Prostaglandin synthesis inhibition and monoamine metabolites in the rat brain

The effect of indomethacin 3 mg/kg on levels of homovanillic acid (HVA), 4-hydroxy-3-methoxy phenyl ethylene glycol (HMPG) and 5-hydroxy indol acetic acid (5HIAA) was studied in rat striatum and olfactory tubercle with and without pretreatment with morphine 10 mg/kg. Indomethacin caused a small decrease in resting levels of HVA in striatum but not in olfactory tubercle. No effects were seen on resting or morphine induced changes in the levels of these monoamine metabolites. Likewise indomethacin 20 mg/kg failed to alter the elevation of HVA induced by chlorpromazine 15 mg/kg or the decrease of HVA induced by apomorphine (1–10 mg/kg) in the rat striatum. Our results do not support a major role for endogenous prostaglandins in the modulation of monoamine neurotransmission in the rat brain.     

Prostaglandin synthesis inhibition and monoamine metabolites in the rat brain.

The effect of indomethacin 3 mg/kg on levels of homovanillic acid (HVA), 4-hydroxy-3-methoxy phenyl ethylene glycol (HMPG) and 5-hydroxy indol acetic acid (5HIAA) was studied in rat striatum and olfactory tubercle with and without pretreatment with morphine 10 mg/kg. Indomethacin caused a small decrease in resting levels of HVA in striatum but not in olfactory tubercle. No effects were seen on resting or morphine induced changes in the levels of these monoamine metabolites. Likewise indomethacin 20 mg/kg failed to alter the elevation of HVA induced by chlorpromazine 15 mg/kg or the decrease of HVA induced by apomorphine (1--10 mg/kg) in the rat striatum. Our results do not support a major role for endogenous prostaglandins in the modulation of monoamine neurotransmission in the rat brain.     

TURNOVER OF FREE AND CONJUGATED (SULPHONYLOXY) DIHYDROXYPHENYLACETIC ACID AND HOMOVANILLIC ACID IN RAT STRIATUM

Abstract— Conjugated (sulphonyloxy) dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were synthesized from free DOPAC and HVA and used as reference compounds in their fluorimetric determination in rat brain (detection limit 0.2 nmol/g). The conjugated DOPAC and HVA form 29 and 36% of the total DOPAC and HVA found in rat striatum, respectively. Dopamine (DA) metabolism was studied in the rat striatum by following the decline of both free and conjugated DOPAC and HVA after treatment with pargyline (100mg/kg. i.p.) either alone or in combination with tropolone (100 mg/kg, i.p.). or from the accumulation of the free and conjugated acids after treatment with probenecid (100-500mg/kg. i.p.). The rates of decline were analysed by a non-linear curve fitting method using a simple model of DA metabolism that postulates the formation of the conjugates exclusively from the free acids, and HVA from DOPAC, with first order kinetics and single open compartments only. The curves computed all passed through the s.e.m. of every experimental point. The rate constants thus found indicate that DOPAC turnover is about 23nmol/g/h. Of this about 16 nmol/g/h are O -methylated to HVA, about 6 nmol/g/h are conjugated and less than 1 nmol/g/h is eliminated as free DOPAC. Of the HVA formed, about 8.5nmol/g/h are conjugated and about 7.5 nmol/g/h eliminated as free HVA. The conjugates accumulated after treatment with probenecid (1 h) faster than the free acids. The maximal accumulation of all four metabolites found (21 nmol/g/h) approximates the total turnover of DOPAC.     

Enhancement of Brain Dopamine Metabolism by Tyrosine During Immobilisation: An In Vivo Study Using Repeated Cerebrospinal Fluid Sampling in Conscious Rats

Central dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism was monitored in conscious, freely moving rats by determination of levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF samples withdrawn repeatedly from the cisterna magna and treated with acid to hydrolyse DOPAC and HVA conjugates. The effect of tyrosine on DA metabolism was investigated. Time courses of metabolite concentrations in individual rats in a quiet room showed that tyrosine (20, 50, or 200 mg/kg i.p.) was without significant effect; brain changes were essentially in agreement. However, the increases of CSF DOPAC and HVA levels that occurred on immobilisation for 2 h were further enhanced by tyrosine (200 mg/kg). The associated increases of 5-HIAA level were unaffected. The corresponding increases of DA metabolite concentrations in the brains of immobilised rats given tyrosine were less marked than the CSF changes and only reached significance for "rest of brain" DOPAC. The CSF studies revealed large interindividual variation in the magnitude and duration of the effects of immobilisation on transmitter amine metabolism. These results may help toward the elucidation of possible relationships between the neurochemical and behavioural effects of stress.     

