effect on l-tryptophan levels. These effects of pirenperone were time- and dose-related. Finally, pizotifen increased 5-hydroxytryptophan accumulation in a dose-related and time-dependent manner, but did not alter 3,4-dihydroxyphenylalanine or l-tryptophan concentrations. All the drug effects generally occurred in all four nuclei. These results suggest that 5-hydroxytryptamine receptor antagonists may affect synthesis in 5-hydroxytryptamine and/or dopamine neurons after l-tryptophan treatment and aromatic-l-amino acid decarboxylase inhibition.     

Evidence for involvement of 5-hydroxytryptamine(1B) autoreceptors in the enhancement of serotonin turnover in the mouse brain following repeated treatment with fluoxetine

The effect of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine on synthesis and turnover of 5-hydroxytryptamine (5-HT) was studied in the mouse brain in vivo. The concentration of 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA) and 5-HT was measured in hypothalamus, hippocampus and frontal cortex after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Fluoxetine 6.9 mg/kg s.c. was injected once daily for three weeks. Three days after the final daily injection of fluoxetine 5-HT synthesis (5-HTP accumulation) and turnover (5-HIAA/5-HT ratio) were significantly enhanced compared with saline-treated mice. The 5-HIAA/5-HT ratio was already significantly elevated after 3 days of fluoxetine treatment and continued to increase during treatment for 2-3 weeks. The increase in 5-HIAA/5-HT ratio was considerably larger (150-200% of controls) than the increase in 5-HTP accumulation (110-120%), which reached significance only after 3 weeks of treatment. The increase in 5-HT synthesis may be secondary to that of the turnover. The 5-HIAA/5-HT ratio returned to control values after a 14 days washout period. Simultaneous treatment with the long-acting 5-HT(1B)-receptor antagonist, SB 224289 for 14 days counteracted the fluoxetine-induced increase in 5-HIAA/5-HT ratio that indicates involvement of 5-HT(1B) autoreceptors in the development of this increase. It is proposed that the fluoxetine-induced enhancement of 5-HT turnover was evoked by the long-lasting stimulation of 5-HT(1B) autoreceptors that resulted in an intraneuronal compensatory adaptation of the basal 5-HT release.     

Streptozotocin-Induced Diabetes Reduces Brain Serotonin Synthesis in Rats

The rate of brain 5-hydroxytryptamine (serotonin) synthesis and turnover in streptozotocin-diabetic rats was assessed using three separate methods: the rate of 5-hydroxytryptophan accumulation following decarboxylase inhibition with Ro 4-4602; the decline in 5-hydroxyindoleacetic acid levels following monoamine oxidase inhibition with pargyline; and the rate of 5-hydroxyindoleacetic acid accumulation following blockade of acid transport with probenecid. Each of the three methods revealed that 5-hydroxytryptamine synthesis and turnover is decreased by 44-71% in diabetic rats with plasma glucose levels of between 500 and 600 mg%. In addition, the levels of free and bound plasma tryptophan were measured and the levels of the free amino acid were found to be the same in control and diabetic rats. Since diabetic rats exhibit a 40% decrease in brain tryptophan, the free tryptophan level in plasma does not predict brain tryptophan levels in diabetic rats. These data are discussed within the context of psychiatric disturbances experienced by diabetic patients.     

Exogenous Tryptophan Increases Synthesis, Storage, and Intraneuronal Metabolism of 5-Hydroxytryptamine in the Rat Hypothalamus

