Extracellular Concentrations of Dopamine and Metabolites in the Rat Caudate After Oral Administration of a Novel Catechol-O-Methyltransferase Inhibitor Ro 40–7592

The effect of the systemic administration of a novel, orally active, catechol-O-methyltransferase (COMT) inhibitor, Ro 40-7592, on the in vivo extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), was studied by transcerebral microdialysis in the dorsal caudate of freely moving rats. Ro 40-7592 (at doses of 3.0, 7.5, and 30 mg/kg p.o.) elicited a marked and long-lasting reduction of HVA, and at doses of 7.5 and 30 mg/kg, an increase of DOPAC output, but it failed to increase DA output. The administration of L-beta-3,4-dihydroxyphenylalanine (L-DOPA, 20 and 50 mg/kg p.o.) with a DOPA decarboxylase inhibitor (benserazide) increased both HVA and DOPAC output, but failed to modify significantly extracellular DA concentrations in dialysates; in contrast, combined administration of L-DOPA+benserazide with Ro 40-7592 (30 mg/kg p.o.) resulted in a significant increase in DA output. Ro 40-7592 prevented the L-DOPA-induced increase in HVA output and markedly potentiated the increase in DOPAC output. To investigate to what extent the increase in extracellular DA concentrations was related to an exocitotic release, tetrodotoxin (TTX) sensitivity was tested. Addition of TTX to Ringer, although abolishing DA output in the absence of L-DOPA, partially reduced it in the presence of L-DOPA+Ro 40-7592 and even more so after L-DOPA without the COMT inhibitor. The results of the present study suggest that metabolism through COMT regulates extracellular concentrations of DA formed from exogenously administered L-DOPA but not of endogenous DA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation

The influence of L-DOPA and reserpine on extracellular dopamine (DA) levels in the striatum of intact and dopaminergic denervated rats was studied using the brain microdialysis technique. In intact rats, reserpine (5 mg/kg s.c.) reduced extracellular DA levels to 4% of basal values. L-DOPA (50 mg/kg i.p.) had no effect on extracellular DA levels in reserpine-pretreated rats. In rats with 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic system, basal levels of extracellular DA were low but markedly increased by L-DOPA (50 mg/kg i.p.). In 6-hydroxydopamine-lesioned rats, pretreatment with reserpine (5 mg/kg s.c.) diminished L-DOPA (50 mg/kg i.p.)-induced increases in extracellular DA levels to 16% of those obtained in denervated animals not pretreated with reserpine (p<0.01). These results suggest that in the intact striatum, extracellular DA stems mainly from vesicular storage sites and that in the striatum with dopaminergic denervation, a large part of the L-DOPA-derived extracellular DA is also derived from a vesicular pool that is released by an exocytosis mechanism.     

An In Vivo Study of Dopamine Release and Metabolism in Rat Brain Regions Using Intracerebral Dialysis

Intracerebral dialysis was used with a specifically designed HPLC with electrochemical detection assay to monitor extracellular levels of endogenous 3,4-dihydroxyphenylethylamine (dopamine, DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in brain regions of the halothane-anesthetized rat. Significant amounts of DA, DOPAC, and HVA were detected in control perfusates collected from striatum and n. accumbens whereas the medial prefrontal cortex showed lower monoamine levels. The ratio of DA in perfusate to DA in whole tissue suggests that in f. cortex, compared to n. accumbens and striatum, there is a greater amount of DA in the extracellular space relative to the intraneuronal DA content. The DOPAC/HVA ratio in control perfusates varied between regions in accordance with whole tissue measurements. This ratio was highest in n. accumbens and lowest in f. cortex. The monoamine oxidase inhibitor pargyline (100 mg/kg i.p.) caused an exponential decline in DOPAC, but not of HVA, in regional perfusates, an effect that was associated with an increase in DA. The data indicated a higher turnover of extracellular DOPAC in n. accumbens than in striatum and the lowest DOPAC turnover in f. cortex. The rate of decline in extracellular DA metabolite levels was slow compared to whole tissue measurements. In the perfusates there was no statistical correlation between basal amounts of DA in the perfusates and DOPAC and HVA levels or DOPAC turnover for any of the areas, indicating that measurement of DA metabolism in the brain under basal conditions does not provide a good index of DA release. In summary, this study shows clear regional differences in basal DA release and metabolite levels, metabolite patterns, and DOPAC turnover rates in rat brain in vivo.     

