Enhancement of 5-Hydroxytryptamine Uptake in Rabbit Hypothalamic Synaptosomes but not in Blood Platelets by Zinc and Lead ex Vivo

Abstract: Lead (0.2%), zinc (0.5%) or their combination was given to rabbits as acetate salts in drinking water for 2 or 4 weeks. Cerebral Pb increased within exposure time but the increase of Zn was marginal when given alone. After combination of Pb+Zn, blood Pb increased but Zn decreased as compared to the administration of the single metal alone. Concurrently brain Pb increased but remained at a lower level as compared with sole Pb administration while brain Zn did not differ from controls. The uptake of 5-hydroxytryptamine (5-HT) into hypothalamic synaptosomes increased 70–85% with Pb, Zn and Pb+Zn after 2 weeks and 93% with Zn and 76% with Pb+Zn after 4 weeks. Dopamine uptake into striatal synaptosomes did not change. Zn decreased endogenous noradrenaline concentrations by 21% and Pb+Zn that of 5-HT by 36% in the striatum. Pb+Zn decreased cortical dopamine concentrations by 26%. Concurrently, 5-HT uptake in blood platelets, platelet numbers and their content of endogenous 5-HT did not change significantly. These results indicate that high Zn and Pb have parallel effects on 5-HT uptake in hypothalamic synaptosomes and their combination may be neurochemically more toxic than the individual metals. The increase of 5-HT uptake in hypothalamic synaptosomes but not in blood platelets requires further methodological work to explain the differences between synaptosomes and platelets.     

Ca-dependence of accumulation of monoamines into synaptosomes and its inhibition by copper

Effects of various concentrations of extracellular Ca on the high affinity uptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) as well as the effects of Ca on Cu-induced uptake inhibition were studied by using striatal, cortical and hypothalamic synaptosomes, respectively. The spontaneous release of all three amines from preloaded synaptosomes by Cu increased slightly with increasing external Ca up to 2.5 mM. The sensitivity to Ca of the accumulation of the amines into synaptosomes decreased in the order of DA greater than NA greater than 5-HT. Below 0.3 mM Ca, DA uptake increased due to concurrent decreased release of DA from synaptosomes. The pattern was similar but less evident for NA while 5-HT uptake and its spontaneous release did not change upon buffer Ca at all. The uptake inhibition of none of the amines depended on extracellular Ca. Zn reversed the Cu-induced inhibition of 5-HT uptake but increased additively the inhibition of DA uptake and that of NA uptake in vitro. The potency of Cu to inhibit uptake decreased when the protein concentration in the incubation medium was increased. Cysteine, added concurrently with Cu, did not protect uptake from the toxic influence of Cu. The results so far suggest that the primary mechanism in the Cu-induced inhibition of uptake is blocking the membrane uptake carrier. The release of an accumulated amine from synaptosomes may rather be secondary and result from the inhibition of the reuptake.     

Interference of Methyl Mercury with Monoamine Uptake and Release in Rat Brain Synaptosomes

Abstract: Interference of methyl mercury (Met-Hg), a known neurotoxin, with the high affinity uptake and the release of tritiated dopamine (DA), noradrenaline (NA) and serotonin (5-HT) was studied in vitro in rat striatal, cortical and hypothalamic synaptosomes respectively. Met-Hg proved to be a potent inhibitor of uptake; the IC50's were 2.5 μM (DA), 3.2 μM (NA) and 3.4 μM (5-HT) in 2 min. incubations. The uptake of NA was slightly inhibited already at 0.1–1 μM Met-Hg whereas DA and 5-HT were not. The inhibition was rapid, already after 1 min. exposure to 3 μM Met-Hg the uptake was inhibited totally. The kinetic pattern of the inhibition of DA uptake best agreed with the non-competitive type. The spontaneous release of monoamines from preloaded synaptosomes was also potently stimulated and was dependent on Met-Hg concentration. The sensitivity decreased in the order of DA>5-HT>NA. The apparent inhibition of uptake is probably partly due to the release of the transmitter amine just taken up. Chelation might also contribute to the inhibition of NA and DA uptake. The detailed mechanisms of these phenomena remain to be studied but they may explain some of the direct CNS effects of Met-Hg.     

Pretreatment with delta 1-tetrahydrocannabinol and psychoactive drugs: effects on uptake of biogenic amines and on behavior.

