Turnover of Dopamine and Dopamine Metabolites in Rat Brain: Comparison Between Striatum and Substantia Nigra

Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.     

Angiotensin-Converting Enzyme Modulates Dopamine Turnover in the Striatum

Abstract: The effect of chronic inhibition of the angiotensin-converting enzyme on dopamine content and release in the striatum was investigated using in vivo microdialysis in awake, freely moving rats. Rats were treated for 1 week with the angiotensin-converting enzyme inhibitor perindopril (1 mg/kg) via the drinking water, whereas the controls were given water alone. One week after perindopril treatment, striatal dopamine dialysate levels in the treated group were markedly elevated compared with control values: control, 233 ± 43 pg/ml; perindopril, 635 ± 53 pg/ml ( p < 0.001). These results were confirmed by a complementary study in which dopamine content was measured in striatal extracts (3.5 ± 0.4 µg of dopamine/g of tissue for controls compared with 9.2 ± 2.4 µg of dopamine/g of tissue for the treated group; p < 0.05). In the rats that were dialyzed, angiotensin-converting enzyme levels in the striatum were decreased by 50% after perindopril treatment. Levels of dopamine D₁ and D₂ receptors and of preprotachykinin and tyrosine hydroxylase mRNAs were unchanged after angiotensin-converting enzyme inhibition. A small, but significant, increase was detected in striatal preproenkephalin mRNA levels in the angiotensin-converting enzyme inhibitor-treated group. These results indicate that peripherally administered angiotensin-converting enzyme inhibitors penetrate the blood-brain barrier when given chronically and modulate extracellular dopamine and striatal neuropeptide levels.     

EPC-K1, a Hydroxyl Radical Scavenger,Prevents 6-Hydroxydopamine-Induced Dopamine Depletion in the Mouse Striatum by Up-Regulation of Catalase Activity

We examined the effect of pretreatment with EPC-K1, a potent hydroxyl radical scavenger, on 6-hydroxydopamine (6-OHDA)-induced reduction of dopamine (DA) and its metabolites in the mouse striatum. EPC-K1 was mixed with diet (0.2%, wt/wt) for 1 or 2 weeks, and then 6-OHDA (60 g in 2l of saline solution) was injected intracereberoventricularly. Mice continued to be fed EPC-K1-containing diet for another one week before they were sacrificed. The concentrations of DA and its metabolites in the striatum were measured by high performance liquid chromatography. 6-OHDA reduced the level of DA and its metabolites in the striatum. Pretreatment with EPC-K1 for 2 weeks, but not for 1 week, abrogated the neurotoxic effect of 6-OHDA on striatal concentrations of DA and its metabolites. Measurement of striatal concentrations of thiobarbituric acid reactive substances, glutathione, and malonaldehyde plus 4-hydroxynonenal, and the activities of superoxide dismutase and catalase in EPC-K1 treated mice showed an increase in catalase activity after 2 weeks of such treatment. No other changes in anti-oxidants levels were noted. Our results suggest that EPC-K1 counteracts the neurotoxicity of 6-OHDA by increasing catalase activities.     

Estimation of the Turnover of 3-Methoxytyramine in the Rat Striatum by HPLC with Electrochemical Detection: Implications for the Sequence in the Cerebral Metabolism of Dopamine

Abstract: A highly sensitive method for the determination of 3-methoxytyramine (3-MT) in nervous tissue is described. The method is based on a rapidly performed isolation of 3-MT on small columns of Sephadex G 10, followed by reverse-phase high-performance liquid chromatography in conjunction with a rotating disk electrochemical detector. The detection limit of the assay (0.5–1 pmol/tissue sample) is about 10% of control value for microwave-killed rats. 3-MT as well as dopamine could be quantified in the same chromatographic run. Inhibition of catechol- O -methyl transferase with tropolone resulted in an exponential decline of 3-MT. From this exponential decline a turnover rate for 3-MT of 1.9 nmol/g/h was calculated. In the same group of rats the turnover rate of homovanillic acid was 9.1 nmol/g/h. From these data it is concluded that in the rat striatum about 80% of homovanillic acid is formed from 3,4-dihydroxyphenylacetic acid and 20% from 3-MT.     