The effects of tryptophan administration on neurochemical estimates of synthesis [5-hydroxytryptophan (5-HTP) accumulation following administration of a decarboxylase inhibitor], storage [5-hydroxytryptamine (5-HT) concentrations], and metabolism [5-hydroxyindoleacetic acid (5-HIAA) concentrations] of 5-HT in selected regions of the hypothalamus were determined using HPLC coupled to an electrochemical detector. Tryptophan methyl ester HCl (30-300 mg/kg i.p.) produced a dose-dependent increase in the rate of 5-HTP accumulation throughout the hypothalamus but had no effect on the rate of accumulation of 3,4-dihydroxyphenylalanine. Peak 5-HTP levels were attained by 30 min following administration of tryptophan (100 mg/kg i.p.) and were maintained for an additional 60 min. Tryptophan also produced concomitant dose-dependent increases in 5-HT and 5-HIAA concentrations in these same regions without changes in the 5-HIAA/5-HT ratio. These results indicate that exogenous tryptophan administration selectively increases the synthesis, storage, and metabolism of 5-HT in the hypothalamus without altering the synthesis of catecholamines. Inhibition of 5-HT uptake with chlorimipramine or fluoxetine produced modest (10-40%) reductions in 5-HIAA concentrations throughout the hypothalamus, revealing that only a minor portion of 5-HIAA is derived from released and recaptured 5-HT, whereas the major portion of this metabolite reflects intraneuronal metabolism of unreleased 5-HT. In both chlorimipramine- and fluoxetine-treated rats, 5-HIAA concentrations were significantly increased by tryptophan administration, indicating that the increase in synthesis of 5-HT following precursor loading is accompanied by an increase in the intraneuronal metabolism of 5-HT.     

Chlorimipramine,fenfluramine and quipazine decrease 5-hydroxytryptamine synthesis in discrete rat brain nuclei

A procedure for studying 5-hydroxytryptamine synthesis by determining the rate of accumulation of 5-hydroxytryptophan after administering m-hydroxybenzylhydrazine, an inhibitor of aromatic-l-amino acid decarboxylase, and large doses of l-tryptophan was characterized. The utility of this method as an index of 5-hydroxytryptamine neuronal activity was studied by determining the effects on 5-hydroxytryptophan accumulation of direct and indirect 5-hydroxytryptamine agonists; viz, chlorimipramine-a 5-hydroxytryptamine uptake inhibitor, fenfluramine-a 5-hydroxytryptamine releaser, and quipazine-a 5-hydroxytryptamine receptor agonist. In the absence of m-hydroxybenzylhydrazine pretreatment 5-hydroxytryptophan and the dopamine precursor 3,4-dihydroxyphenylalanine were not readily detectable in any brain region studied. They both accumulated after m-hydroxybenzylhydrazine treatment in a time-dependent manner with the 30 min time point being on the linear portion of the curve. Administration of l-tryptophan 60 min before sacrifice increased 5-hydroxytryptophan, but not 3,4-dihydroxyphenylalanine, in a dose-related manner with the peak effect occurring after 100–300 mg/kg. Chlorimipramine, fenfluramine and quipazine all decreased 5-hydroxytryptophan, but not 3,4-dihydroxyphenylalanine, in m-hydroxybenzylhydrazine and l-tryptophan-treated animals. Chlorimipramine produced these effects in a dose-related manner only after l-tryptophan loading and without affecting brain concentrations of l-tryptophan. These results suggest that the measurement of 5-hydroxytryptophan after l-tryptophan administration and aromatic-l-amino acid decarboxylase inhibition might serve as a useful index of 5-hydroxytryptamine synthesis.     

Tryptamine Concentrations in Areas of 5-Hydroxytryptamine Terminal Innervation After Electrolytic Lesions of Midbrain Raphe Nuclei

