Striatal Homovanillic Acid Levels Research Articles

Dynamic of neurochemical alterations in striatum, hippocampus and cortex after the 6-OHDA mesostriatal lesion

Immediate neurochemical alterations produced by 6-OHDA could explain the general toxic pattern in the central nervous system. However, no evidences describe the effects of 6-OHDA on early changes of neurotransmitters in rats’ striatum, cortex and hippocampus. In our study, unilateral 6-OHDA injection into medial forebrain bundle (MFB) was used in rats, then five neurotransmitters were analyzed at 3, 6, 12, 24, 48 and 72h, respectively. Results showed that 6-OHDA injection caused a sharp decline of striatal dopamine (DA) levels in the first 12h followed by a further reduction between 12 and 48h. However, striatal levels of homovanillic acid (HVA) were stable in the first 12h and showed a marked reduction between 12 and 24h. Striatal levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased linearly for 72h, whereas levels of norepinephrine (NE) showed a slight reduction in the first 48h, and returned back to normal afterwards. Striatal HVA/DA ratio increased significantly in the first 12h, but 5-HIAA/5-HT ratio showed a sharp increase between 12 and 72h. Besides, neurochemical alterations were also found in hippocampus and cortex, and the correlations of neurotransmitters were analyzed. Our study indicated that NE system had little influence in the early phase of 6-OHDA injection, moreover, early neurochemical alterations were involved with striatum, hippocampus and cortex.

L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice.

The intraperitoneal administration of L-dopa and a series of ester prodrugs of L-dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with L-dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following L-dopa administration. Overall the m-trifluoromethylbenzyl, phenylethyl, p-chlorophenylethyl and p-methoxyphenylethyl ester prodrugs produced greater elevations of striatal and tuberculum olfactorium HVA, but not DOPAC, compared with L-dopa. The administration of the 2-tetrahydropyranyl-methyl derivative only enhanced striatal HVA and striatal and tuberculum olfactorium DOPAC concentrations. Changes of HVA and DOPAC tissue concentrations following administration of the 2-hydroxypropyl, n-propyl, methyl, ethyl and 2-(1-methoxy)propyl ester prodrugs were comparable with those produced by the administration of L-dopa itself. The alterations in striatal and tuberculum olfactorium HVA and DOPAC levels observed did not correlate with the ability of these compounds to elicit locomotor activity in reserpinized mice.

Biphasic effects of neonatal allopregnanolone on striatal dopamine metabolism

Neurosteroids are known to modulate the development of the mesocorticolimbic system. We examined the effects of low (1 mg/kg) and high (10 mg/kg) doses of allopregnanolone on monoamine metabolism during the neonatal period (postnatal days 3-7) in rats. At 10 weeks of age, increases in homovanillic acid/dopamine (DA) ratios were found in the striatum in both allopregnanolone-treated groups compared with control rats. However, striatal DA levels decreased only in the low-allopregnanolone group and striatal homovanillic acid levels increased only in the high-allopregnanolone group. Allopregnanolone did not significantly affect cortical DA metabolism, or cortical or striatal serotonin metabolism. Data indicate that neonatal allopregnanolone treatment has a biphasic effect on striatal DA metabolism.

Effect of high-fat intake on motor activity, homovanillic acid and 5-hydroxyindoleacetic acid levels in striatum and cortex of rats exposed to stress

The aim of the present study was to investigate whether high fat consumption changes the effects of stress on both motor activity performance, striatal and cortical dopamine and serotonin metabolites in rats. The animals were fed either with high fat or standard diet for 4 weeks. Restraint stress lasting for 15 min at +4°C was applied daily to stress-exposed groups. Motor activity performance was measured weekly by using motor activity monitoring systems. At the end of the study, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels of the striatum and cerebral cortex were measured by HPLCEC. It was observed that restraint stress increased locomotor activity and high-fat diet prevented this effect. Stress and high-fat intake had an additive decreasing effect on striatal HVA levels. 5-HIAA levels, on the other hand, were lower in both high fat and high fat + stress groups compared to the stress group. These results suggest that high-fat intake differentially affected the stress response on striatal dopaminergic and serotonergic neurons in rat brain regions studied and this may be related to the effects observed in motor activity performance.