Subchronic methamphetamine treatment selectively attenuates apomorphine-induced decrease in 3,4-dihydroxyphenylacetic acid level in mesolimbic dopaminergic regions

To investigate mechanisms of behavioral enhancement produced by repeated doses of amphetamines, the effects of apomorphine on 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were examined in various brain regions of the rat on the 4th day of withdrawal after repeated administration of saline or methamphetamine (3 mg/kg, s.c.) twice daily for 14 days. Apomorphine (0.1 and 1.0 mg/kg, i.p.) produced a dose-dependent decrease in DOPAC levels and no effect on DA levels in the olfactory tubercle, nucleus accumbens, striatum, frontal and cingulate cortices of saline-treated animals. A decrease in DOPAC levels produced by a low dose of apomorphine was attenuated selectively in the olfactory tubercle and nucleus accumbens of methamphetamine-treated animals. A high dose of apomorphine produced a significant decrease in DOPAC levels in both regions. No such attenuation was obtained in the striatum and the frontal and cingulate cortices.These results suggest that subchronic methamphetamine may induce development of hyposensitivity of presynaptic DA receptors in the mesolimbic regions, which contribute to the behavioral enhancement produced by the drug.     

The Selective Inhibition of the D1 Dopamine Receptor Results in an Increase of Metabolized Dopamine in the Rat Striatum

Our aim was to study the specific role of the postsynaptic D(1) receptors on dopaminergic response and analyze the metabolized dopamine (DA) in the rat striatum. We used male Wistar rats to evaluate the effects of different doses of a D(1) agonist (SKF-38393) and a D(1) antagonist (SCH-23390), and their co-administration. The levels of DA and L-3, 4-dihydroxyphenylacetic acid (DOPAC) were measured using high performance liquid chromatography. The systemic injection of SKF-38393 alone at 1, 5 and 10 mg/kg did not alter the DA and DOPAC levels or the DOPAC/DA ratio. In contrast, injection of SCH-23390 alone at 0.25, 0.5 and 1 mg/kg significantly increased the DA and DOPAC levels, as well as the DOPAC/DA ratio, compared with the respective control groups. The co-administration of SCH-23390+SKF-38393 did not alter the DA or DOPAC levels, but it did significantly inhibit the SCH-23390-induced increase of the DA and DOPAC levels. The SCH-23390+SKF-38393 and the SCH-23390-only groups showed an increase in the DOPAC/DA ratio. The co-administration of SCH-23390+PARGYLINE significantly decreased the DOPAC levels and the DOPAC/DA ratio compared with the control and SCH-23390 groups. Taken together, our results showed that selective inhibition with SCH-23390 produced an increase in metabolized DA via striatal monoamine oxidase. These findings also contribute to the understanding of the role of postsynaptic D(1) receptors in the long-loop negative feedback system in the rat striatum.     

Cross-tolerance of dopamine metabolism to baclofen, γ-butyrolactone and HA-966 in the striatum and olfactory tubercle of the rat

Rats received 7 daily injections with baclofen (40 mg/kg), GBL (750 mg/kg) or HA-966 (100 mg/kg). Dopamine (DA) was measured in the striatum and olfactory tubercle (OT) of rats, sacrificed 0.5 h or 1 h after the last injection. Marked tolerance and cross-tolerance for the DA-elevating effect of these drugs was seen in the striatum, but not in OT. When on day 7 a unilateral lesion of the nigrostriatal pathway was made, also some tolerance to the DA increase in the striatum on the lesioned side was seen in HA-966-pretreated rats, but it was small compared to the tolerance after an additional drug administration in non-lesioned animals. A low dose of apomorphine (0.25 mg/kg, i.p.) had no effect on DA, dihydroxyphenylacetic acid DOPAC) or homovanillic acid (HVA) levels in the lesioned striata, whether the rats had been pretreated for 6 days with HA-966 or not. However, this dose of apomorphine had a significantly more lowering effect on striatal DOPAC and HVA levels on the unlesioned side of HA-966 pretreated rats. The results show that tolerance develops to the increase of DA synthesis, which is possibly receptor-mediated. This tolerance develops more readily in the striatum than in the olfactory tubercle.     