The possible existence of tryptamine-containing neurons originating in the midbrain raphe is suggested by several reports of tryptamine-mediated responses to electrical stimulation of the raphe nuclei. To assess this hypothesis, we have investigated the effects of electrolytic lesions of the median and dorsal raphe nuclei on striatal, hypothalamic, and hippocampal concentrations of tryptamine, 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid. In addition, the rat striatal tryptophan concentrations were also determined. No changes in the concentrations of tryptamine were observed at 1 or 2 weeks after lesioning the dorsal and median raphe nuclei, at which time the other 5-hydroxyindoles were markedly reduced; furthermore, no reductions were observed in tryptamine concentrations in the striatum, hypothalamus, or hippocampus of rats pretreated with a monoamine oxidase inhibitor. The only change observed in these rats was a limited increase in striatal tryptamine and tryptophan observed at 1 day after lesioning. The results indicate that tryptamine concentration is independent of the integrity of 5-HT-containing neurons of the midbrain raphe nuclei. Furthermore, if tryptamine-containing neurons that have terminal projections to the striatum, hypothalamus, and hippocampus exist, their cell bodies are located in regions outside the dorsal and median raphe nuclei. Another possibility could be that tryptamine is located in glial cells.     

Effect of 3,4-Methylenedioxymethamphetamine on 3,4-Dihydroxyphenylalanine Accumulation in the Striatum and Nucleus Accumbens

The effect of the racemic mixture of 3,4-methylenedioxymethamphetamine (MDMA) on the synthesis of dopamine in the terminals of nigrostriatal and mesolimbic neurons was estimated by measuring the accumulation of 3,4-dihydroxyphenylalanine (DOPA) in the striatum and nucleus accumbens 30 min following the administration of the L-aromatic amino acid decarboxylase inhibitor, 3-hydroxybenzylhydrazine. MDMA produced an increase in DOPA accumulation in the striatum which was greater in magnitude and longer in duration than that in the nucleus accumbens. Although the concentrations of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in both the striatum and nucleus accumbens were reduced 3 h following an injection of MDMA (20 mg/kg), 5-HT and 5-HIAA concentrations were significantly reduced only in the striatum 7 days after the administration of MDMA. Pretreatment with a 5-HT2 antagonist, ketanserin, significantly attenuated the reduction in 5-HT concentration in the striatum 3 h following MDMA administration and completely blocked 5-HT depletion at 7 days post administration. Moreover, ketanserin completely blocked MDMA-induced DOPA accumulation in the striatum. The results obtained in these studies suggest that MDMA activates nigrostriatal dopaminergic pathways via 5-HT2 receptors. In addition, these data are supportive of the hypothesis that dopamine plays a role in MDMA-induced 5-HT depletion.     

Long-Term Effects of Portacaval Anastomosis on the 5-Hydroxytryptamine, Histamine, and Catecholamine Neurotransmitter Systems in Rat Brain

Abstract: Portacaval anastomosis (PCA) in the rat is used as a model for portal systemic encephalopathy. Changes in the serotonergic, histaminergic, and catecholaminergic neurotransmitter systems are often found shortly after PCA. We have examined the long-term effects of PCA on the aminergic systems in brains of male Wistar rats, which 8 months previously had been subjected to PCA. Precursors, amines, and metabolites were assayed by HPLC. Eight months after PCA, the catecholamine levels were unchanged in all brain regions. In contrast, tryptophan was evenly increased throughout the brain. The accumulation of 5-hydroxytryptophan after decarboxylase inhibition (NSD-1015; 100 mg/kg i.p.) and the endogenous levels of 5-hydroxyindoleacetic acid were significantly higher in PCA rats, particularly in the hypothalamus and midbrain, whereas 5-hydroxytryptamine concentrations were unchanged. Histamine levels were elevated throughout the brain with the greatest increase found in the hypothalamus and in the striatum. tele -Methylhistamine levels were significantly elevated in cortex and hypothalamus. We conclude that 8 months after PCA, catecholaminergic systems had reestablished their homeostasis, whereas serotonergic and histaminergic systems still show profound disturbances in their function. With histamine, this is reflected as an increase in the amounts of both transmitter and metabolite; serotonergic neurons respond by increasing only the level of the metabolite.     