DIFFERENTIATION OF DOPAMINERGIC AND NORADRENERGIC NEURONS IN RAT SPINAL CORD

Abstract— Norepinephrine (NE), dopamine (DM) and 3-methoxy-4-hydroxyphenylacetic acid (HVA) content have been measured in different parts of rat spinal cord and cerebellum by a gas chromatographic mass spectrometric method. In cerebellum, which does not contain dopaminergic neurons, the ratio of NE to DA content was 47, whereas in parts of the spinal cord this ratio varied between 11 and 19. In the cord after desipramine (25 mg/kg, i.p.) plus 6-hydroxydopamine (6-HDA, 100/jg intracisternally), there was a significant depletion of DM but not of NE. Conversely, after benztropine (25 mg/kg, i.p.) plus 6-HDA there was a significant depletion of NE but not of DM. Chlorpromazine (10 mg/kg, i.p.) or clozapine (25 mg/kg, i.p.) caused a significant increase in spinal cord HVA concentration 1 h after treatment. Evidence is presented which suggests that the increased HVA measured in the cord did not originate in the brain. After electrolytic lesion of the locus coeruleus there was a significant reduction of NE but not of DM. Spinal cord DM and NE were depleted by reserpine in a dose-dependent manner, the threshold dose for DM depletion being less than that for NE depletion. Seven days after cord transection at T₁₀ spinal cord DM was significantly reduced in the lumbar region. These results suggest that dopaminergic neurons exist in rat spinal cord independently of noradrenergic neurons and that the DM is likely to be present in the terminals of descending axons.     

Tolerance develops to the haloperidol-induced increase in the efflux of dopamine metabolites from the brains of unanesthetized, freely-moving rats

The lateral cerebral ventricles of freely moving rats were perfused by means of chronically implanted push-pull cannulae every second day for 2 weeks. Perfusates were analyzed for metabolites of dopamine [dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] and of 5-hydroxytryptamine [5-hydroxyindoleacetic acid (5HIAA)] using high performance liquid chromatography and an amperometric detector. Rats received daily subcutaneous injections of haloperidol (1 mg/kg) or its vehicle. After the first injection of haloperidol the concentrations of DOPAC and HVA were markedly increased while that of 5HIAA was unchanged. Complete tolerance developed to the haloperidol-induced increased efflux of dopamine metabolites by day 9, although a higher dose of haloperidol (2 mgf/kg) on day 15 was still capable of eliciting a modest increase in the efflux of DOPAC and HVA.     

Ventricular Cerebrospinal Fluid Monoamine Transmitter and Metabolite Concentrations Reflect Human Brain Neurochemistry in Autopsy Cases

Concentrations of dopamine (DA), its metabolites 3-methoxytyramine and homovanillic acid (HVA), noradrenaline (NA), its metabolites normetanephrine (NM) and 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxytryptamine (5-HT, serotonin), and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in 14 brain regions and in CSF from the third ventricle of 27 human autopsy cases. In addition, in six cases, lumbar CSF was obtained. Monoamine concentrations were determined by reversed-phase liquid chromatography with electrochemical detection. Ventricular/lumbar CSF ratios indicated persistence of rostrocaudal gradients for HVA and 5-HIAA post mortem. Ventricular CSF concentrations of DA and HVA correlated positively with striatal DA and HVA. CSF NA correlated positively with NA in hypothalamus, and CSF MHPG with levels of MHPG in hypothalamus, temporal cortex, and pons, whereas CSF NM concentration showed positive correlations with NM in striatum, pons, cingulate cortex, and olfactory tubercle. CSF 5-HT concentrations correlated positively with 5-HT in caudate nucleus, whereas the concentration of CSF 5-HIAA correlated to 5-HIAA levels in thalamus, hypothalamus, and the cortical areas. These data suggest a specific topographic origin for monoamine neurotransmitters and their metabolites in human ventricular CSF and support the contention that CSF measurements are useful indices of central monoaminergic activity in man.     

