Dopaminergic Metabolism Research Articles

Does dantrolene influence central dopamine and serotonin metabolism in the neuroleptic malignant syndrome? A retrospective study

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) were determined twice in nine cases of neuroleptic malignant syndrome (NMS) during the active phase. During the test period, three cases received no dantrolene and six cases received dantrolene prior to the second CSF examination. In the group not administered dantrolene, the levels of HVA and 5-HIAA were lower on the second examination compared to the first, suggesting that the levels of these substances decreased during the course of NMS. In the group receiving dantrolene, the levels of HVA and 5-HIAA increased after administration compared with the preadministration levels. In particular, a significant difference in the changes in HVA was demonstrated between the two groups. This suggests that dantrolene influences central dopaminergic metabolism in the active phase of NMS.

Antagonism of ceruletide, a cholecystokinin analog, to the neurochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine and MK-801, on regional dopaminergic neurons in the rat brain

In the present study, we investigated the effects of ceruletide (CL), a cholecystokinin analog, on the neurochemical response to non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine (PCP) and MK-801, of the dopaminergic neuron systems in the discrete regions of the rat brain. Systemically administered PCP (7.5 mg/kg, i.p.) or MK-801 (1.0 mg/kg, i.p.) produced significant increases in the tissue contents of dopamine metabolite, homovanillic acid (HVA), in the prefrontal cortex, the nucleus accumbens and the olfactory tubercle but not in the nucleus caudatus putamen after 60 min. The effects of NMDA receptor antagonists in the nucleus accumbens and the prefrontal cortex were partially antagonized by pretreatment with CL (80 and 400 μg/kg, i.p., at 60 min prior to the drugs). While CL alone decreased the dopaminergic metabolism only in the nigrostriatal pathways in naive rats, the present results indicated that CL also attenuates the activities of the meso-limbic and meso-cortical dopaminergic neuron systems when these are enhanced by either PCP or MK-801.

Difference in the effects of the antidepressant tianeptine on dopaminergic metabolism in the prefrontal cortex and the nucleus accumbens of the rat. A voltammetric study

The effects of the new tricyclic antidepressant tianeptine were investigated on dopaminergic (DAergic) metabolism in the anteromedian prefrontal cortex and the nucleus accumbens of the rat. DAergic metabolism was assessed by the measurement of DOPAC, the main presynaptic metabolite of dopamine, using in vivo voltammetry in rats ventilated with halothane (0.5–0.75% in air). Acute treatment with tianeptine (10 mg/kg, 20 mg/kg) only increased significantly DOPAC levels in the anteromedian prefrontial cortex. After chronic treatment with tianeptine (15 days, 2 times/day) the increases in DOPAC levels i n this structure were altered and less pronounced with the 20 mg/kg dose. Previous studies led to suggest that both acute and chronic effects on DAergic terminals in the anteromedian prefrontal cortex may be involved in the therapeutic action of this new antidepressant.

Relationship between plasma and cerebrospinal fluid norepinephrine and dopamine metabolites in a nonhuman primate.

Major and minor pathways of metabolism in the mammalian CNS result in the formation of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and normetanephrine (NMN) from norepinephrine (NE), and homovanillic acid (HVA) and 3-methoxytyramine (3-MT) from dopamine (DA), respectively. The correlational relationships between HVA and 3-MT and between MHPG and NMN in primate CSF and plasma have not been described. These relationships may help to elucidate the usefulness of CSF and plasma metabolites as indices of CNS NE and DA activity. In addition, because NMN is unlikely to cross the blood-brain barrier. CSF NMN concentrations would not be confounded by contributions from plasma, which is a major issue with CSF MHPG. We have obtained repeated samples of plasma and CSF from drug-naive male squirrel monkeys and have measured the concentrations of MHPG, HVA, NMN, and 3-MT to define their correlational relationships. For the NE metabolites, significant correlations were obtained for CSF MHPG and NMN (r = 0.806, p less than 0.001), plasma MHPG and CSF NMN (r = 0.753, p less than 0.001), and plasma and CSF MHPG (r = 0.776, p less than 0.001). These results suggest that CSF and plasma MHPG and CSF NMN may reflect gross changes in whole brain steady-state noradrenergic metabolism. Only a single significant relationship was demonstrated for the DA metabolites, with CSF 3-MT correlating with plasma HVA (r = 0.301, p less than 0.025). The results for the DA metabolites probably reflect regional differences in steady-state brain dopaminergic metabolism.