Turnover of Dopamine and Serotonin and Their Metabolites in the Striatum of Aged Rats

Turnover of dopamine (DA), serotonin [5-hydroxytryptamine (5-HT)], and their metabolites has been measured in adult and aged rats. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxy-3-indoleacetic acid (5-HIAA) have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase (MAO) and from the accumulation rates by probenecid inhibition of the probenecid-sensitive transport system. DA and 5-HT turnover rates have been measured as accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015) and as accumulation rates of DA and 5-HT after pargyline inhibition of MAO. The DA turnover rate after NSD-1015 was 23.9% lower in aged rats than in adults, whereas after pargyline there was no significant difference between the two age groups. The HVA fractional rate constant and turnover after pargyline were lower in aged rats than in adults, and HVA turnover after probenecid was higher in aged rats than in adults. The DOPAC-HVA pathway seems to be reinforced at the expense of DOPAC conjugation. In aged and adult rats whose 5-HT steady-state levels were not statistically different, the 5-HT turnover rate after pargyline and NSD-1015 treatment was lower in aged rats than in adults. An increase of 5-HIAA levels after pargyline and probenecid treatment in aged rats could be due to the handling stress.     

Effect of the Cerebral Tryptaminergic System on the Turnover of Dopamine in the Striatum of the Rat

The effect of the cerebral 5-hydroxytryptamine system on the turnover of striatal 3,4-dihydroxyphenyl-ethylamine (dopamine) was investigated by measuring the level of dopamine and one of its metabolites in rats depleted of cerebral 5-hydroxytryptamine or treated with a 5-hydroxytryptamine receptor blocker. Treatment with p-chlorophenylalanine induced, in addition to a reduction in striatal 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid, an increase in the striatal concentration of dopamine, a diminution in the concentration of homovanillic acid in the same cerebral area, and a reduction in the rise of this acid after the administration of a butyrophenone derivative or tetrabenazine. Treatment with methysergide also reduced the increase of homovanillic acid induced by the butyrophenone. When probenecid was given to rats treated with p-chlorophenylalanine, homovanillic acid failed to accumulate, whereas the accumulation of 5-hydroxyindol-3-ylacetic acid was unaffected. The decay of dopamine after alpha-methyl-p-tyrosine administration was normal for the first 6 h but was later reduced in rats given p-chlorophenylalanine or methysergide. The results suggest that the lack of activation of 5-hydroxytryptamine receptors leads to a reduction in the turnover of dopamine in the nigrostriatal pathway.     

Activation of Dopamine Receptors Does Not Affect Phosphoinositide Turnover in NCB-20 Cells

Dopamine inhibits and serotonin stimulates adenylate cyclase activity in a neuroblastoma X Chinese hamster brain explant cell line (NCB-20). The inhibition of cyclic AMP accumulation by dopamine was blocked by pretreatment of the cells with pertussis toxin. Carbachol and bradykinin stimulated the accumulation of water-soluble inositol phosphates whereas thyrotropin-releasing hormone, vasopressin, neurotensin, and phenylephrine were without effect. Dopamine and serotonin had no significant effect on carbachol-induced phosphoinositide hydrolysis or the levels of the parent lipids within the membrane. Forskolin induced a much larger stimulation of cyclic AMP than did serotonin, and caused an increase in the levels of phosphatidylinositol-4-phosphate and phosphatidyl inositol-4,5-bisphosphate in the cell membrane.     

Increase in Extracellular Dopamine in the Striatum During Cerebral Ischemia: A Study Utilizing Cerebral Microdialysis

Unilateral ligation of the left common carotid artery in anesthetized Mongolian gerbils resulted in a steep rise in extracellular dopamine in the ipsilateral striatum in 9 out of 19 animals. Extracellular dopamine was measured by cerebral dialysis in vivo and reached a peak of 0.19 mM at 40 min. At the same time, the level of homovanillic acid fell, whereas the levels of ascorbate and 3,4-dihydroxyphenylacetic acid remained relatively constant. In a separate group of animals studied with a combined dialysis/electrochemistry probe, a rise in the in vivo chronoamperometric signal in three out of six animals correlated with a rise in extracellular dopamine. The number of animals responding in these experiments (roughly 50%) corresponds to the frequency of incompetent Circle of Willis, as well as literature reports of the frequency of signs of stroke in unanesthetized gerbils. These results show a remarkable accumulation of dopamine in extracellular fluid in response to cerebral ischemia. Released dopamine appears to be responsible for the elevated in vivo electrochemical signal previously reported.     