Echinacoside prevents the striatal extracellular levels of monoamine neurotransmitters from diminution in 6-hydroxydopamine lesion rats

We investigated the effects of echinacoside, a phenylethanoid glycoside isolated and purified from the stems of Cistanche salsa, a Chinese herbal medicine, on the striatal extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in 6-hydroxydopamine (6-OHDA) lesion rats. Seven days after 6-OHDA was injected into the right striatum of rats, the striatal extracellular levels of DA, DOPAC and HVA fell significantly ( P < 0.01 vs. vehicle), as demonstrated by the method of cerebral microdialysis and high performance liquid chromatography with electrochemical detection. However, simultaneous treatment with echinacoside (7.0, 3.5 mg/kg) attenuated the diminution of them ( P < 0.01 vs. model). The results implied that echinacoside could protect the striatal dopaminergic neurons from injury induced by 6-OHDA and may be useful in the prevention and treatment of Parkinson's disease (PD).

Effects of Manganese on Extracellular Levels of Dopamine in Rat Striatum: An Analysis In vivo by Brain Microdialysis

The aim of this study is to determine the effects of intrastriatal administration of MnCl2, on the extracellular levels of dopamine (DA) and metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in basal conditions and stimulated by depolarization with KCl and pargyline administration. Also, we studied the effect of MnCl2 on extracellular levels of l-Dopa in the presence of aromatic amino acid decarboxylase (AADC) inhibitor 3-hydroxybencilhydracine-HCl (NSD 1015). This study concluded that MnCl2, reduced the basal and K+-stimulated DA-release in striatum, without notably affecting the DOPAC and HVA levels. Intraperitoneal injection of pargyline increased striatal DA levels, decreasing DOPAC and HVA levels. The infusion of MnCl2 removed the increase in DA levels, without affecting DOPAC and HVA levels. Perfusion of NSD 1015 increased the extracellular levels of L-DOPA in striatum, and MnCl2 increased the effect of NSD1015 on L-Dopa.

Pineal melatonin and brain transmitter monoamines in CBA mice during chronic oral nicotine administration

The effects of chronic oral nicotine administration on the pineal melatonin and brain transmitter monoamines were studied in male CBA mice, which possess a clear daily rhythm of melatonin secretion. On the 50th day of nicotine administration, pineal melatonin as well as cerebral dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined at various times. The chronic nicotine treatment did not alter the timing of the pineal melatonin peak, which occurred at 10 h after the light offset. However, in mice drinking nicotine solution, the nocturnal pineal melatonin levels were lower than in control mice drinking tap water. The chronic nicotine treatment increased the striatal DA, DOPAC, HVA and 5-HIAA levels, the hypothalamic NE, MHPG and 5-HIAA and the cortical MHPG. Most prominent effects of nicotine were found at 8 h after the light offset, when the striatal levels of DA and HVA, hypothalamic NE and MHPG as well as cortical MHPG were significantly elevated in the nicotine-treated mice compared with the control mice. No direct correlation between nicotine’s effects on brain transmitter monoamines and on pineal melatonin levels was apparent. The results suggest that chronic nicotine treatment slightly suppresses the melatonin production but does not alter the daily rhythm of pineal melatonin in mice maintained on a light–dark cycle. However, the results indicate that nicotinic receptors might be involved in the regulation of pineal function.

Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice.

Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.

Differences in pre- and post-synaptic sensitivity to apomorphine between saline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mice as reflected in climbing activity

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of l-DOPA-treated monkeys

The effects of monoamine oxidase (MAO) inhibitors on the metabolism of dopamine synthesized from exogenous l-DOPA were investigated in the striatum and substantia nigra of squirrel monkeys. Administration of a single dose of l-DOPA (methyl ester, 40 mg/kg, i.p.) caused a significant increase in the levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and in the DOPAC/dopamine ratio in the putamen, caudate and substantia nigra. These changes were more pronounced in the substantia nigra than in the striatum and within the striatum of l-DOPA-treated monkeys, levels of dopamine and its metabolites were higher in the putamen than in the caudate nucleus. When l-DOPA treatment was preceded by the injection of clorgyline or deprenyl at a concentration (1 mg/kg) which selectively inhibited MAO A or MAO B, respectively, striatal dopamine was increased while the striatal DOPAC and HVA levels and DOPAC/dopamine ratio were significantly reduced as compared to the values obtained with l-DOPA alone. The two MAO inhibitors also counteracted the increase in the DOPAC and HVA levels and DOPAC/dopamine ratio induced by l-DOPA in the substantia nigra. Thus, both MAO A and MAO B contribute to the metabolism of dopamine when higher levels of this neurotransmitter are generated from l-DOPA in the squirrel monkey. The extent of reduction of dopamine catabolism (as assessed by the decrease in DOPAC and HVA levels) in the striatum and substantia nigra was similar with clorgyline and deprenyl even if the ratio MAO A/MAO B was approximately 1 to 10. This indicates that, though catalyzed by both MAO A and MAO B, dopamine deamination following treatment with l-DOPA preferentially involves MAO A.

