Extracellular Levels Of Homovanillic Acid Research Articles

TheGinkgo bilobaextract EGb 761®and its main constituent flavonoids and ginkgolides increase extracellular dopamine levels in the rat prefrontal cortex

Experimental and clinical data suggest that extracts of Ginkgo biloba improve cognitive function. However, the neurochemical correlates of these effects are not yet fully clarified. The purpose of this study was to examine the effects of acute and repeated oral administration of the standardized extract EGb 761((R)) on extracellular levels of dopamine, noradrenaline and serotonin (5-HT), and the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex (PFC) and striatum of conscious rats. Monoamines and their metabolites were monitored by the use of microdialysis sampling and HPLC with electrochemical or fluorescence detection. A single oral dose of EGb 761 (100 mg.kg(-1)) had no effect on monoamine levels. However, following chronic (100 mg.kg(-1)/14 days/once daily) treatment, the same dose significantly increased extracellular dopamine and noradrenaline levels, while 5-HT levels were unaffected. Chronic treatment with EGb 761 showed dose-dependent increases in frontocortical dopamine levels and, to a lesser extent, in the striatum. The extracellular levels of HVA and DOPAC were not affected by either acute or repeated doses. Treatment with the main constituents of EGb 761 revealed that the increase in dopamine levels was mostly caused by the flavonol glycosides and ginkgolide fractions, whereas bilobalide treatment was without effect. The present results demonstrate that chronic but not acute treatment with EGb 761 increased dopaminergic transmission in the PFC. This finding may be one of the mechanisms underlying the reported effects of G. biloba in improving cognitive function.

Monoaminergic dysregulation in glutathione-deficient mice: Possible relevance to schizophrenia?

Several lines of research have implicated glutathione (GSH) in schizophrenia. For instance, GSH deficiency has been reported in the prefrontal cortex of schizophrenics in vivo. Further, in rats postnatal GSH-deficiency combined with hyperdopaminergia led to cognitive impairments in the adult. In the present report we studied the effects of 2-day GSH-deficiency with l-buthionine-( S, R)-sulfoximine on monoaminergic function in mice. The effect of GSH-deficiency per se and when combined with the amphetamine and phencyclidine (PCP) models of schizophrenia was investigated. GSH-deficiency significantly altered tissue levels of dopamine (DA), 5-hydroxytryptamine (5-HT) and their respective metabolites homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in a region-specific fashion. The effects of GSH-deficiency on tissue monoamines were distinct from and, generally, did not interact with the effects of amphetamine (5 #x00A0;mg/kg; i.p.) on tissue monoamines. Microdialysis studies showed that extracellular DA-release after amphetamine (5 #x00A0;mg/kg, i.p.) was two-fold increased in the nucleus accumbens of GSH-deficient mice as compared with control mice. Basal DA was unaltered. Further, extracellular levels of HVA in the frontal cortex and hippocampus and 5-HIAA in the nucleus accumbens were elevated by GSH-deficiency per se. Spontaneous locomotor activity in the open field was unchanged in GSH-deficient mice. In contrast, GSH-deficiency modulated the locomotor responses to mid-range doses of amphetamine (1.5 and 5 #x00A0;mg/kg, i.p.). Further, GSH-deficient mice displayed an increased locomotor response to low (2 and 3 #x00A0;mg/kg, i.p.) doses of phencyclidine (PCP). In conclusion, the data presented here show that even short-term GSH-deficiency has consequences for DA and 5-HT function. This was confirmed on both neurochemical and behavioral levels. How GSH and the monoamines interact needs further scrutiny. Moreover, the open field findings suggest reduced or altered N-methyl- d-aspartate (NMDA) receptor function in GSH-deficient mice. Thus, GSH-deficiency can lead to disturbances in DA, 5-HT and NMDA function, a finding that may have relevance for schizophrenia.

Effects of peripheral and central catechol- O-methyltransferase inhibition on striatal extracellular levels of dopamine: a microdialysis study in freely moving rats

Tolcapone is a mixed (peripheral and central) catechol- O-methyltransferase (COMT) inhibitor, whereas entacapone is a preferential peripheral COMT inhibitor. Both drugs are able to decrease the peripheral conversion of l-DOPA into 3- O-methyl-DOPA and thereby increase plasma and cerebral levels of l-DOPA, the precursor of dopamine (DA). Tolcapone may also impair the extraneuronal catabolism of DA by inhibiting COMT activity in the brain. To evaluate the role played by peripheral and central COMT inhibition, we compared the effects of tolcapone and entacapone on COMT activity in peripheral tissues, and on striatal extracellular levels of l-DOPA and DA in rats. Tolcapone and entacapone, at the dose of 15 mg/kg p.o., were almost equally effective in inhibiting COMT activity in duodenum and liver. Tolcapone decreased striatal extracellular levels of homovanillic acid (HVA), thus confirming its central COMT inhibitory effect, whereas entacapone did not alter HVA efflux. Following l-DOPA/benserazide administration (50/15 mg/kg p.o.), both COMT inhibitors significantly increased striatal levels of l-DOPA and DA compared with saline. The levels of l-DOPA were similar after treatment with either COMT inhibitors, whereas the increase in DA output was significantly greater in rats given tolcapone compared to those given entacapone. We conclude that the blockade of central DA catabolism by tolcapone contributes to the greater increase in striatal DA levels achieved with this drug.