Effect of Quinine on Autoreceptor-Regulated Dopamine Release in the Rat Striatum

In vivo brain microdialysis was used to examine the role of potassium channel activation in dopamine (DA) autoreceptor function in the striatum of freely moving rats. Local application of the D2 receptor agonists quinpirole or N-0437 through the dialysis probe significantly reduced extracellular concentrations of DA. Local application of the D2 antagonist (-)-sulpiride produced significant increases in DA. Local perfusion with quinine, a K+ channel blocker, completely blocked the (-)-sulpiride-induced increases in DA but did not affect the DA agonist-induced decreases. (-)-Sulpiride completely blocked the effect of quinpirole on DA both in control and in quinine-treated animals. At the highest dose used, quinine caused a large transient increase in extracellular DA. Local application of tetrodotoxin or infusion of Mg2+ in the absence of Ca2+ did not prevent this quinine-induced transient increase in extracellular DA. These results demonstrate that DA autoreceptors in the striatum regulate DA release in awake, behaving animals. Local application of (-)-sulpiride increases DA levels by blocking the tonic activation of autoreceptors by endogenous DA. Quinine blocks the neuroleptic-induced increase in DA, perhaps by preventing the K+ channel opening that would normally accompany endogenous autoreceptor activation. The fact that exogenously applied DA receptor agonists can decrease extracellular DA levels in the presence of quinine suggests that they may be acting at extrasynaptic autoreceptors that are not tonically active in vivo. The effect of DA agonists on this site is via a DA receptor because it is blocked by (-)-sulpiride. However, this receptor does not appear to be coupled to a quinine-sensitive potassium channel.     

Dopamine Release in Rat Striatum: Physiological Coupling to Tyrosine Supply

Intracerebral microdialysis was used to monitor dopamine release in rat striatal extracellular fluid following the intraperitoneal administration of dopamine's precursor amino acid, L-tyrosine. Dopamine concentrations in dialysates increased transiently after tyrosine (50-100 mg/kg) administration. Pretreatment with haloperidol or the partial lesioning of nigrostriatal neurons enhanced the effect of tyrosine on dopamine release, and haloperidol also prolonged this effect. These data suggest that nigrostriatal dopaminergic neurons are responsive to changes in precursor availability under basal conditions, but that receptor-mediated feedback mechanisms limit the magnitude and duration of this effect.     

Role of Adenylate Cyclase in the Modulation of the Release of Dopamine: A Microdialysis Study in the Striatum of the Rat

In the present study, we have applied the brain microdialysis technique to investigate the effect of the stimulation of adenylate cyclase on the extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of freely moving rats. Infusion of 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), 3-isobutyl-1-methylxanthine, or forskolin produced a significant increase in the release of DA. The effect of 8-Br-cAMP was tetrodotoxin, Ca2+, and dose dependent and was saturable. 8-Br-cAMP also caused an increase in the output of DOPAC and HVA. No effects were seen on the output of 5-HIAA, except at the highest 8-Br-cAMP concentration studied. Infusion of 8-Br-cAMP (25 microM, 1.0 mM, and 3.3 mM) together with infusion of (-)-sulpiride (1 microM) or systemic administration of (+/-)-sulpiride (55 mumol/kg i.p.) produced an additive effect on the release of DA. Infusion or peripheral administration of (-)-N-0437 (1 microM or 1 mumol/kg) both decreased the 8-Br-cAMP-induced increase in the release of DA. These results demonstrate that cyclic AMP may stimulate the release of DA, but it is unlikely that this second messenger is linked to presynaptic D2 receptors controlling the release of DA.     