Effects of an acute dose of ethanol on dopaminergic and serotonergic systems from rat cerebral cortex and striatum

Intraperitoneal injection 10 min before sacrifice of 1.5 g ethanol/kg weight produced an increase in rat striatal levels of homovanillic acid (HVA) (p < 0.05) but did not affect the striatal concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). A similar ethanol treatment led to decreases in 5-HT (p < 0.05) and 5-HIAA (p < 0.05) from cerebral cortex (prefrontal and anterior cingulate areas). The results point to several ethanol-linked alterations in central serotonergic and dopaminergic systems.

Unilateral neonatal intracerebroventricular 6-hydroxydopamine administration in rats: II. Effects on extracellular monoamine, acetylcholine and adenosine levels monitored with in vivo microdialysis.

6-hydroxydopamine (6-OHDA, 100 micrograms in 5 microliters) was injected into the right ventricle of 3-day-old Sprague-Dawley rats in order to produce a unilateral dopamine (DA) lesion. At adult stage, the rats were implanted with microdialysis probes into the left and right striata. On the injected side, basal extracellular levels of DA were reduced by > 65%, as compared to the contralateral side or to the levels found in vehicle-injected rats. Extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced by > 95%, while acetylcholine (ACh) was decreased by > 50%. d-Amphetamine (2 mg/kg SC) produced a 10-fold increase in extracellular DA levels in the striatum contralateral to the 6-OHDA-injected side, while on the ipsilateral side. DA levels were not affected by d-amphetamine. d-Amphetamine produced an increase (> 2 fold) in extracellular ACh levels, on both ipsilateral and contralateral sides. Choline and adenosine levels were unaffected by any of the experimental conditions. Thus, neonatal unilateral ICV administration of 6-OHDA produced an ipsilateral decrease in striatal extracellular DA, DOPAC and HVA levels, compared to the contralateral side. A reduction of extracellular ACh levels was also observed on the 6-OHDA-injected side. The DA releasing effect of d-amphetamine was abolished on the 6-OHDA-injected side, but not that on ACh levels, indicating that striatal DA and ACh d-amphetamine-induced release are produced by independent mechanisms in the neonatally unilateral 6-OHDA-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions.

Brain-derived neurotrophic factor (BDNF) promotes the survival of dopamine (DA) neurons, enhances expression of DA neuron characteristics, and protects these cells from 6-hydroxydopamine (6-OHDA) toxicity in vitro. We tested the ability of BDNF or neurotrophin-3 (NT-3) to exert similar protective effects in vivo during chronic delivery of 6-OHDA to the rat neostriatum. Chronic infusions of BDNF or NT-3 (12 micrograms/day) above the substantia nigra were started 6 days before and continued during an 8-day chronic intrastrial infusion of 6-OHDA. In control and neurotrophin-treated animals, 6-OHDA treatment selectively depleted 50-60% of nigrostriatal DA nerve terminals but produced little if any loss of pars compacta DA cell bodies. This partial DA lesion resulted in three rotations per minute toward the lesioned hemisphere after treatment with the DA release-inducing drug d-amphetamine. Compared with supranigral infusions of vehicle, BDNF and NT-3 decreased the number of these ipsiversive rotations by 70 and 48% and increased by 20- and 10-fold, respectively, the number of contraversive rotations observed after amphetamine injection. When challenged with the DA receptor agonist apomorphine, BDNF- and NT-3-treated animals also exhibited a seven- and 3.5-fold increase in the number of contraversive rotations relative to the vehicle group, respectively. Compared with vehicle, BDNF increased striatal levels of homovanillic acid (HVA; 86%), 3,4-dihydroxyphenylacetic acid (DOPAC; 42%), and 5-hydroxyindoleacetic acid (5-HIAA; 32%) and the HVA/DA (43%) and 5-HIAA/serotonin (34%) ratios in the DA-denervated striatum. NT-3 augmented only striatal 5-HIAA levels (24%). Neither factor altered the 6-OHDA-induced decrease in striatal DA levels or high-affinity DA uptake and thus did not protect against the destruction of DA terminals and did not alter striatal D1 or D2 ligand binding. Choline, GABA, and glutamate uptake in the striatum were not altered by the lesion or neurotrophin treatment. Thus, BDNF and to a lesser extent NT-3 reverse rotational behavioral deficits and augment striatal DA and 5-HT metabolism in a partial DA lesion model.