Metabolism of Catecholamines in the Developing Spinal Cord of the Rat

The metabolism of 3,4-dihydroxyphenylethylamine (DA, dopamine) and norepinephrine (NE) both normally, and after the administration of levo-3,4-dihydroxyphenylalanine (L-DOPA), has been studied in several regions of the developing spinal cord of the rat from fetal day (FD) 16 to the young adult stage. During late fetal (from FD 16) and most of neonatal life [to neonatal day (ND) 20], dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were either just detectable or present in very low concentration in all regions in the untreated developing rat. However, the developing spinal cord possesses an enormous capacity to metabolize the large amounts of DA synthesized from injected L-DOPA. At the end of 1 h after 100 mg/kg i.p. of L-DOPA, DOPAC and HVA are 54 +/- 14 (n = 5) and 16 +/- 5 (n = 5) nmol/g, respectively, in the thoracic zona intermedia in the 12-h-old (ND 0.5) rat. This metabolic capability is already highly developed as early as FD 16, peaks during the first half of neonatal life (ND 4 for DOPAC, and ND 15 for HVA), and is considerably reduced toward the end of neonatal life (approximately ND 28) and in the young adult. Control experiments suggest that a substantial part of this synthesis (from L-DOPA) and metabolism of DA occurs in elements other than the descending monoaminergic nerve fibers. By comparison, the synthesis and metabolism of NE develop more slowly, peak in the latter half of neonatal life, and then decline to the level found in the young adult.(ABSTRACT TRUNCATED AT 250 WORDS)     

A method for very rapid determinations of catechols using ion-pairing reverse phase HPLC with electrochemical detection: effects of L-dopa treatment on the catechol content in various rat brain structures

A simple and rapid method for determination of 12 catechols (9 endogenous and 3 internal standards, i.s.) using ion-pairing reverse phase HPLC with electrochemical detection is presented. This study basically concentrates on the importance of optimizing the mobile phase composition in isocratic systems where ordinary 25 cm X 4.6 mm i.d. columns are used. Mobile phase compositions for three different purposes are reported: 1) separation of 9 endogenous catechols, possibly occurring in the samples, and 3 i.s. in a moderately short retention time (tR) (L-DOPA, DOPEG, alpha-Methyldopa (alpha-MeDOPA, i.s.), Noradrenaline (NA), DOPAC, Adrenaline (A), Dihydroxybensylamine (DHBA, i.s.), Norsalsolinol (NS), Dopamine (DA), Epinine (EPI), Salsolinol (S) and Isoprenaline (ISO, i.s.) within 11 min), 2) ultra rapid separation of detectable endogenous catechols except L-DOPA (NA, DOPAC, A, DHBA (i.s.), NS and DA within 5.2 min and with S within 5.7 min) and 3) moderately fast separation of detectable endogenous catechols (L-DOPA, NA, A, DHBA (i.s.), NS, DOPAC and DA within 7.6 min and with S within 10 min). By balancing the pH, concentration of organic modifier (2-propanol) and pairing ion (1-heptanesulphonic acid) as well as preconditioning new columns with more packing material (Nucleosil 5 micron C18) and to high pressures (5000 psi) for 7 days, very fast separations with good baseline resolution between the peaks are possible. The method was applied on L-DOPA treated rats (100 mg/kg), where the catechol content was analysed in 7 different brain structures during the time course of synthesis and degradation (4 hours) of catechols from L-DOPA.     

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)     

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

(1) The treatment of choice for Parkinson’s disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.     

左旋千金藤啶碱对不同脑区DA更新率的影响

应用ＨＰＬＣ－ＥＣＤ测定ＤＡ更新率（ＤＯＰＡＣ／ＤＡ）,证明（－）ＳＰＤ对黑质－纹状体、中脑－边缘系统、下丘脑－垂体ＤＡ神经系统的ＤＡ含量影响不明显,却显著增加ＤＯＰＡＣ含量,并显著加强这些脑区的ＤＡ更新率,这可能是通过末梢的ＤＡ自身受体实现的。但（－）ＳＰＤ既不显著影响中脑－前额叶和中脑－扣带回的ＤＡ含量,也不影响其中ＤＯＰＡＣ含量,表明它不影响这些脑区ＤＡ更新率。这可能是由于皮层ＤＡ系统神经末     

Role of high-affinity dopamine uptake and impulse activity in the appearance of extracellular dopamine in striatum after administration of exogenous L-DOPA: studies in intact and 6-hydroxydopamine-treated rats