Modulatory Effect of Dopamine on High-Affinity Glutamate Uptake in the Rat Striatum

In vivo electrical stimulation of the frontal cortical areas was found to enhance sodium-dependent high-affinity glutamate uptake (HAGU) measured in rat striatal homogenates. This activating effect was counteracted by in vivo administration of apomorphine and by in vitro addition of dopamine (DA; 10(-8) M) in the incubation medium, and potentiated by in vivo haloperidol administration. At the doses used, the dopaminergic compounds had no effect on basal HAGU. alpha-Methylparatyrosine pretreatment was found to enhance slightly basal HAGU as well as the activating effects of cortical stimulation. Interestingly enough, lesion of dopaminergic neurons by substantia nigra injection of 6-hydroxydopamine (6-OHDA) did not cause any significant change either in basal HAGU or in the effect of cortical stimulation. Measurement of DA effects in vitro in experiments combined with in vivo manipulations of the dopaminergic nigrostriatal and corticostriatal systems showed that the capacity of DA to inhibit striatal HAGU depends directly on the level of the uptake activation reached over basal value. These results suggest that under physiological conditions, the dopaminergic nigrostriatal pathway exerts a modulatory presynaptic action on corticostriatal glutamatergic transmission, counteracting increasing glutamatergic activity. In the case of chronic DA depletion induced by 6-OHDA, striatal adaptations may occur modifying the mechanisms acting at corticostriatal nerve terminal level.     

Dopamine D2 Receptor-Deficient Mice Exhibit Decreased Dopamine Transporter Function but No Changes in Dopamine Release in Dorsal Striatum

Abstract : Presynaptic D₂ dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity. To examine the effects of D₂ DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D₂^+/+), one (D₂^+/-), or no (D₂^-/-) functional copies of the gene coding for the D₂ DA receptor. In vivo microdialysis studies demonstrated that basal and K⁺-evoked extracellular DA concentrations were similar in all three genotypes. However, using in vivo electrochemistry, the D₂^-/- mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D₂^+/+ mice. In D₂^+/+ mice, but not D₂^-/- mice, local application of the D₂-like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [³H]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D₂ DA receptor subtype modulates activity of the striatal DAT.     

In Vitro Release of Endogenous Dopamine from the Striatum of the Weaver Mutant Mouse

The weaver mutant mouse has a genetically determined defect in the nigrostriatal dopaminergic system. The present study was undertaken to test the hypothesis that in the weaver mutant mouse, striatal nerve terminals undergo compensatory changes in response to this deficiency. To test this hypothesis, we studied the basal and stimulated release of dopamine from striatal slices of weaver mutant mice and matched controls. By using a superfusion system and concentrating the superfusate by passage over alumina, resting dopamine release could be determined in the weaver mutant despite the fact that striatal tissue content of dopamine in these mice is reduced by greater than 75% compared with control mice. Fractional resting release of dopamine in weaver striatal slices was significantly elevated compared with that in controls, suggesting that the release mechanisms in the weaver may be adapting to overcome the dopamine deficit. Potassium-evoked release (24 and 48 mM potassium) was not significantly different between the two genotypes. In contrast, amphetamine-evoked release (1 microM) was significantly greater in the weaver mice than in controls. In both genotypes, release evoked by amphetamine was completely inhibited by cocaine, implicating the dopamine uptake carrier in this release process. These findings suggest that fundamental differences in dopamine release mechanisms exist between weaver and control mice and support the hypothesis that compensatory mechanisms may develop in neurons in response to dopamine deficits.     

Conjugated Dopamine in Superfusates of Slices of Rat Striatum

Abstract: An acid-hydrolyzable conjugate of 3,4-dihydroxyphenylethylamine (dopamine, DA) was detected in superfusates from slices from rat striatum. The concentrations of endogenous free and conjugated DA, and of the acid metabolites (3,4-dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) in superfusates were measured using HPLC with electrochemical detection. Conjugated DA in superfusates represented 10–20% of the free DA under basal conditions and during release evoked by p -tyramine (5 × 10⁻⁶ M to 5 × 10⁻⁴ M ); much smaller amounts of conjugated DA overflowed into superfusate when DA was released by equimolar concentrations of β-phenylethyl-amine. Surprisingly, inhibition of monoamine oxidase by the inhibitors N -methyl- N -propargyl-3-(2,4-dichlorophenoxy)propylamine hydrochlo-ride (clorgyline) or N -methyl- N -2-propynylbenylamine (pargyline) had little effect on the amounts of conjugated DA present in superfusate. Under basal conditions, the amounts of conjugated DA in superfusate were always less than the amounts of DOPAC but quite similar to the amounts of HVA. However, during release of DA evoked by p -tyramine the concentrations of conjugated DA in superfusate showed much more pronounced increases than those of the acidic metabolites.     