Role of Monoamine Oxidase Type A and B on the Dopamine Metabolism in Discrete Regions of the Primate Brain

The role of monoamine oxidase (MAO) type A and B on the metabolism of dopamine (DA) in discrete regions of the monkey brain was studied. Monkeys were administered (–)-deprenyl (0.25 mg/kg) or clorgyline (1.0 mg/kg) or deprenyl and clorgyline together by intramuscular injections for 8 days. Levels of DA and its metabolites, dihydroxy phenylacetic acid (DOPAC) and homovanillic acid (HVA) were estimated in frontal cortex (FC), motor cortex (MC), occipital cortex (OC), entorhinal cortex (EC), hippocampus (HI), hypothalamus (HY), caudate nucleus (CN), globus pallidus (GP) and substantia nigra (SN). (–)-Deprenyl administration significantly increased DA levels in FC, HY, CN, GP and SN (39–87%). This was accompanied by a reduction in the levels of DOPAC (37–66%) and HVA (27–79%). Clorgyline administration resulted in MAO-A inhibition by more than 87% but failed to increase DA levels in any of the brain regions studied. Combined treatment of (–)-deprenyl and clorgyline inhibited both types of MAO by more than 90% and DA levels were increased (57–245%) in all brain regions studied with a corresponding decrease in the DOPAC (49–83%) and HVA (54–88%) levels. Our results suggest that DA is metabolized preferentially, if not exclusively by MAO-B in some regions of the monkey brain.     

Kinetics of Drug-Induced Changes in Dopamine and Serotonin Metabolite Concentrations in the CSF of the Rat

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Every 15 min, CSF dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined by direct injection of CSF into a liquid chromatographic system coupled with electrochemical detection. Mean CSF concentrations of DOPAC, HVA, and 5-HIAA were 1.29 microM, 0.88 microM, and 2.00 microM, respectively. In order to determine the turnover rates of dopamine (DA) and serotonin, experiments using monoamine oxidase (MAO) inhibition were performed. Tranylcypromine (20 mg/kg i.p.) induced a sharp exponential decrease of CSF DOPAC, HVA, and 5-HIAA, with respective half-lives of 15.60 min, 16.91 min, and 77.23 min. Their respective turnover rates were 3.74, 2.22, and 1.18 nmol X ml-1 X h-1. m-Hydroxybenzylhydrazine (NSD-1015, 100 mg/kg i.p.) and monofluoromethyl-DOPA (100 mg/kg i.p.), two decarboxylase inhibitors, induced a slow exponential decrease of all three CSF metabolites. alpha-Methyl-p-tyrosine (250 mg/kg i.p.) also induced a slow exponential decrease of DOPAC and HVA. These decreases of CSF DOPAC and HVA induced by DA synthesis inhibitors may reflect the turnover of DA in vivo. Haloperidol (0.5 mg/kg i.p.) considerably enhanced CSF DOPAC and HVA without affecting 5-HIAA, confirming that dopaminergic receptors modulate DA neurotransmission in vivo. Haloperidol administered 1.5 h after NSD-1015 did not increase DOPAC and HVA, in contrast to reserpine (5 mg/kg i.p.) injected under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain Dialysis: In Vivo Metabolism of Dopamine and Serotonin by Monoamine Oxidase A but Not B in the Striatum of Unrestrained Rats

