DA), 3,4-dihydroxyphenylacetic Acid Research Articles

Comparison of the effects of the dopamine D 2 agonist quinelorane on tuberoinfundibular dopaminergic neuronal activity in male and female rats

The purpose of the present study was to examine the effects of quinelorane (LY163502), a potent and selective D 2 dopaminergic (DA) receptor agonist, on the activity of tuberoinfundibular DA neurons in male and female rats as estimated by determining the concentration of the primary metabolite of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), in terminals of these neurons in the median eminence (ME). In males, quinelorane produced dose- and time-related increases in the concentration of DOPAC in the ME which was blocked by the D 2 receptor antagonist raclopride. The activity of tuberoinfundibular neurons in female rats is higher than it is in males because circulating levels of prolactin tonically stimulate these neurons in the female. In female rats, quinelorane markedly lowered plasma concentrations of prolactin but failed to alter DOPAC concentrations in the ME. Pretreatment of female rats with prolactin antiserum induced hypoprolactinemia and reduced DOPAC concentrations in the ME; in these animals quinelorane increased ME DOPAC concentrations. These results indicate that by acting on D 2 receptors quinelorane is able to stimulate tuberoinfundibular DA neurons in both male and female rats, but in female rats the ability of quinelorane to reduce circulating levels of prolactin indirectly reduces the activity of tuberoinfundibular DA neurons and thereby masks the stimulatory action of this drug on these neurons.

Interaction with pups enhances dopamine release in the ventral striatum of maternal rats: A microdialysis study

A growing body of evidence suggests that an interference with dopamine (DA) transmission disrupts maternal behavior in the rat. The present brain microdialysis study was therefore conducted to investigate whether infants can modulate ventral striatal DA release in mother rats. There was a significant rise in the extracellular concentrations DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the ventral striatum when mothers were reunited with their litters following separation overnight. Nursing was the predominant behavior during this phase of the experiment. More active behaviors were elicited by soiling pups with flowerpot earth, and this was accompanied by further increases in DA, DOPAC, HVA, and 5-HIAA. It is suggested that pup-induced stimulation of ventral striatal DA release facilitates parental responses such as pup retrieval.

Electrical stimulation of reward sites in the ventral tegmental area increases dopamine transmission in the nucleus accumbens of the rat

Abstract In vivo microdialysis with HPLC-ED was used to measure dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens of the rat, prior, during, and after 15-min periods of electrical brain stimulation at sites in the ventral tegmental area (VTA) that supported intracranial self-stimulation (ICSS). In the first experiment, both ICSS and yoked stimulation of the VTA evoked significant increases in extracellular concentrations of DA, its metabolites, and 5-HIAA. Comparable results from ICSS and yoked groups were interpreted as evidence that the rewarding properties of VTA stimulation were a causal factor in the elevated DA transmission in the nucleus accumbens, rather than intense operant behavior. Further evidence for this hypothesis came from a second set of data in which changes in extracellular DA levels during the measurement of rate/intensity functions for ICSS were positively correlated. 5-HIAA concentrations also increased during ICSS but these changes were not correlated with either ICSS rate or current intensity, suggesting that changes in serotonin metabolism were unlikely to subserve brain stimulation reward in the VTA. These results add to the growing body of evidence linking changes in extracellular DA in the mesolimbic DA system with both brain stimulation reward and the conditioned and unconditioned rewarding effects of biologically relevant stimuli.