Different Effects of Opiate Withdrawal on Dopamine Turnover,Uptake, and Release in the Striatum and Nucleus Accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.     

Ontogeny of Dopamine D1 Receptors in Rat Striatum

The development of dopamine D1 receptors in rat striatum during the early postnatal period is described, using [3H]piflutixol as ligand. Dopamine D1 receptors increase in number from day of birth until about 21 days of age, when they reach adult levels. This increase in number parallels the increase in several other dopamine markers in striatum during the same time period. The increase is reflected in an increase in Bmax of ligand binding to D1 receptors. All other properties of D1 receptors that were examined do not change throughout this developmental period and are essentially the same as those found in adult tissue. These include association and dissociation rates, affinity for piflutixol as determined by kinetic and saturation studies, and pharmacology. These studies provide a biochemical and pharmacological basis for further studies on the ontogeny of dopamine receptors and of striatum and on factors regulating development of this region.     

Biotransformation of l-DOPA to Dopamine in the Substantia Nigra of Freely Moving Rats: Effect of Dopamine Receptor Agonists and Antagonists

Abstract: We investigated the effects of continuous intranigral perfusion of dopamine D1 and D2 receptor agonists and antagonists on the biotransformation of locally applied l -DOPA to dopamine in the substantia nigra of freely moving rats by means of in vivo microdialysis. The "dual-probe" mode was used to monitor simultaneously changes in extracellular dopamine levels in the substantia nigra and the ipsilateral striatum. Intranigral perfusion of 10 µ M l -DOPA for 20 min induced a significant 180-fold increase in extracellular nigral dopamine level. No effect of the intranigral l -DOPA administration was observed on dopamine levels in the ipsilateral striatum, suggesting a tight control of extracellular dopamine in the striatum after enhanced nigral dopamine levels. Continuous nigral infusion with the D1 receptor agonist CY 208243 (10 µ M ) and with the D2 receptor agonist quinpirole at 10 µ M (a nonselective concentration) attenuated the l -DOPA-induced increase in dopamine in the substantia nigra by 85 and 75%, respectively. However, perfusion of the substantia nigra with a lower concentration of quinpirole (1 µ M ) and the D1 antagonist SCH 23390 (10 µ M ) did not affect the nigral l -DOPA biotransformation. The D2 antagonist (−)-sulpiride (10 µ M ) also attenuated the l -DOPA-induced dopamine release in the substantia nigra to ∼10% of that of the control experiments. We confirm that there is an important biotransformation of l -DOPA to dopamine in the substantia nigra. The high concentrations of dopamine formed after l -DOPA administration may be the cause of dyskinesias or further oxidative stress in Parkinson's disease. Simultaneous administration of D1 receptor agonists with l -DOPA attenuates the biotransformation of l -DOPA to dopamine in the substantia nigra. The observed effects could occur via changes in nigral GABA release that in turn influence the firing rate of the nigral dopaminergic neurons.     

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.     

Characterisation of Inhibitory 5-Hydroxytryptamine Receptors That Modulate Dopamine Release in the Striatum

Abstract: The effect of a series of indoleamines on the potassium-evoked tritium release of previously accumulated [³H]dopamine from rat striatal slices has been investigated. The indoleamines 5-hydroxytryptamine, 5-methoxy-tryptamine, 5-methoxy- N, N' -dimethyltryptamine and tryptamine (10⁻⁷ to 10⁻³ M) all reduced potassium-evoked release of tritium, to a maximum of 50%. The uptake of [³H]dopamine was unaffected by these compounds. A series of 5-hydroxytryptamine antagonists were examined for their ability to reduce the inhibition of potassium-evoked tritium release induced by 5-methoxytryptamine. The relative order of antagonist potency obtained was methysergide > metergoline > methiothepin > cinanserin > cyproheptadine > mianserin, and was consistent with an action on 5-hydroxytryptamine receptors. It is concluded that there are inhibitory 5-hydroxytryptamine receptors located on the terminals of dopaminergic neurones in the striatum.