Auditory Evoked Potential Modifications according to Clinical and Biochemical Responsiveness to Fenfluramine Treatment in Children with Autistic Behavior

Evoked potentials to auditory stimulations varying in intensity were studied in 13 children with autistic behavior treated with fenfluramine. Modifications of both amplitude and single-trial potential variability were considered according to the clinical and biochemical responsiveness to this drug. Six children (responders) were clinically improved by the treatment. Electrophysiological data were affected according to the clinical and biochemical responsiveness to fenfluramine: the auditory evoked potential amplitude increased, and the single-trial potential variability decreased at each intensity level only in responders whose dopaminergic metabolism was significantly modified by fenfluramine treatment. No modification was found in nonresponders. Both biochemical and electrophysiological results argued for an amphetamine-like action of fenfluramine in those autistic children whose attention deficits are associated with motor disturbances including hyperactivity.

Effects of immobilization stress on dopamine and its metabolites in different brain areas of the mouse: role of genotype and stress duration

Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress indcued the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.

Striatal dopamine release and metabolism in sinoaortic-denervated rats by in vivo microdialysis

The purpose of this study was to provide new evidence favoring the hypothesis that cardiovascular information from arterial baroreceptors is integrated with the nigrostriatal system that contributes to regulation of motor activity. Samples of extracellular striatal dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were collected by the technique of in vivo microdialysis and analyzed by high-performance liquid chromatography-electron capture detection. Rats were prepared with a guide tube placed in the caudate-putamen for subsequent insertion of microdialysis probes. During the 1st wk after sinoaortic denervation (SAD) or sham operation (SO), a microdialysis probe was inserted and perfused with Ringer solution at the rate of 2 microliter/min in the freely moving rats. Samples were collected every 20 min before and after injection of pargyline, 100 mg/kg ip. The results showed that SAD rats have approximately 50% less extracellular striatal DA, DOPAC, and HVA than SO rats (P less than 0.01). After blockade of monoamine oxidase activity with pargyline, striatal DA accumulated three times faster in SO than SAD rats suggesting DA synthesis is reduced in SAD rats. These data provide further evidence that the arterial baroreceptor system affects dopaminergic metabolism in the nigrostriatal system possibly as a means for integration of cardiovascular and motor activity.

Chronic morphine and testosterone treatment. Effects on sexual behavior and dopamine metabolism in male rats.

The effects of sustained delivery of morphine and/or testosterone (T) on male rat copulatory behavior, penile reflexes and dopaminergic metabolism in selected brain regions were examined. Castration was followed by (1) a decrease in the number of male rats exhibiting intromissive and ejaculatory behavior in mating tests, (2) decreased erections in ex copula tests, and (3) increases in dopamine and dihydroxyphenylacetic acid (DOPAC) concentrations in the mediobasal hypothalamus (MBH) and the preoptic area-anterior hypothalamus (POA-AH). The decreased incidence of copulatory behavior and penile reflexes seen after castration was effectively prevented by a 4-day treatment with 5-mm T-containing Silastic capsules. Chronic morphine implants, conversely, accentuated the castration-induced decrements in copulatory behavior and prevented the 5-mm-T-induced facilitation, but did not alter the number of animals displaying erection (although the number of erections displayed by testosterone-treated rats was reduced) in ex copula tests. Treatment of castrated rats with 5 mm T, but not morphine alone, nor the combination of 5 mm T plus morphine, significantly reduced dopamine and DOPAC levels in the MBH. In the POA-AH, 5 mm T was without effect, whereas morphine, alone or in combination with 5 mm T, reduced the levels of dopamine and DOPAC. These data suggest that (1) the decline in sexual behavior induced by chronic morphine is primarily due to a failure of sexual arousal, and not of erectile ability, and (2) although the decline in sexual activity seen after castration is associated with alterations in dopaminergic metabolism, the effects of morphine and testosterone on sexual activity are opposite and dissociated from alterations in dopaminergic metabolism.