A dialysis cannula was implanted into rat striatum while the animals were anesthetized, and the area was perfused with Ringer solution while the animals were unanesthetized after at least 3 days following surgery. Concentrations of the metabolites of 3,4-dihydroxyphenylethylamine (DA) and 5-hydroxytryptamine (5-HT) in the perfusate were determined by HPLC with electrochemical detection. Levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perfusate significantly decreased after pargyline administration (50 mg/kg i.p.), which may inhibit not only monoamine oxidase (MAO)-B but also MAO-A in these high doses. The level of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) also decreased after pargyline treatment, although change in the relative level of 5-HIAA was less than that of DOPAC or HVA. To clarify the mechanisms for the metabolism of monoamines in rat striatum, highly specific MAO-A and -B inhibitors were used in the following experiments. Treatment with l-deprenyl (10 mg/kg), a specific inhibitor for MAO-B, did not cause any statistically significant change in DOPAC, HVA, and 5-HIAA levels. No significant change was found in rat striatal homogenates at 2 h after the same treatment with l-deprenyl. In contrast, low-dose treatment (1 mg/kg) with clorgyline, a specific inhibitor for MAO-A, caused a significant decrease in levels of these three metabolites in both the perfusates and tissue homogenates. In addition to the above three metabolites, the level of 3-methoxytyramine, which is an indicator of the amount of DA released, greatly increased after treatment with a low dose (1 mg/kg) of clorgyline.(ABSTRACT TRUNCATED AT 250 WORDS)     

3,4-Dihydroxyphenylethylamine and 5-Hydroxytryptamine Metabolism in the Rat: Acidic Metabolites in Cisternal Cerebrospinal Fluid Before and After Giving Probenecid

3,4-Dihydroxyphenylethylamine (DA, dopamine) and 5-hydroxytryptamine (5-HT) turnover values were determined in freely moving male rats by measuring the rates of accumulation of the acidic metabolites of the above transmitters, i.e., 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (CSF) samples after probenecid (200 mg/kg i.p.) administration. Determinations on samples before and after acid hydrolysis showed that the latter procedure was necessary for DA turnover determination. Thus whereas total (DOPAC + HVA) increased linearly with time after probenecid, free (DOPAC + HVA) did not. This was because the percentage of DOPAC + HVA in conjugated form increased with time. Determinations on a group of 28 rats during the dark (red light) period showed that cisternal amine metabolite concentrations before probenecid injection did not parallel turnover values. This was probably because individual differences in metabolite egress strongly affect the pre-probenecid values. The poor correlations between CSF tryptophan and 5-HT turnover suggested that differences of brain tryptophan concentration were not major determinants of differences of brain 5-HT metabolism within this group of normal rats. Considering that the rats were of similar weight and that the turnover values were all determined at approximately the same time of day, the three- to fourfold ranges of the turnover values are remarkable. The positive correlation between the DA and 5-HT turnovers of individual rats suggests the existence of common effects on DA and 5-HT turnover in normal rats.     

Bombesin increases dopamine function in rat brain areas

Bombesin is a tetradecapeptide heterogenously distributed in the mammalian brain. Bombesin (45 micrograms) given intracisternally (IC) to unanesthetized rats increased the accumulation of dihydroxyphenylalanine (DOPA) in striatum, olfactory tubercles and hypothalamus after DOPA-decarboxylase inhibition, thus indicating an increased dopamine synthesis. A dose-dependent increase in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the principal dopamine metabolites, was seen in several brain areas 1 hr after IC injection of bombesin (0-60 micrograms). In striatum and olfactory tubercles HVA increased more than DOPAC with a maximal increase after 30-45 micrograms. In a time-course experiment a biphasic change of dopamine metabolites was observed in the olfactory tubercles with an actual decrease in metabolite levels 4 hr after 60 micrograms IC bombesin injection. Co-administration of bombesin and naloxone (8 mg/kg IP) or ethanol (2.25 g/kg IP) did not affect the increase in dopamine metabolites seen after bombesin alone. The action of IC administered bombesin on dopamine function was most pronounced in hypothalamus indicating a neuroendocrine regulatory of the peptide.     

SELECTIVE INCREASE OF BRAIN DOPAMINE SYNTHESIS BY SULPIRIDE

—Sulpiride (5–200 mg/kg) increases brain HVA and DOPAC levels, causes no change in dopamine concentration, does not interfere with the outflow of HVA from the CNS and enhances the disappearance of brain dopamine after inhibition of tyrosine hydroxylase. The compound influences neither 5-HT nor NE metabolism. The central action of sulpiride differs from that of classic neuroleptics in that this drug stimulates dopamine turnover without producing catalepsy.     