The differential behavioral and neurochemical effects of exogenous L-DOPA in animals with intact versus dopamine (DA)-denervated striata raise questions regarding the role of DA terminals in the regulation of dopaminergic neurotransmission after administration of exogenous L-DOPA. In vivo microdialysis was used to monitor the effect of exogenous L-DOPA on extracellular DA in intact and DA-denervated striata of awake rats. In intact striatum, a small increase in extracellular DA was observed after administration of L-DOPA (50 mg/kg i.p.) but in DA-denervated striatum a much larger increase in extracellular DA was elicited. Additional experiments assessed the role of high-affinity DA uptake and impulse-dependent neurotransmitter release in the effect of exogenous L-DOPA on extracellular DA in striatum. Pretreatment with GBR-12909 (20 mg/kg i.p.), a selective DA uptake inhibitor, enhanced the ability of L-DOPA to increase extracellular DA in intact striatum. However, in DA-denervated striatum, inhibition of DA uptake did not alter the extracellular DA response to L-DOPA. Impulse-dependent neurotransmitter release was blocked by the infusion of tetrodotoxin (TTX; 1 microM), an inhibitor of fast sodium channels, through the dialysis probe. Application of TTX significantly attenuated the L-DOPA-induced increase in extracellular DA observed in striatum of intact rats pretreated with GBR-12909. In a similar manner, TTX infusion significantly attenuated the increase in extracellular DA typically observed in striatum of 6-OHDA-lesioned rats after the administration of L-DOPA. The present results indicate that DA terminals, via high-affinity uptake, play a crucial role in the clearance of extracellular DA formed from exogenous L-DOPA in intact striatum. This regulatory mechanism is absent in the DA-denervated striatum. In addition, this study has shown that DA synthesized from exogenous L-DOPA primarily is released by an impulse-dependent mechanism in both intact and DA-denervated striatum. The latter result suggests an important role for a nondopaminergic neuronal element in striatum that serves as the primary source of extracellular DA formed from exogenous L-DOPA.     

Amphetamine-Induced Dopamine Release in the Rat Striatum: An In Vivo Microdialysis Study

The effects of a number of biochemical and pharmacological manipulations on amphetamine (AMPH)-induced alterations in dopamine (DA) release and metabolism were examined in the rat striatum using the in vivo brain microdialysis method. Basal striatal dialysate concentrations were: DA, 7 nM; dihydroxyphenylacetic acid (DOPAC), 850 nM; homovanillic acid (HVA), 500 nM; 5-hydroxyindoleacetic acid (5-HIAA), 300 nM; and 3-methoxytyramine (3-MT), 3 nM. Intraperitoneal injection of AMPH (4 mg/kg) induced a substantial increase in DA efflux, which attained its maximum response 20-40 min after drug injection. On the other hand, DOPAC and HVA efflux declined following AMPH. The DA response, but not those of DOPAC and HVA, was dose dependent within the range of AMPH tested (2-16 mg/kg). High doses of AMPH (greater than 8 mg/kg) also decreased 5-HIAA and increased 3-MT efflux. Depletion of vesicular stores of DA using reserpine did not affect significantly AMPH-induced dopamine efflux. In contrast, prior inhibition of catecholamine synthesis, using alpha-methyl-p-tyrosine, proved to be an effective inhibitor of AMPH-evoked DA release (less than 35% of control). Moreover, the DA releasing action of AMPH was facilitated in pargyline-pretreated animals (220% of control). These data suggest that AMPH releases preferentially a newly synthesised pool of DA. Nomifensine, a DA uptake inhibitor, was an effective inhibitor of AMPH-induced DA efflux (18% of control). On the other hand, this action of AMPH was facilitated by veratrine and ouabain (200-210% of control). These results suggest that the membrane DA carrier may be involved in the actions of AMPH on DA efflux.     

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.     

Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study

We have studied striatal dopamine (DA) metabolism in monoamine oxidase (MAO) B-deficient mice using brain microdialysis. Baseline DA levels were similar in wild-type and knock-out (KO) mice. Administration of a selective MAO A inhibitor, clorgyline (2 mg/kg), increased DA levels and decreased levels of its metabolites in all mice, but a selective MAO B inhibitor, l-deprenyl (1 mg/ kg), had no effect. Administration of 10 and 50 mg/kg L-DOPA, the precursor of DA, increased the levels of DA similarly in wild-type and KO mice. The highest dose of L-DOPA (100 mg/kg) produced a larger increase in DA in KO than wild-type mice. This difference was abolished by pretreating wild-type mice with l-deprenyl. These results suggest that in mice, DA is only metabolized by MAO A under basal conditions and by both MAO A and B at high concentrations. This is in contrast to the rat, where DA is always metabolized by MAO A regardless of concentration.     

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.     

The influence of substance P central administration on ethanol intake in rats chronically exposed to alcohol

The influence of central substance P (SP) administration on alcohol intake and brain dopamine metabolism within mesocortico-limbic and nigrostiatal systems of rats exposed to ethanol, was studied. During 6 months, the rats consumed 15% ethanol solution instead of water. Central administration of SP (3 mcg/kg) decreased alcohol consumption by 41% in alcohol-preference animals. After long-term ethanol exposure ratios DOPAC/DA and HVA/DA were reduced in striatum and accumbens. SP in dose 3 mcg/kg increased content of DOPAC by 17% and HVA by 23% as well as DOPAC/DA by 9%, HVA/DA by 19% in accumbens. Whereas in striatum only increased DOPAC (28%) and HVA (29%) were observed as compared with saline-treated rats.     