Plasma levels and renal clearance of two isomers of dopamine sulfate in patients with essential hypertension.

Two isomers of dopamine sulfate, dopamine 3-O-sulfate(3-O-S) and dopamine 4-O-sulfate(4-O-S), in the plasma and urine of patients with essential hypertension and normotensive controls were measured by HPLC-fluorometry. The plasma level of 3-O-S was significantly higher in patients with essential hypertension than in normotensive controls (20.9 +/- 2.2 pmol/ml and 16.3 +/- 1.4 pmol/ml respectively, p less than 0.05) and the plasma levels of 4-O-S were slightly increased in hypertensive patients. The plasma level of 3-O-S was correlated with the serum level of creatinine in both normotensives and hypertensives. In hypertensives, the plasma level of 3-O-S was also correlated with that of noradrenaline. However the creatinine clearances were similar in the two groups, the urinary clearance of 3-O-S was slightly lower in patients with essential hypertension than in normotensive controls. These data indicate that the plasma level of 3-O-S is elevated in essential hypertension because of the abnormality in dopaminergic metabolism and renal disturbance in its excretion.

Modulation de l'amplitude des potentiels evoques auditifs en fonction de l'intensite de la stimulation. relation avec le metabolisme dopaminergique

Relationships between augmenting/reducing (aug/red) in auditory modality and dopaminergic metabolism were investigated in young normal adults. Auditory evoked potentials (AEP) to tones (750 Hz, 200 msec) varying from 50 to 80 sB SPL were recorded at Cz and Fz sites. Individual differences in dopaminergic metabolism were estimated by assaying homovanillic acid levels in urines (u-HVA). The slopes values of P1, N1 and P2 amplitude changes with increasing stimulus intensities were used to evaluate the relationships between aug/red and u-HVA levels. The results of this study showed significant negative correlations between the aug/red of the N1 component recorded at Fz site and the u-HVA concentrations: the higher the aug/red slopes (augmenting tendency), the lower the u-HVA levels. In fact, the main result was that this finding was in accordance with previous ones relating aug/red to HVA when assayed in cerebrospinal fluid (CSF). Our data also showed that in further studies on auditory aug/red, the interest should be focused on the N1 component at Fz site.

Haloperidol prevents the methamphetamine-induced apomorphine subsensitivity of dopamine metabolism in rat striatum.

Our previous experiment showed that the sensitivity of striatal dopaminergic metabolism to apomorphine was lowered after pretreating rats with methamphetamine. This study further demonstrated that haloperidol administered with methamphetamine prevented the effect of the methamphetamine pretreatment. Since gamma-butyrolactone was administered in combination with apomorphine so as to remove complications which might arise from the modification of impulse flow through the striatonigral feedback loop, it is possible that the observed effect of apomorphine upon striatal dopaminergic metabolism and its antagonism with haloperidol may be mediated by autoreceptors of dopaminergic axon terminals in rat striatum.

Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry

Buspirone is a non-benzodiazepine drug with anxiolytic properties. It has been reported to induce a marked increase in the metabolism of dopamine in the striatum and the nucleus accumbens which is similar to that induced by neuroleptics. It has been suggested that the effect observed in the striatum reflects an action of buspirone on dopaminergic autoreceptors in both terminals and cell bodies. In the present study, presynaptic effects of buspirone on dopaminergic metabolism in the nucleus accumbens were investigated, and they were compared to the effects of the classical neuroleptic, haloperidol. Dopaminergic terminals were isolated by infusion of tetrodotoxin into the median forebrain bundle in order to evaluate the effects of buspirone and haloperidol on presynaptic receptors. Changes in dopamine metabolism were determined by in vivo voltammetry. Buspirone administered after interruption of the impulse flow did not affect dopamine metabolism. In contrast haloperidol treatment led to an increase in metabolism of dopamine. It is concluded that buspirone did not act at the presynaptic level and furthermore on dopaminergic autoreceptors.