Neurochemical correlates of behavioral sensitization following repeated apomorphine treatment: Assessment of the role of D1 dopamine receptor stimulation

Previous research has revealed a role of repeated D1 dopamine receptor stimulation in the development of behavioral sensitization to the D1/D2 agonist apomorphine. The present experiments assessed the role of repeated D1 receptor stimulation in neurochemical changes accompanying locomotor sensitization to apomorphine. To assess direct effects of D1 stimulation on dopamine synthesis, rats were injected with the D1 agonist SKF 38393 (8 mg/kg), followed by an injection with the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitor, NSD-1015. DOPA accumulation, assessed in striatal, nucleus accumbens-olfactory tubercle (NAOT), and ventral mesencephalon (VM) tissue samples, was not affected by acute SKF 38393. In the second experiment, rats were treated with 10 daily injections of vehicle, apomorphine (5 mg/kg) or the D1 agonist SKF 38393 (8 or 16 mg/kg). Daily measures of locomotor activity demonstrated a progressive increase in the apomorphine-treated rats, but not the SKF 38393-treated rats, across the 10 days. On day 11, all rats were injected with NSD-1015 for measurement of DOPA accumulation. Dopamine synthesis was enhanced in the striatum after repeated apomorphine treatment. In contrast, repeated SKF 38393 treatment resulted in either a small decrease or no change in DOPA accumulation in the different brain regions (striatum, NAOT, VM). In the third experiment, tissue levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and [3H]SCH 23390 binding to D1 receptors were measured in rats treated with 10 daily injections of vehicle, apomorphine (5 mg/kg), or SKF 38393 (16 mg/kg). In the striatum and NAOT, none of the repeated drug treatments had an effect on DOPAC or dopamine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age and dopamine agonists and antagonists on striatal dopamine release in the rat: An in vivo microdialysis study

The in vivo microdialysis technique was used to measure the extracellular output of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in adult and aged rats; as well as in response to the perfusion of dopamine agonist and antagonists, high-potassium Ringer solution and 1-methyl-4-phenyl-pyridinium ion (MPP +). The DA basal release before the drug treatment was higher in adult rats compared with the aged animals. The perfusion of dopaminergic drugs (nomifensine, sulpiride and quinpirole) through the probe at 1 μM concentration produced the same effect on DA, DOPAC and HVA outflow in adult and aged rats. 5-HIAA levels were not affected. The application of a high-potassium (60 mM) Ringer solution did not produce any significant difference on DA, DOPAC, HVA and 5-HIAA extracellular content when adult and aged rats were compared. The perfusion of MPP + (1 mM) for 15 min produced a greater increase in DA release in aged than in adult rats. Greater susceptibility in the adult rats could explain these results.

Effects of monoamine oxidase inhibitors on the acid metabolites of some trace amines and of dopamine in the rat striatum

The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1−100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of α-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that its removal via transport or further metabolism regulates its concentration.

Haloperidol and clozapine increase intraneuronal dopamine metabolism, but not γ-butyrolactone-resistant dopamine release

In a previous study, two coexisting mechanisms of dopamine release were identified in dopamine neuron terminals. One can be blocked with γ-butyrolactone, suggesting it is impulse flow-dependent, while the other one cannot and is apparently impulse flow-independent. The goal of this study was to further characterize the γ-butyrolactone-resistant mechanism and its relation to dopamine metabolism. Following acute and chronic haloperidol or clozapine treatment, γ-butyrolactone-resistant mechanism and its relation to dopamine neuronal impulse flow. In all groups, 3-methoxytyramine levels after monoamine oxidase inhibition with pargyline (an index of dopamine release) were measured in the frontal cortex, nucleus accumbens and striatum. Regional steady-state levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also measured in the rats treated acutely with neuroleptics. In all three regions, γ-butyrolactone reduced the 3-methoxytyramine levels by over 50% after chronic neuroleptic treatment. This indicates that dopamine release from the terminals is primarily impulse flow-dependent during chronic neuroleptic treatment, both in the dopamine neurons which do undergo depolarization block, and in those that do not. No neuroleptic effect on the γ-butyrolactone-resistant dopamine release was observed, while DOPAC and HVA were markedly elevated by the acute treatment, suggesting a predominant production of these metabolites from unreleased dopamine.