Rapid, concurrent analysis of dopamine, 5-hydroxytryptamine, their precursors and metabolites utilizing high performance liquid chromatography with electrochemical detection: analysis of brain tissue and cerebrospinal fluid

Assays capable of measuring picomole quantities of dopamine (DA), 5-hydroxytryptamine (5-HT), several of their precursors and metabolites concurrently within 25 minutes were developed utilizing high performance liquid chromatography with electrochemical detection (LCEC). Several parameters of the LCEC were altered in order to separate the compounds while maintaining a short assay time. The final LCEC systems demonstrated biological utility in that the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the 5-HT metabolite 5-hydroxy-3-indoleacetic acid (5-HIAA) were detected in rat cerebrospinal fluid; in addition to these compounds, DA and 5-HT were measurable in the striatum, hypothalamus and median eminence of the rat brain. Pargyline decreased the concentrations of DOPAC, HVA and 5-HIAA and increased the 5-HT concentration in all three brain regions, and increased the DA concentration in the striatum. Probenecid increased all three acid metabolite concentrations in the hypothalamus and median eminence, while only the HVA and 5-HIAA concentrations were increased in the striatum. The DA and 5-HT concentrations were unaltered. The LCEC methods described in this paper should be useful in elucidating the mechanisms and roles of 5-HT and DA neurons in experimental paradigms of biological interest.     

Concurrent Determination of Brain Dopamine and 5-Hydroxytryptamine Turnovers in Individual Freely Moving Rats Using Repeated Sampling of Cerebrospinal Fluid

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.     

Central dopamine agonistic activity and microsomal biotransformation of lisuride, lergotrile and bromocriptine.

Lisuride (0.05 – 0.1 mg/kg), lergotrile (1 mg/kg) and bromocriptine (5 mg/kg) reduced the turnover of dopamine (DA) in rat brain, as indicated by a pronounced decrease of cerebral homovanillic acid (HVA) without appreciable changes in DA level. Time curves revealed that lisuride injected intracerebroventricularly or i.p. caused a rapid reduction of HVA lasting for a few hours, whereas after p.o. administration the decrease of HVA was delayed. Pretreatment of the rats with the microsomal enzyme inhibitor proadifen potentiated and prolonged, rather than prevented, the effect of i.p. injected lisuride on rat cerebral DA turnover. The HVA reduction obtained with lergotrile and bromocriptine was also somewhat retarded after p.o. administration; the HVA diminution seen after i.p. injection was again potentiated and prolonged by proadifen. In addition, this microsomal enzyme inhibitor prolonged and intensified, rather than prevented, the hypothermic effect of all of the 3 ergolines. It is concluded that, in the rat, the central DA agonistic activity of the ergolines studied is caused by the drugs themselves and does not require previous biotransformation into active metabolites. The retarded onset and the prolonged duration of action after oral administration is probably due to slow intestinal absorption and slow microsomal inactivation, respectively.     

INHIBITION BY APOMORPHINE OF DOPAMINE DEAMINATION IN THE RAT BRAIN

Abstract— Apomorphine (A) inhibited dopamine deamination by rat brain mitochondria, but did not influence catechol- O -methyltransferase (COMT) activity by brain homogenates. The administration of apomorphine (10mg/kg i.p.) to normal rats increased brain dopamine (DA) by 34 per cent and decreased homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) by 60 per cent. In rats treated with reserpine 15 min prior to A, the latter prevented the rise of cerebral HVA and DOPAC and the depletion of DA produced by the former. Finally, A decreased the L-DOPA-induced accumulation of HVA and DOPAC in the rat basal ganglia. These results indicate that A inhibits DA deamination by monoamine oxidase.
This inhibition seems to be specific since apomorphine did not influence 5-HIAA levels in normal rats and prevented neither central 5-HT depletion nor 5-HIAA rise induced by reserpine.     