On the origin of striatal cholecystokinin release: studies with in vivo microdialysis.

In the present study, extracellular levels of the neuropeptide cholecystokinin (CCK), of the monoamine dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and of the excitatory amino acids glutamate and aspartate were simultaneously monitored by microdialysis in the neostriatum of halothane-anesthetized rats under basal and K(+)-depolarizing conditions. Extracellular CCK and dopamine levels, but not glutamate and aspartate levels, were decreased by perfusion with a Ca(2+)-free medium, under both basal and K(+)-depolarizing conditions. HPLC revealed that the majority of the CCK-like immunoreactivity in the perfusates coeluted with CCK octapeptide. Striatal extracellular CCK levels were decreased by decortication plus callosotomy, with a parallel decrease in glutamate levels. Striatal extracellular levels of dopamine, DOPAC, and HVA were significantly decreased in animals treated previously with a unilateral 6-hydroxydopamine injection into the medial forebrain bundle. In these animals, however, the effect of decortication plus callosotomy on CCK and glutamate levels was not further augmented. Thus, this study supports the hypothesis of a neuronal origin of extracellular CCK and dopamine monitored with microdialysis in the striatum of the rat, and also supports the idea of a partly contralateral origin of corticostriatal CCK and glutamate inputs.

Effects of amitraz on motor function.

The effects of amitraz, a formamidine derivative, on motor function were studied in rats. Behavioural and neurochemical studies were performed. Results show that amitraz was able: 1) to decrease locomotion and rearing frequencies of rats and to increase their immobility time in an open-field; 2) to displace to the left the control dose-response curve constructed to apomorphine-induced stereotyped behavior; 3) to potentiate both pentobarbital sleeping time and amphetamine effects on open-field behaviour of rats and 4) to increase not only the whole brain levels of noradrenaline but also the striatal levels of dopamine. In relation to control animals, the pesticide also induced 5) a decrease in the striatal levels of homovanillic acid, 6) pesticide effects on open-field behaviour of rats were not antagonized by yohimbine administration, and 7) metoclopramide administration on amitraz pretreated rats antagonized not only amphetamine effects on open-field behaviour, but also apomorphine-induced stereotypy. These results are discussed in the light of the actions of amitraz on biogenic amines. It is suggested that the pesticide effects on motor function are consequences of the inhibitory effects on MAO activity, most probably through the increases produced on catecholamine levels within the central nervous system.

Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase

The extraneuronal and intraneuronal metabolism of rat brain endogenous dopamine was stimulated by amphetamine (5 mg/kg) and pimozide (2 mg/kg), respectively. Additional metabolic effects of two inhibitors of catechol O-methyltransferase (entacapone and tolcapone (both 30 mg/kg)) and a putative central uptake 2 inhibitor (CGP 28014 (30 mg/kg)) were assessed. Amphetamine increased striatal dopamine and 3-methoxytyramine and decreased 3,4-dyhydroxyphenylacetic acid (DOPAC) levels. The latter two effects were reversed by tolcapone and CGP 28014, but not by entacapone. Tolcapone, CGP 28014 and even entacapone decreased striatal homovanillic acid (HVA) levels. Pimozide-induced striatal DOPAC levels were further increased by tolcapone and CGP 28014. Both substances also decreased striatal HVA levels. Striatal 3-methoxytyramine levels were significantly lowered only by tolcapone. Our results show that enhanced central dopamine metabolism is modified by the inhibition of catechol O-methyltransferase even in the absence of L-3,4-dihydroxyphenylalanine (L-DOPA). The results also suggest that the mechanism of action of CGP 28014 may be other than true inhibition of catechol O-methyltransferase.