Reduced Turnover of Dopamine and 5‐Hydroxytryptamine in Discrete Dopaminergic, Noradrenergic and Serotonergic Rat Brain Areas after Acutely Administered Medetomidine, a Selective α2‐Adrenoceptor Agonist

Monoamine metabolism and turnover were investigated in discrete dopaminergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective alpha 2-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 micrograms/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). In a separate experiment, the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) was measured after inhibition of L-aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 micrograms/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5-HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective alpha 2-adrenoceptor blocking agent, on the medetomidine-induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5-HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the alpha 2-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1-C1 area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1-C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECTS OF MIDAZOLAM AND FLUNITRAZEPAM ON THE RELEASE OF DOPAMINE FROM RAT STRIATUM MEASURED BY IN VIVO MICRODIALYSIS

We have studied the effects of midazolam and flunitrazepam on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum in freely moving animals using in vivo microdialysis. I.v. injections of midazolam 0.075 and 0.15 mg kg-1 decreased striatal dopamine concentrations in a dose-dependent manner without affecting the concentrations of DOPAC and HVA. Flunitrazepam 0.015 and 0.03 mg kg-1 also decreased striatal dopamine concentrations in a dose-related manner, but the reductions in DOPAC and HVA were not significant. Flumazenil 6 micrograms kg-1 alone did not affect striatal concentrations of dopamine, DOPAC and HVA, but it prevented the effects of midazolam and flunitrazepam. Flunitrazepam 10 mumol litre-1 also decreased striatal dopamine release when infused through a dialysis probe placed into the striatum, but it failed to affect striatal dopamine release when infused into the ipsilateral substantia nigra. Central administrations of midazolam were effective only when the drug was infused into both sites simultaneously (10 and 100 mumol litre-1) or given by intraventricular injection (0.5 and 1 micrograms). These results suggest that midazolam and flunitrazepam affect striatal dopamine release in a different manner.

Effects of catechol-O-methyltransferase inhibitors and L-3,4-dihydroxyphenylalanine with or without carbidopa on extracellular dopamine in rat striatum.

The effects of two new catechol-O-methyltransferase (COMT) inhibitors, OR-611 and Ro 40-7592, in combination with L-3,4-dihydroxyphenylalanine (L-dopa) with or without carbidopa on extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-O-methyldopa (3-OMD), and 5-hydroxyindoleacetic acid in rat striatum were studied. A dose of 10 mg/kg i.p. of Ro 40-7592 alone, in contrast to the same dose of OR-611, decreased the dialysate level of HVA and increased that of DOPAC; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. L-Dopa (50 mg/kg i.p.) alone slightly increased extracellular levels of DA, DOPAC, and HVA. The effects of L-dopa were potentiated by carbidopa (50 mg/kg i.p.), and even 3-OMD levels in dialysate samples became detectable. Both OR-611 and Ro 40-7592 significantly further increased the DA and DOPAC efflux from striatum produced by L-dopa. This increase was more pronounced when carbidopa was added to the treatment. OR-611 did not modify the effect of L-dopa or carbidopa/L-dopa on dialysate HVA levels, whereas Ro 40-7592 markedly reduced those levels. Both OR-611 and Ro 40-7592 very clearly suppressed dialysate 3-OMD levels produced by carbidopa/L-dopa. Ro 40-7592 was more effective than OR-611 in potentiating the effects of L-dopa or carbidopa/L-dopa. These in vivo data show that the new COMT inhibitors markedly inhibit the O-methylation of L-dopa and increase its availability to brain, which is reflected as increased DA formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Scheduled feeding caused activation of dopamine metabolism in the striatum of rats

The effects of a time-restricted feeding schedule on dopamine (DA) release and its metabolites output in the striatum of freely moving rats were studied. Rats had access to food for only 2 h daily for 7 successive days. On the 1st or 7th day, the extracellular concentrations of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the ventrolateral striatum were measured by in vivo brain microdialysis during 2 h of exposure to food-related stimuli followed by 2 h of access to food. Extracellular concentrations of DA and its metabolites did not change during the period of exposure to food-related stimuli or during feeding on the 1st day. On the 7th day, extracellular DOPAC and HVA concentrations increased significantly during 2 h of feeding, but not during exposure to food-related stimuli, compared with basal levels. Extracellular DA concentration did not change significantly. These results indicate that scheduled feeding caused activation of DA metabolism in the ventrolateral striatum and facilitate feeding-related motor activity in feeding behavior.