EFFECTS OF INGESTION OF A CARBOHYDRATE-FAT MEAL ON THE LEVELS AND SYNTHESIS OF 5-HYDROXYINDOLES IN VARIOUS REGIONS OF THE RAT CENTRAL NERVOUS SYSTEM

—The concentrations of tryptophan, serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in spinal cord and most brain regions increase 2 h after fasted rats begin to consume a carbohydrate-fat meal: indole levels rise in all portions of the brain studied, but the increase is not statistically significant in the hypothalamus and corpus striatum. The rate at which the brain synthesizes 5-hydroxy-indoles (as estimated in vivo by measuring 5-hydroxytryptophan accumulation following an injection of the decarboxylase inhibitor RO4-4602) is also accelerated in all of the regions in which the experimental diet elevates tryptophan, 5-HT and 5-HIAA levels. These observations indicate that the previously reported increase in brain 5-hydroxyindole levels following consumption of a protein-free meal reflects accelerated serotonin synthesis, and occurs within both the cell bodies and the terminals of serotonin-containing neurons. It is possible that diet-induced changes in neuronal serotonin levels influence the quantities of the neurotransmitter released into synapses, either spontaneously or in response to drugs.     

Determination of Amino Acids and Monoamine Neurotransmitters in Caudate Nucleus of Seizure-Resistant and Seizure-Prone BALB/c Mice

Abstract: Amino acid and monoamine concentrations were examined in tissue extracts of caudate nucleus of genetic substrains of BALB/c mice susceptible or resistant to audiogenic seizures. Amino acids [aspartate, glutamate, glycine, taurine, serine, γ-aminobutyric acid (GABA)], monoamines, and related metabolites were separated by isocratic reverse-phase chromatography and detected by a coulometric electrode array system. In situ activity of tyrosine hydroxylase and tryptophan hydroxylase were determined by measuring the accumulation of L-DOPA and 5-hydroxytryptophan after administration of the decarboxylase inhibitor NSD-1015. Highly significant decreases in concentrations of both excitatory (glutamate and aspartate) and inhibitory amino acids (GABA and taurine) were observed in extracts of caudate nucleus of seizure-prone mice. Substantial decreases in concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were also noted. Decreased accumulation of L-DOPA after NSD-1015 administration provided evidence for decreased tyrosine hydroxylase activity and decreased DA synthesis in striatum of seizure-prone mice compared with seizure-resistant mice. Decreased concentrations of the DA metabolite 3-methoxytyramine (after NSD-1015 administration) suggested that DA release was also compromised in seizure-prone mice. No significant difference in 5-hydroxytryptophan accumulation in striatum of seizure-prone and seizure-resistant mice suggested that tryptophan hydroxylase activity and serotonin synthesis were not affected. The data suggest that seizure-prone BALB/c mice have a deficiency in intracellular content of both excitatory and inhibitory amino acids. The data also raise the issue of whether GABAergic interactions with the nigrostriatal DA system are important in the regulation of audiogenic seizure susceptibility.     

6R-L-erythro-5,6,7,8-tetrahydrobiopterin as a regulator of dopamine and serotonin biosynthesis in the rat brain

6R-L-Erythro-tetrahydrobiopterin (6R-BH4), the natural isomer of tetrahydrobiopterin, was synthesized from 7,8-dihydrobiopterin using dihydrofolate reductase. The effects of intracerebroventricular injection of 6R-BH4 on the biosyntheses of neurotransmitter monoamines in the rat brain were investigated by measuring accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after the inhibition of aromatic L-amino acid decarboxylase by NSD 1015 and the contents of metabolites of dopamine (DA) and 5-hydroxytryptamine (5-HT). The formation of DOPA and 5-HTP increased after the injection, reached a maximum level at about 1 h, then leveled off and reached a plateau over 2 h up to 8 h. The formation of DOPA and 5-HTP increased dose-dependently in the whole brain after the injection of 6R-BH4, and reached a plateau when the dose was more than 300 micrograms/rat. The enhancement was 100 and 70% for DOPA and 5-HTP, respectively. The formation of DOPA and 5-HTP increased in four brain regions, but the degree of stimulation was different among the brain regions. The contents of DA and 5-HT metabolites increased after the injection of 6R-BH4 in all brain regions tested, especially in the diencephalon and brain stem. The contents of DA and 5-HT increased slightly after the injection of 6R-BH4. These results suggest that 6R-BH4 concentration may be submaximal within DA and 5-HT neurons, and that an increase in 6R-BH4 in the brain enhances the biosyntheses of DA and 5-HT.     