Distinct activation of monoaminergic pathways in chick brain in relation to auditory imprinting and stressful situations: a microdialysis study

In the forebrain of the domestic chick (Gallus gallus domesticus), an area termed the mediorostral neostriatum/hyperstriatum ventrale is strongly involved in emotional learning paradigms such as acoustic filial imprinting. Furthermore, the involvement of the mediorostral neostriatum/hyperstriatum ventrale in stressful situations, such as social separation, has been demonstrated in 2-deoxyglucose studies. The aim of the present study was to examine whether quantitative changes of dopamine, serotonin and their metabolites occur during auditory filial imprinting and during social separation. Using in vivo microdialysis in tone-imprinted and in naive, control chicks, we compared the extracellular levels of homovanillic acid, a metabolite of dopamine, and 5-hydroxyindoleacetic acid, a metabolite of serotonin, during the presentation of the imprinting tone. A small, but statistically significant, decrease of extracellular homovanillic acid levels was found in the mediorostral neostriatum/hyperstriatum ventrale of imprinted chicks compared to control animals, whereas changes of 5-hydroxyindoleacetic acid were not detected. In a second experiment, we investigated the levels of homovanillic acid and 5-hydroxyindoleacetic acid in the mediorostral neostriatum/hyperstriatum ventrale of socially reared chicks during different stress situations, such as handling or separation from their cage mates. Handling induced a significant increase of homovanillic acid and 5-hydroxyindoleacetic acid, while social separation resulted in a significant increase of 5-hydroxyindoleacetic acid and only a slight increase of homovanillic acid. Despite considerable inter-individual variability, the increase of distress vocalizations (duration of distress calls) after social separation displayed a good correlation to the increased 5-hydroxyindoleacetic acid levels in all animals analysed.These results provide the first evidence that the physiological response of the mediorostral neostriatum/hyperstriatum ventrale related to different emotional conditions after acoustic imprinting and during stressful situations is, at least in part, mediated by dopaminergic and/or serotonergic pathways. Furthermore, the results from the present study indicate a distinct activation of dopaminergic and serotonergic pathways in relation to the behavioural situation and the associated changes of emotional status.

Effect of chloral hydrate on in vivo KCl-induced striatal dopamine release in the rat.

The release of striatal dopamine (DA) and its metabolites in response to locally-induced K+ depolarization was investigated in vivo in chloral hydrate-anesthetized and freely moving rats. KCl at concentrations of 30, 50, and 100 mM induced significant dose-dependent increases in extracellular DA overflow in both chloral hydrate-anesthetized and freely moving rats (P < 0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were decreased. The DA overflow in response to 30 mM KCl stimulation in anesthetized rats was significantly greater than that in freely moving rats (P < 0.05). In addition, chloral hydrate anesthesia resulted in a significant decrease in extracellular levels of DOPAC and significant increases in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P < 0.05). Furthermore, the basal level of extracellular HVA in chloral hydrate-anesthetized rats was significantly higher than that in freely moving rats. These results suggest that chloral hydrate anesthesia could have significant effects on the pharmacological response of the striatal dopaminergic neurons.

Effects of tolcapone, a novel catechol- O-methyltransferase inhibitor, on striatal metabolism of L-DOPA and dopamine in rats

In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol- O-methyltransferase on striatal 3,4-dihydroxyphenyl- l-alanine (L-DOPA) and dopamine metabolism. The oral administration of 30 mg/kg of tolcapone failed to change dopamine output but elicited a marked and long-lasting decrease of the extracellular levels of homovanillic acid (HVA) and 3-methoxytyramine with a concomitant increase of 3,4-dihydroxyphenylacetic acid (DOPAC). The administration of L-DOPA (20 and 60 mg/kg p.o.) + benserazide (15 mg/kg p.o.) resulted in a dose-dependent increase of dialysate levels of L-DOPA and 3- O-methyl-DOPA. Tolcapone (30 mg/kg p.o.), given as adjunct to both doses of L-DOPA, markedly enhanced the elevation or extracellular L-DOPA, while it completely prevented the formation of 3- O-methyl-DOPA. In another experiment, the administration of L-DOPA + benserazide (30 + 15 mg/kg p.o.) resulted in increased extracellular levels of dopamine, DOPAC, HVA and 3-methoxytyramine. The co-administration of tolcapone (30 mg/kg p.o.) further increased dopamine and DOPAC levels, whereas HVA and 3-methoxytyramine effluxes were reduced. These findings support the notion that tolcapone has the ability to enhance striatal dopamine neurotransmission by increasing L-DOPA bioavailability through peripheral and central inhibition of L-DOPA O-methylation, as well as by blocking the central conversion of dopamine into 3-methoxytyramine.