EFFECTS OF BAY K 8644 AND NIFEDIINE ON LOCOMOTOR ACTIVITY AND STRIATAL HOMOVANILLIA ACID CONCENTRATION IN ACUTELY ETHANOL-TREATED RATS

The possible involvement of voltage sensitive calcium channels (VSCCs) in both locomotor activity and striatal homovanillic acid (HVA) alterations in acutely low (0.5 g/kg) and high (2 g/kg) dose ethanol-treated rats was investigated. Both doses of ethanol produced inhibitory effects on both locomotor activity and striatal HVA levels. Bay K 8644 significantly potentiated and nifedipine reversed the locomotor inhibitory effect of low-dose ethanol, whereas both drugs did not alter locomotor activity and striatal HVA levels, when used alone. On the other hand, both Bay K 8644 and nifedipine significantly reversed the decrease in striatal HVA levels induced by the low and high doses of ethanol.

Avoidance behavior, prolactin, HVA and DOPAC in offspring of bromopride-treated rats

The effects of perinatal treatments with bromopride (BRO), a dopaminergic blocking agent, on serum prolactin (PRL), striatal dihydrixyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels, and active and inhibitory avoidance behavior of both sexes, were examined in adult Wistar rats. Offspring were divided into four groups depending upon the treatment received by the dams: BV-offspring of dams exposed to BRO only during pregnancy; VB-offspring of dams receiving BRO only during lactation; BB-offspring of dms treated with BRO during pregnancy and lactation; and VV-offspring of dams receiving vehicle during both periods. Active avoidance responses were reduced in males of all experimental groups. Other parameters such as inhibitory avoidance, serum PRL levels, and striatal HVA and DOPAC levels were not different from the control group. The results suggest that there is no relationship between HVA and DOPAC striatal levels, serum PRL levels and the behavioral modifications described here.

Intracerebral dialysis monitoring of striatal dopamine release and metabolism in response to L-dopa.

We have used intracerebral dialysis to monitor the striatal extracellular fluid (ECF) in rats with unilateral lesions of the nigrostriatal dopamine (DA) pathway. Dialysis samples were collected before and after L-dihydroxy-phenylalanine (L-DOPA) administration both in the presence and absence of carbidopa, an extracerebral DOPA decarboxylase (DDC) inhibitor. The baseline ECF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were always higher in the intact than in the lesioned striata. In the normal striata, dopamine (DA) concentrations increased following L-DOPA administration. Pretreatment with carbidopa prolonged the duration of the DA increase. In the lesioned striata, DA levels increased following L-DOPA administration only in animals pretreated with carbidopa. Following L-DOPA administration, striatal HVA and DOPAC levels increased considerably more in animals not pretreated with carbidopa than they did in pretreated animals. This increase was particularly marked in the lesioned striata and leads us to conclude that extracerebrally produced HVA and DOPAC can enter the brain extracellular space.

Differential modulation of striatal dopamine release by intranigral injection of γ-aminobutyric acid (GABA), dynorphin A and substance P

The effects of intranigral injection of γ-aminobutyric acid (GABA) (dose range: 10.0–300.0 nmol), dynorphin A (0.005–0.5 nmol) and substance P (0.00007–7.0 nmol) on striatal dopamine (DA) release, and dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) formation were studied by microdialysis. It was found that both GABA and dynorphin A produced a dose-dependent decrease in the release of striatal DA following injection into the ipsilateral substantia nigra, the pars reticulata. In contrast, intranigral injection of substance P produced an increase in DA release. However, the dose-response curve for the substance P effect had a biphasic shape. The maximum effect was produced by 0.007 nmol, whereas higher doses (0.07–0.7 nmol) produced less pronounced effects. At the highest dose (7.0 nmol), substance P produced a strong decrease of DA release. Striatal levels of DOPAC and HVA were enhanced by GABA, dynorphin A and substance P. The present results support the concept that substance P, directly or indirectly, provides a positive feed-back regulation for the release of striatal DA, whereas GABA and dynorphin exert a negative feed-back regulation.