Sham feeding of sucrose increases the ratio of 3,4-dihydroxyphenylacetic acid to dopamine in the hypothalamus

Recent pharmacological experiments suggested that central dopaminergic (DA) mechanisms are necessary for the normal eating response to sweet stimuli. To test this hypothesis, we measured the ratio of dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) in forebrain DA terminal fields during the sham feeding of sucrose (1–40%) by rats after 17 hr of food deprivation. After 9 min of sham feeding 10% or 40% sucrose, DOPAC/DA increased in the hypothalamus, but not in other forebrain regions including the n. accumbens, amygdala, and pyriform cortex. This increase in hypothalamic DOPAC/DA did not occur after 9 min of sham feeding 1%, 1.25%, or 2.5% sucros. The increased DA metabolism required that sham feeding of 10% or 40% sucrose be maintained for longer than 3 min, because no increase of DOPAC/DA was observed in any forebrain region after 3 min of sham feeding. These results are strong evidence that hypothalamic DA mechanisms are activated by the sham feeding of sucrose solutions and they support the hypothesis that central DA mechanisms are necessary for the normal eating response to sweet stimuli.

Altered striatal dopaminergic metabolism 36 hours after unilateral trauma to the human mesencephalon

Markers of dopaminergic synaptic activity and choline acetyltransferase (CAT) were measured in the putamen and caudate nucleus of a patient who lived 36 hours after a unilateral mechanical lesion of the mesencephalon. After cessation of impulse flow along the nigrostriatal tract, dopamine was elevated, dihydroxyphenylacetic acid was diminished, and CAT and tyrosine hydroxylase activity were enhanced in the putamen ipsilateral to the lesion. [3H]-spiperone binding indicated an increase in D2-dopamine receptor density in the caudate nucleus. These findings indicate that the changes predicted from experimental neurochemical models occur in human nigrostriatal systems.

A study of the effects of buspirone, BMY 13805, and 1-PP on dopaminergic metabolism in the nucleus accumbens using in vivo voltammetry in freely moving rats

The effects of buspirone, a buspirone analogue (BMY 13805) and a buspirone metabolite ( 1-PP) on dopaminergic metabolism in the nucleus accumbens were investigated using in vivo voltammetry. Differential pulse voltammetry coupled with electrochemically pretreated carbon fiber electrodes was used to provide a continuous and selective measure of the 3,4-dihydroxyphenylacetic acid (DOPAC). An implanted micromanipulator enabled the use of freely moving animals. Buspirone injections induced a marked and rapid increase of the DOPAC peak in the nucleus accumbens. Buspirone was 10 times more potent when injected subcutaneously than intraperitoneally. BMY 13805 and 1-PP were without effect on dopaminergic metabolism in the nucleus accumbens. In conclusion, the anxiolytic properties of these drugs and their effects on dopaminergic metabolism do not appear related.

Motor Activity Increases Tryptophan, 5‐Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.

Frontal auditory-evoked potential augmenting-reducing and urinary homovanillic acid.

Relationships between augmenting-reducing (Aug/Red) in auditory modality and dopaminergic metabolism were investigated in young adults with respect to sex. The slope values of evoked potential amplitude changes with increasing intensities were used to evaluate Aug/Red both at Cz and Fz for each of the five components: P1, N1, P2, P1N1, N1P2. The greatest slopes (Aug) were found in females. Individual differences in dopaminergic metabolism were estimated by assaying free and conjugated forms of homovanillic acid (HVA) in urines. HVA excretion rates were significantly more variable in males than in females. Relationships between Aug/Red and HVA levels were only found in males. The lower the Aug/Red slopes recorded at Fz site for the N1 component (weak augmenter or reducer responses), the higher the urinary HVA level and particularly the conjugated forms of HVA. These results are of interest for further applications in psychopathology.