Differential behavioural and neurochemical effects of competitive and non-competitive NMDA receptor antagonists in rats

The behavioural and biochemical effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, dizocilpine and memantine, and the competitive NMDA receptor antagonist, CGP 39551, were investigated in rats. Systemic injections of dizocilpine (0.33 mg/kg) increased locomotion and rearing in an open field, whereas memantine (20 mg/kg) increased only locomotor activity. CGP 39551 (10 and 20 mg/kg) did not change open field activity. Dopamine (DA) metabolism - as measured by the ratio of dihydroxyphenylacetic acid/dopamine (DOPAC/DA) - increased in response to dizocilpine in the prefrontal cortex and the nucleus accumbens. Memantine enhanced DOPAC/DA in the prefrontal cortex, the nucleus accumbens and to a lesser degree in the posterior striatum. In contrast to non-competitive NMDA receptor antagonists, CGP 39551 did not increase DA metabolism of subcortical structures and even decreased DOPAC/DA in the prefrontal cortex. These results indicate that competitive and non-competitive NMDA receptor antagonists affect spontaneous locomotion differentially in rats. The biochemical data imply that the stimulant actions of non-competitive NMDA receptor antagonists are at least partially due to activation of ascending dopaminergic systems. Potential mechanisms involved in the differential effects of both types of NMDA receptor antagonists are discussed.

Biogenic monoamine levels in the central nervous system of the sea hare, Aplysia kurodai

1. By using a three-dimensional-coulometric HPLC system, biogenic monoamines and their metabolites were quantified simultaneously in the central nervous system of the sea hare, Aplysia kurodai. 2. Precursor amino acids, tyrosine-4 (TYR-4) and tryptophan (TRP), and dopamine (DA), 3, 4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) were detected in all the ganglia examined. 3. Levels of these compounds in the cerebral, pedal and parieto-visceral ganglia were higher than those of the other ganglia examined. 4. In some ganglia, epinephrine (E), 3- O-methyldopa (30MD), 3-methoxytyramine (3-MT), dihydroxyphenylethleneglycol (DOPEG), metanephrine (MN), vanillic acid (VA), octopamine (OCT), kynurenine (KYN) and 5-hydroxyindoleacetic acid (5-HIAA) were also detected. 5. The main metabolic pathways of biogenic monoamines were shown to be TYR-4DADOPAC and TRP5-HT5-HIAA. Furthermore, following five pathways were also suggested to be present; TYR-4DAEMNVA, TYR-4TYRAOCT, TYR-43OMD, DA3-MT. EDOPEG and TRPKYN.

Enhanced monoamine release in the median preoptic area following reduced extracellular fluid volume in rats

The role of monoaminergic neural inputs to fluid regulatory systems in the median preoptic nucleus (MnPO) was investigated by examination of monoamine metabolism during reduction of systemic extracellular fluid volume in freely moving rats. Extracellular fluid volume was decreased iso-osmotically by subcutaneous polyethylene glycol (PEG), and extracellular noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured using intracerebral microdialysis techniques. PEG treatments significantly increased NA, DA and DOPAC release in the MnPO area. The results suggest that monoaminergic neural systems in the region of the MnPO are important in the control of extracellular fluid balance.