Effects of naloxone-precipitated withdrawal after a single dose of morphine on catecholamine concentrations in guinea-pig brain

The effect of naloxone-precipitated withdrawal after acute morphine was studied on the concentrations of noradrenaline (NA), 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and on the metabolite/parent amine ratios MHPG/NA, DOPAC/DA and HVA/DA, in eight regions of the guineapig brain. Guinea-pigs were treated with a single dose of morphine sulphate (15 mg/kg s.c.) or saline (control) and 2h later with naloxone hydrochloride (15 mg/kg s.c.) to precipitate withdrawal. The animals were decapitated at 0.5 h or 1 h after naloxone injections and their brains analysed for monoamine concentrations by HPLC-ECD. At 0.5 h after naloxone-precipitated withdrawal NA and MHPG levels, and the MHPG/NA ratio, were increased in the hypothalamus, and the NA levels were increased in the hypothalamus, medulla/pons and cortex 1 h after naloxone. Naloxoneprecipitated withdrawal also produced increased DA metabolism in the cortex, midbrain and medulla 0.5 h later, and in the cortex, hypothalamus and striatum 1 h later. Hence naloxone-precipitated withdrawal from acute morphine treatment produced a complex pattern of increased synthesis and metabolism of NA and DA which varied over time and with the brain region examined.     

Sodium selenite stimulates neurobehavior and neurochemical activities in rats

The effect of 0.05, 0.1, and 0.2 mg sodium selenite/kg body weight ip on the activities of neurobehavioral, acetyl cholinesterase, monoamine oxidase, and the content of dopamine and its metabolites in circadian rhythm centers of male Wistar rats was studied after 7 d of treatment. The results show an appreciable increase in locomotion, stereo-events, distance traveled, and average speed at the dose of 0.1 and 0.2 mg sodium selenite/kg. The data have shown hyperactivity of animals with various doses of sodium selenite, and it was significant and dose-dependent after 3 d of treatment. The activity of acetylcholinesterase (AChE) was inhibited dose dependently, and it was significant in preoptic area with 0.1 or 0.2 mg sodium selenite/kg. Conversely, in the posterior hypothalamus its activity was significantly elevated with the dose of 0.2 mg sodium selenite/kg, but its alteration in brain stem was not significant. Monoamine oxidase (MAO) activity was increased in preoptic area with the dose of 0.1 mg sodium selenite/kg, but its alteration in posterior hypothalamus and brain stem was not significant. The content of dopamine (DA), 3,4-dihydroxyphenyl acetic acid (DOPAC), and homovanilic acid (HVA) was elevated dose dependently and it was significant with the doss of 0.1 and 0.2 mg sodium selenite/kg, but the content of DOPAC and HVA in posterior hypothalamus was not significant with the dose of 0.1 mg sodium selenite/kg.     

Dopaminergic denervation enhances susceptibility to hydroxyl radicals in rat neostriatum

To determine if greater amounts of hydroxyl radical (*OH) are formed by dopamine (DA) denervation and treatment with L-dihydroxyphenylalanine (L-DOPA), the neostriatum was DA denervated (99% reduction in DA content) by 6-hydroxydopamine treatment (134microg icv, desipramine pretreatment) of neonatal rats. At 10 weeks the peripherally restricted dopa decarboxylase inhibitor carbidopa (12.5mg/kg i.p.) was administered 30min before vehicle, L-DOPA (60mg/kg i.p.), or the known generator of reactive oxygen species, 6-hydroxydopa (6-OHDOPA) (60mg/kg i.p.); and this was followed 30min later (and 15 min before termination) by the spin trap, salicylic acid (8micromoles icv). By means of a high performance liquid chromatographic method with electrochemical detection, we found a 4-fold increase in the non-enzymatically formed spin trap product, 2,3-dihydroxybenzoic acid (2,3-DHBA), with neither L-DOPA nor 6-OHDOPA having an effect on 2,3-DHBA content of the neostriatum. Basal content of 2,5-DHBA, the enzymatically formed spin trap product, was 4-fold higher vs. 2,3-DHBA in the neostriatum of untreated rats, while L-DOPA and 6-OHDOPA each reduced formation of 2,5-DHBA. We conclude that DA innervation normally suppresses *OH formation, and that the antiparkinsonian drug L-DOPA has no effect (2,3-DHBA) or slightly reduces (2,5-DHBA) *OH formation in the neostriatum, probably by virtue of its bathing the system of newly formed *OH.