Effect of DN-1417, a thyrotropin releasing hormone analog, on dopaminergic neurons in rat brain

Acute and chronic effects of γ-butyrolactone-γ-carbonyl-histidyl-prolinamide (DN-1417) were investigated on motor activity, dopamine (DA) metabolites and DA receptors in various brain regions of rats. The motor activity, as measured with Automex recorder, was enhanced after a single injection with DN-1417 (20 mg/kg, IP), and the motor stimulating action persisted during 21 daily injections. Acute DN-1417 elevated both homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in 7 brain regions, prefrontal cortex polar, medial and lateral fields, nucleus accumbens, olfactory tubercles, amygdala and striatum. After chronic treatment for 7 days, the acute effect of DN-1417 on DA metabolites disappeared in all regions except for the striatum in which DN-1417 still increased HVA and DOPAC. The response of striatal DA metabolites was also observed after chronic treatment for 21 days. Chronic DN-1417 produced no significant change in ³H-spiperone binding in the prefrontal cortex, nucleus accumbens, olfactory tubercles and striatum, while striatal ³H-DA binding displaced by 30 nM spiperone was enhanced after chronic treatment. These results indicate that DN-1417 interacts with mesocortical, mesolimbic and nigrostriatal DA systems in the different modes of action. The lack of tolerance to motor hyperactivity, however, raises the question as to whether DN-1417-induced hyperactivity may be mediated by the activation of mesolimbic DA neurons. The involvement of nigrostriatal neurons in DN-1417-induced motor hyperactivity is suggested.     

The potent, selective mGlu2/3 receptor agonist LY379268 increases extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole-3-acetic acid in the medial prefrontal cortex of the freely moving rat

Previous work has shown that the potent, selective metabotropic glutamate mGlu2/3 receptor agonist LY379268 acts like the atypical antipsychotic clozapine in behavioral assays. To investigate further the potential antipsychotic actions of this agent, we examined the effects of LY379268 using microdialysis in awake, freely moving rats, on extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) in rat medial prefrontal cortex. Systemic LY379268 increased extracellular levels of dopamine, DOPAC, HVA, and 5-HIAA in a dose-dependent, somewhat delayed manner. LY379268 (3 mg/kg s.c. ) increased levels of dopamine, DOPAC, HVA, and 5-HIAA to 168, 170, 169, and 151% of basal, respectively. Clozapine (10 mg/kg) also increased dopamine, DOPAC, and HVA levels, with increases of 255, 262, and 173%, respectively, but was without effect on extracellular 5-HIAA levels by 3 mg/kg LY379268 were reversed by the selective mGlu2/3 receptor antagonist LY341495 (1 mg/kg). Furthermore, LY379268 (3 mg/kg)-evoked increases in DOPAC and HVA were partially blocked and the increase in 5-HIAA was completely blocked by local application of 3 microM tetrodotoxin. Therefore, we have demonstrated that mGlu2/3 receptor agonists activate dopaminergic and serotonergic brain pathways previously associated with the action of atypical antipsychotics such as clozapine and other psychiatric agents.     

Inhibition of rat liver tryptophan pyrrolase activity and elevation of brain tryptophan concentration by administration of DL-alpha-amino-beta-pyridinepropanoic acid (pyridylalanine) analogs

Single doses of DL-alpha-amino-beta-(2-pyridine)propanoic acid (2-PA, 100 mg/kg) significantly decreased the holoenzyme and apoenzyme activities of rat liver tryptophan pyrrolase (TP) and increased brain tryptophan, serotonin (5-HT) and 5-hydroxyindole-3-ylacetic acid concentrations. 2-PA had no inhibitory effect on either of the enzyme activities in vitro, but its expected metabolites were effective. Single doses of DL-alpha-amino-beta-(3-pyridine)propanoic acid (3-PA, 100 mg/kg) decreased only the holoenzyme activity and elevated brain tryptophan and its metabolites levels in rats. 3-PA and its metabolite, 3-pyridylpyruvate, inhibited only the holoenzyme activity in vitro. DL-alpha-Amino-beta-(4-pyridine)propanoic acid (4-PA) caused significant changes in liver TP (holo- and apoenzyme forms) activity and brain tryptophan concentration only after repeated administration (100 mg/kg/day). 4-PA was a weak inhibitor of the holoenzyme, but its metabolites apparently inhibited the holo- and apoenzyme activities in vitro. These findings suggest that PA analogs (and/or their metabolites) increased brain tryptophan (and hence 5-HT synthesis) by directly inhibiting liver TP activity.