Responses of the pigmented rabbit retina to NMPTP, a chemical inducer of Parkinsonism

The electrophysiological and neurochemical effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP), a chemical inducer of Parkinsonism in man and monkeys, on the pigmented rabbit retina were determined under both chronic and acute conditions. The implicit time, the oscillatory potentials, and the amplitude of the b-wave of the rabbit electroretinogram were affected; both dopamine and dihydroxyphenylalanine (DOPA) levels were depressed. Ultrastructural analysis of acute and chronic retinas showed the occurrence of an intranuclear filamentous inclusion in the nucleus of some cells in the inner nuclear and ganglion cell layer of chronic samples. The effects of the neurotoxin NMPTP on the retina suggest that dopaminergic metabolism is impaired, which then affects the components of the electroretinogram attributed to both bipolar and amacrine cells. In addition, the retina may provide a model in which to study the bichemical and pharmacological mechanisms of NMPTP toxicity.

Interactions of photoperiod and ectopic pituitary grafts on hypothalamic and pituitary function in male hamsters.

Exposure of adult male hamsters to short days (less than 12.5 light/day) leads to suppression of gonadal function which is secondary to reductions in gonadotropin and prolactin (PRL) secretion. PRL secretion is decreased in short days despite a reduction of dopaminergic (DA) input from the hypothalamus, suggesting that the pituitary may become more sensitive to the inhibitory effects of DA. Although hypothalamic DA metabolism is altered by short-day exposure, it is not known whether the DA system can respond to PRL feedback or whether these changes in DA or PRL levels are responsible for the observed changes in gonadotropin secretion. To address these questions, the effects of PRL-secreting ectopic pituitary grafts on hypothalamic catecholamine metabolism and the effects of experimental manipulations of catecholamine metabolism on PRL and gonadotropin secretion were evaluated in adult male hamsters exposed to a 14 h light: 10 h dark (14L:10D) or a 5L:19D photoperiod. Short-photoperiod exposure led to expected reductions in testes weight, plasma PRL levels, and in vitro PRL secretion, but circulating levels of luteinizing hormone or follicle-stimulating hormone were not affected. Norepinephrine and DA turnover in the median eminence and in the medial basal hypothalamus was also reduced in the 5L:19D as compared to the 14L:10D animals. Pituitary grafts elevated PRL levels and hypothalamic DA turnover in animals from either photoperiod, but in vitro PRL secretion was reduced only from the pituitaries of 14L:10D hamsters. Short-photoperiod exposure increased the ability of DA to suppress PRL secretion, and this effect could be reversed by the presence of an ectopic pituitary graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Caerulein peripheral injection: A study on the correlation with dopaminergic metabolism

Immunocytochemical and electrophysiological studies indicate the existence of a functional relationship between Cholecystokinin (CCK) and dopaminergic transmission. In order to gain more information on this relationship, the effect of Caerulein, a CCK stable analogue, on rat spontaneous locomotor activity and on biochemical markers of dopaminergic transmission were measured simultaneously. The concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and the spontaneous or K+ evoked release of dopamine were studied in rat striatum and nucleus accumbens immediately after testing for motor activity. An almost complete reduction in locomotor activity but not significant changes in DOPAC content and dopamine release were observed in rats injected with the peptide (0.25/microgram/Kg, intraperitoneally). DOPAC concentrations were slightly (30%) decreased by increasing 200 folds caerulein dose. In addition, a very minute dose of haloperidol (25 /microgram/Kg) potentiated the caerulein (0.25/microgram/Kg) induced hypomotility, while the parameters of dopaminergic metabolism were unaffected. Our results indicate the existence of a relevant pharmacological interaction between caerulein and dopamine antagonists, although it is not clear whether this interaction takes place at the dopamine terminals level.