The effects of quipazine on serotonin metabolism in rat brain.

Quipazine, 2-(1-piperazinyl)-quinoline, is a drug that has been reported to stimulate serotonin receptors in brain. We therefore studied the effect of quipazine on several parameters of serotonin metabolism in rat brain. Quipazine caused a slight, dose-related elevation of serotonin levels and decrease in 5-hydroxyindoleacetic acid levels for 2–4 hrs after it was administered. The decrease in 5-hydroxyindoleacetic acid levels was probably due primarily to a depression of 5-hydroxyindole synthesis, since quipazine also decreased the rate of 5-hydroxytryptophan accumulation after NSD 1015, the rate of serotonin decline after α-propyldopacetamide, and the rate of 5-hydroxyindoleacetic acid accumulation after probenecid. The elevation of serotonin was probably due to weak inhibition of monoamine oxidase. Quipazine reversibly inhibited the oxidation of serotonin by rat brain monoamine oxidase $\text{in}$$\text{vitro}$ and protected against the irreversible inactivation of the enzyme $\text{in}$$\text{vivo}$. Quipazine also was a potent inhibitor of serotonin uptake into brain synaptosomes $\text{in}$$\text{vitro}$ and attained concentrations in brain higher than the $\text{in}$$\text{vitro}$ IC₅₀. However, quipazine did not prevent the depletion of brain serotonin by p-chloroamphetamine $\text{in}$$\text{vivo}$. In addition to stimulating serotonin receptors in brain, quipazine may inhibit monoamine oxidase and serotonin reuptake $\text{in}$$\text{vivo}$.     

Caffeine injection raises brain tryptophan level,but does not stimulate the rate of serotonin synthesis in rat brain

Acute caffeine injection (100 mg/kg) elevates brain levels of tryptophan (TRP), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA). Experiments were performed to determine if the increases in 5HT and 5HIAA result from a stimulation of the rate of 5HT synthesis. Both the rate of 5-hydroxytryptophan (5HTP) accumulation following NSD-1015 injection, and the rate of ³H-5-hydroxyindole synthesis from ³H-tryptophan were measured $\text{in vivo}$ following caffeine administration and found to be normal. Tryptophan hydroxylase activity, as measured $\text{in vitro}$ in brain homogenates, was also unaffected by caffeine. The results suggest that the elevations in brain 5HT and 5HIAA levels produced by caffeine do $\text{not}$ reflect enhanced 5HT synthesis, despite significant elevations in brain TRP level. Some other mechanism(s) must therefore be responsible for these elevations in brain 5-hydroxyindole levels.     

Effects of alterations in the activity of tuberohypophysial dopaminergic neurons on the secretion of alpha-melanocyte stimulating hormone

Administration of gamma-butyrolactone (GBL), an anesthetic which reduces dopaminergic neuronal activity, decreased the concentration of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the intermediate lobe of the pituitary gland, and increased alpha-melanocyte stimulating hormone (alpha MSH) concentrations in the serum of male rats. Bilateral electrical stimulation of the rostral arcuate nucleus, which contains perikarya of tuberohypophysial DA neurons, increased DOPAC concentrations in the intermediate lobe and decreased alpha MSH concentrations in the serum of GBL-anesthetized rats. Administration of the DA antagonist haloperidol prevented the decline in serum alpha MSH levels following arcuate nucleus stimulation, but had no effect on serum alpha MSH concentrations in sham-stimulated GBL-treated rats. These results indicate that GBL-induced decreases or stimulation-induced increases in the activity of tuberohypophysial DA neurons are accompanied by corresponding changes in the metabolism of DA in the intermediate lobe of the rat pituitary gland, and by reciprocal changes in the secretion of alpha MSH.     