Electron microscopic and voltammetric analysis of carbon fibre electrode pretreatments

The comparison between the differential pulse voltammetric capability of untreated or treated 12 µm or 30 µm diameter carbon fibre electrodes (CFE) to detect electroactive compoundsin vitro has been analysed. Their affinity for ascorbic acid (AA), catechols (dopamine (DA); 3,4-dihydroxyphenylacetic acid (DOPAC)), indoles (serotonin (5HT); 5-hydroxyindoleacetic acid (5HIAA)) and uric acid (UA) has been quantified. It appeared that only the 12 µm CFE, when electrically pretreated, can selectively and simultaneously detect the oxidation of AA, catechols and indoles, while the electrically pretreated 30 µm CFE are specifically sensitive to the indoles. However, both electrodes displayed highest sensitivity for serotonin. To avoid the detection of acids and selectively monitor the oxidation of DA and 5HT the 12 µm CFE and the 30 µm CFE were chemically (chromic acid) and electrically pretreated then electrically coated with Nafion. However, the 30 µm CFE alone selectively measured these compoundsin vitro as the 12 µm CFE did not accept the coat of Nafion. Using transmission electron microscopy (TEM) and scanning electron microscopy (SEM), we have investigated the effect of electrical and/or chemical pretreatments on the structural characteristics of the CFE. It appeared that both pretreatments increased the surface area of the carbon fibres by pitting, roughening and fracturing the carbon. Holes were also observed on the surface of the 30 µm dia. carbon fibres following the electrical pretreatment. The possibility of a correlation between these modifications and the pretreatment-induced voltammetric high sensitivity of the CFE is discussed.

Biogenic monoamine system detected simultaneously in the neural complex of the ascidian, Ciona intestinalis

1. By using a three dimension coulometric HPLC system, a wide range of monoamines and related metabolites were quantified simultaneously in the neural complex of the ascidian, Ciona intestinalis. 2. The main biogenic monoamine metabolic pathways were shown to be catecholamines: Tyrosine-4- l-Dopa-Dopamine-Norepinephrine-Normetanephrine and Dopamine-Dihydroxyphenylacetic acid, and indolalkylamines: Tryptophan-5-Hydroxytryptophan-5-Hydroxytryptamine. 3. In addition to these, Tyramine and Vanillic acid were suggested to be present.

Increased monoamine turnover in the subfornical organ area following body fluid depletion

To clarify whether monoaminergic inputs to the subfornical organ (SFO) area participate in fluid regulatory systems, we examined the effects of body fluid depletion on monoamine turnover in the region of the SFO using microdialysis techniques in rats. An iso-osmotic reduction of fluid volume following subcutaneous treatment with polyethylene glycol (PEG) significantly increased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the SFO area. 5-hydroxytryptamine (5-HT) in the SFO area could be detected after the PEG treatment, while 5-HT was undetectable before the treatment. The data imply that both dopaminergic and serotonergic systems in the SFO area may be involved in controlling body fluid balance.

Effects of cortical ablation on apomorphine- and scopolamine-induced changes in dopamine turnover and ascorbic acid catabolism in the rat striatum

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid and dehydroascorbic acid (DHAA) were measured by HPLC in the striatum of rats whose fronto-parietal cortex had been unilaterally ablated after a single injection of apomorphine (1 mg/kg s.c.), scopolamine (0.6 mg/kg s.c.) or L-glutamate (500 mg/kg i.p.). Unilateral cortical ablation decreased striatal levels of glutamate in both striata ipsilateral (35%) and contralateral (17–25%) to the lesion. Apomorphine and scopolamine significantly increased (+94 and +122%, respectively) the DHAA/ ascorbic acid ratio in the striata ipsilateral to the lesion in unoperated and sham-operated rats (+72 and +34%, respectively), but both drugs failed to increase it in ablated rats. L-Glutamate significantly increased the DHAA/ ascorbic acid ratio in unoperated (+53%) and ablated rats (+37%). The increase in sham-operated rats (+34%) did not reach statistical significance. Apomorphine and scopolamine significantly decreased the DOPAC/DA ratio in the striata ipsilateral to the lesion of unoperated, sham-operated and ablated rats. The decrease in the DOPAC/DA ratio induced only minor changes in striatal DA and DOPAC levels. We conclude that the apomorphine- and scopolamine-induced increase in ascorbic acid oxidation in the striatum requires intact cortico-striatal glutamatergic pathways. Cortical ablation potentiates the apomorphine- and scopolamine-induced inhibition of striatal DA turnover.