Behavioral and neurochemical effects of continuous infusion of cocaine in rats

The ability of continuous intravenous infusion of cocaine (60 mg/kg per day for 11 or 12 days; by osmotic minipump) to alter responses to acute injection of cocaine (20 mg/kg, i.p.; given 24 hr after termination of the infusion by minipump) was tested in conscious, tethered Sprague-Dawley rats. Extracellular levels of cocaine, dopamine and metabolites of dopamine in the striatum were determined by in vivo microdialysis. Locomotor activity and stereotyped behavior were evaluated simultaneously during dialysis sampling. Prior infusion of cocaine blunted the ability of acute challenge with cocaine to increase the efflux of dopamine in the striatum, locomotor activity and stereotypy. Increases in extracellular levels of homovanillic acid in the striatum were significantly greater in cocaine-infused rats than vehicle-infused controls, both prior to and after acute injections of cocaine. However, no differences between these two groups were observed in levels of cocaine in the striatum after acute challenge. Extracellular levels of dopamine in the striatum correlated significantly ( P < 0.05) with stereotypy in both groups but with locomotor activity only in cocaine-infused rats. The results indicate that behavioral tolerance occurred after continuous intravenous infusions of cocaine, that this was correlated with neurochemical tolerance to acute cocaine challenge and that alterations in the metabolism of cocaine did not account for the observed behavioral responses.

Lever pressing for food reward and in vivo voltammetry: Evidence for increases in extracellular homovanillic acid, the dopamine metabolite, and uric acid in the rat caudate nucleus

Linear sweep voltammetry at chronically implanted carbon paste electrodes was used to study extracellular levels of homovanillic acid, a metabolite of dopamine, in the caudate nucleus of freely moving rats. Local infusion of homovanillic acid close to the electrode confirmed that peak 3, at about 550 mV, could be used for this purpose. Thirty minutes of lever pressing for food reward was followed by an increase in homovanillic acid, maximal about 30 min later (+ 42%). An earlier and larger (+ 51 %) increase in peak 2 (350–400 mV) was seen, highly correlated ( r = 0.98) with the rate of lever pressing across individuals. A smaller decrease (−23%) in peak 1 (200 mV; ascorbic acid) was seen 75 min after the behavioural session. Administration of allopurinol, an inhibitor of uric acid production, selectively abolished peak 2. Allopurinol prior to lever pressing reduced the increase in peak 2 very substantially (by 77%), confirming that this too was mainly due to uric acid. These results indicate that linear sweep voltammetry can be used to study the time course of changes in dopamine metabolism, and in other neurochemicals, in individual freely moving rats in relation to behaviour under experimental control. More specifically, they demonstrate directly that rewarded lever pressing increases dopamine metabolism in the caudate, which had previously only been inferred from indirect approaches. The level of uric acid is also increased, and it is suggested that this may serve as an index of metabolic activity.

Increased dopamine release from striata of rats after unilateral nigrostriatal bundle damage

Dopaminergic control of striatal neurons is retained in rats sustaining lesions of the nigrostriatal bundle (NSB) as long as 10% of the projection remains, suggesting that enhanced efficiency of dopamine (DA) transmission may compensate for the denervation of the striatum. To examine this hypothesis we have studied the extracellular concentration of striatal DA using brain dialysis. In control rats, haloperidol (1 mg/kg, i.p.) or depolarization of striatal tissue with 25 mM KCl increased, and γ-butyrolactone (500 mg/kg, i.p.) decreased DA and homovanillic acid (HVA) levels in striatal dialysates. Three weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) to substantia nigra, DA content in the ipsilateral was decreased by 60–98%. Nevertheless, extracellular DA concentration in the lesioned striata remained unchanged in rats with 60–90% DA depletions. More extensive lesions (96% DA depletion) were accompanied by 60% reduction in DA release. In contrast, extracellular HVA levels in the lesioned striata decreased proportionally to the depletion of tissue DA, indicating decreased inactivation of extracellular DA. We propose that the capacity of the residual DA terminals to maintain normal levels of extracellular DA after 60–90% NSB lesions may serve to compensate for the partial denervation of the striatal tissue. Disruption of striatal DA functions and postsynaptic supersensitivity after more extensive lesions may be associated with the failure of the NSB to fully compensate for loss of DA terminals. In striata contralateral to the 6-OHDA lesion, increased DA release was also observed. In addition, 60–90% ipsilateral DA depletions were accompanied by 32% and 42% increases in DA and HVA content in contralateral tissue, respectively. The possibility of the contralateral sprouting of DA terminals is discussed.