Terminal Autoreceptor Control of 5-Hydroxytryptamine Release as Measured by In Vivo Microdialysis in the Conscious Guinea-Pig

In vivo microdialysis in the frontal cortex of the freely moving guinea-pig was used to measure extracellular 5-hydroxytryptamine (5-HT) and study terminal autoreceptor control of its release. The indoleamine levels were determined by HPLC with electrochemical detection. Release of extracellular 5-HT and, to a lesser extent, 5-hydroxyindoleacetic acid was sensitive to tetrodotoxin, confirming the neuronal origin of measured neurotransmitter levels. Both systemic and local administration of the 5-HT1 agonist 5-carboxamidotryptamine caused inhibition of extracellular 5-HT levels, confirming the regulatory role of the terminal, and possibly also the somatodendritic, 5-HT autoreceptor on neuronal 5-HT release. Levels of extracellular 5-hydroxyindoleacetic acid were not affected by 5-carboxamidotryptamine following either central or peripheral administration.     

Serotonergic control of prolactin release in male rats.

To further clarify the relationship between the central serotonergic system and the control of prolactin secretion, we studied the effect of dorsal raphe' lesions, electrical stimulation of the midbrain raphe' nucleus and treatment with parachlorophenylalanine (PCPA) on prolactin secretion. Radio frequency destruction of serotonergic cell bodies in the midbrain dorsal raphe' nucleus or PCPA decreased forebrain serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) concentration and prolactin secretion. Electrical stimulation of the raphe' increased forebrain serotonin turnover and prolactin secretion. These observations indicate that serotonergic neurons located in the raphe' nuclei may be involved in regulating prolactin secretion in male rats.     

Effect of dopamine agonists and antagonists on DOPA formation in the substantia nigra

Abstract: The effect of different psychotropic drugs on the rate of DOPA accumulation after administration of a decarboxylase inhibitor (NSD 1015) was compared in the substantia nigra (SN) and caudate nucleus (CN) by a new radioenzymatic method. Inhibition of monoamine oxidase with pargyline or stimulation of dopamine (DA) receptors with apomorphine, N -n-propyl-norapomorphine or d -amphetamine reduced DOPA formation in the CN and SN to the same extent. Vice versa, both inhibition of DA receptors with haloperidol or (-)sulpiride and depletion of DA concentration with reserpine enhanced DOPA formation to a greater extent in the CN than in the SN. Apomorphine antagonized not only the effect of haloperidol and (-)sulpiride, but also, and even more effectively, that of reserpine. The results indicate that DA synthesis in the SN is controlled by both end-product inhibition and DA receptor-mediated mechanisms.     

Turnover of Dopamine and Serotonin and Their Metabolites in the Striatum of Aged Rats

Turnover of dopamine (DA), serotonin [5-hydroxytryptamine (5-HT)], and their metabolites has been measured in adult and aged rats. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxy-3-indoleacetic acid (5-HIAA) have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase (MAO) and from the accumulation rates by probenecid inhibition of the probenecid-sensitive transport system. DA and 5-HT turnover rates have been measured as accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015) and as accumulation rates of DA and 5-HT after pargyline inhibition of MAO. The DA turnover rate after NSD-1015 was 23.9% lower in aged rats than in adults, whereas after pargyline there was no significant difference between the two age groups. The HVA fractional rate constant and turnover after pargyline were lower in aged rats than in adults, and HVA turnover after probenecid was higher in aged rats than in adults. The DOPAC-HVA pathway seems to be reinforced at the expense of DOPAC conjugation. In aged and adult rats whose 5-HT steady-state levels were not statistically different, the 5-HT turnover rate after pargyline and NSD-1015 treatment was lower in aged rats than in adults. An increase of 5-HIAA levels after pargyline and probenecid treatment in aged rats could be due to the handling stress.