Effects of ( d-amphetamine on dopaminergic neurotransmission; a comparison between the substantia nigra and the striatum

The effects of ( d-amphetamine (d-AMP) on dopaminergic neurotransmission in the cell body/dendritic region of the nigrostriatal pathway, the substantia nigra, have been investigated and compared to the effects obtained in the terminal region of the pathway, the striatum. The rate of synthesis of dopamine (DA) was quantified as accumulation of 3,4-dihydroxyphenylalanine (DOPA), after inhibition of aromatic l-amino acid decarboxylase with 3-hydroxybenzyl-hydrazine (NSD 1015). As measures of the metabolism of DA the concentrations of the metabolites of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined. As indices of release of DA, the accumulation of 3-methoxytyramine (3-MT), after inhibition of monoamine oxidase with pargyline and the disappearance of DA, after inhibition of its synthesis with α-methyl- p-tyrosine were assessed. ( d-Amphetamine insignificantly increased the concentration of DA in the striatum but profoundly decreased it in the substantia nigra (to 60% of controls). Both in the striatum and in the substantia nigra treatment with d-AMP induced clearcut decreases of the concentrations of DOPAC. Also the concentration of HVA was profoundly decreased in the striatum but only marginal effects on HVA were observed in the substantia nigra. In both structures of the brain, d-AMP increased the concentration of 3-MT. Depending on the dose, d-AMP increased or had no effect on the accumulation of DOPA in the striatum but consistently decreased it in the substantia nigra. In the striatum, d-AMP increased the pargylineinduced accumulation of 3-MT, without affecting the concentration of DA. However, in the substantia nigra the concentration of DA was profoundly decreased (to 50% of controls) in combination with unaltered accumulation of 3-MT, unless the rats were pretreated with haloperidol. If so, the effects of d-AMP on the concentration of DA and accumulation of 3-MT were the same in the substantia nigra and in the striatum. The results indicate that d-AMP depleted stores of DA in the substantia nigra, due to its releasing action, in combination with its decreasing effect on the rate of synthesis of DA. The decrease in rate of synthesis of DA is suggested to be due to the d-AMP-induced decrease in the firing rate of dopaminergic neurones.

Bilateral neurochemical changes induced by unilateral cerebral haloperidol administration: Evidence for cerebral asymmetry in the rat

Bilateral alterations in dopamine metabolism were determined in the striatum, olfactory tubercle, and frontal cortex of rats pretested for circling behavior. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine, and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography 15 min after right or left intracarotid infusion of haloperidol. Concentrations of DOPAC and HVA were significantly increased in the striatum and frontal cortex ipsilateral to the side haloperidol infusion, regardless of whether it was right or left. In contrast, the concentrations of these metabolites were unchanged in the olfactory tubercle after a right side infusion, but bilateral increases were evident after a left side infusion. Higher levels of DOPAC and HVA were also apparent in the left striatum and olfactory tubercle after intravenous jugular administration of haloperidol. Dopamine levels were significantly lower in the left striatum and right olfactory tubercle after intravenous haloperidol infusions. 5-HIAA concentrations were higher in the left olfactory tubercle following left side infusions of haloperidol. These data indicate that unilateral cerebral administration of haloperidol induces asymmetric and side-dependent alterations in dopamine and serotonin metabolites. These differences appear to be due to intrinsic variations in the sensitivity to haloperidol, but are not associated with the direction of circling behavior.