Injection of delta 1-tetrahydrocannabinol (THC) into mice increased the uptake into brain synaptosomes of radioactive DA, NE, 5-HT and GABA, with the effect on GABA being the greatest; uptake of leucine was not stimulated, indicating that THC does not facilitate the transport of amino acids in general. The effect of THC was stereospecific because pretreatment with the non-psychoactive isomer, (+) delta 6-THC had no effect on uptake of DA into cortical synaptosomes. The effect on DA uptake was correlated with psychoactive potency. THC enhanced uptake more than did SP-111 (a water soluble ester of THC but less potent than THC) and much more than cannabidiol (a non-psychoactive ingredient of marijuana). THC increased the uptake of DA into striatal synaptosomes but much less than into cortical synaptosomes. The enhancing effect of THC on uptake in cortex showed tolerance after chronic (1 week) treatment with THC. Catecholaminergic receptor antagonists (chlorpromazine, propranolol), like THC, stimulated the uptake of DA or NE into cortical synaptosomer. In contrast, pretreatment with MAO (pargyline) or uptake (tricyclic antidepressants) inhibitors, or with amphetamine, decreased uptake. Thus THC does not inhibit MAO uptake, or stimulate the release of catecholamines but may interact with a receptor. The notion of a THC--receptor interaction is supported by behavioral experiments.     

3H-dopamine uptake and 3H-haloperidol binding in striatum after administration of methyl mercury to rats

Methyl mercury inhibits dopamine (DA) and serotonin (5-HT) uptake by brain synaptosomes and decreases antagonist binding to striatal dopaminergic D₂ receptors in vitro. To assess the effects in vivo, adult rats were given methyl mercury, either as a single dose (10 mg/kg by gavage) or a cumulative total dose of 50 mg/kg in 2 weeks. The repeated dosing decreased body weight and caused neuromuscular dysfunction. In spite of this overt toxicity, neither ³H-DA uptake nor ³H-haloperidol binding changed in striatal synaptosomes. There were no significant alterations in ³H-5-HT uptake by hypothalamic synaptosomes or ³H-flunitrazepam binding in cerebellar synaptosomes. The results suggest that monoaminergic synapses and the benzodiazepine binding sites, associated with cerebellar GABA receptors, remain functionally normal at doses of methyl mercury that are otherwise toxic. The results also emphasize the importance of due care when extrapolating cellular or biochemical data to the level of the whole organism.     

Monoamine Uptake in Brain Synaptosomes after Administration of Copper to Rats

Abstract: In our previous studies, divalent copper (Cu) has proved to be a potent inhibitor of monoamine uptake in rat brain synaptosomes in vitro. To study whether Cu affects monoamine uptake in the brain in vivo, rats were given Cu (as CuCl₂) acutely as a single dose of 30, 100, 200 or 300 mg/kg by gavage, intravenously 9 mg/kg or subacutely in drinking water, 200, 400, or 600 mg/l Cu for 3 weeks. Control animals were given deionized water. Cu was an order of magnitude more toxic intravenously than orally as judged by the Cu dose. The high affinity uptake of dopamine, 5-hydroxytryptamine and noradrenaline did not change in striatal, hypothalamic and cortical synaptosomes, respectively, after these Cu administrations. A single dose of 300 mg/kg Cu orally was lethal and increased hypothalamic Cu by 13% and cortical Cu by 26%. Lower doses increased neither blood nor brain Cu significantly 24 hrs after administration of Cu. After the 3 week administration of 600 mg/l Cu in drinking water blood Cu had increased by 22% and cerebral Cu by 19%. The results indicate that Cu is not liable to affect monoamine uptake in nerve endings in vivo. This may be explained by effective endogenous protective mechanisms against Cu.     

Biogenic monoamine uptake by rat brain synaptosomes during aging. Effects of nootropic drugs

1. In experiments on young (3–5-month-old), adult (10–11-month-old) and old (21–22-month-old) rats, it was found that significant age-related changes occurred in the high-affinity uptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) by cortical and striatal synaptosomes.2. Changes in DA, NA and 5-HT uptake during aging are suggested to be neurochemical correlates of cognition and memory deficits that develops in senescence.3. The in vitro effects of the nootropic drugs piracetam, aniracetam, meclofenoxate and adafenoxate on the DA, NA and 5-HT uptake by cortical and striatal synaptosomes from young rats were studied. Administered in increasing concentrations (1 × 10⁻⁴ to 5 × 10⁻³ M) these drugs inhibited monoamine uptake.4. Adafenoxate proved to be a more potent monoamine uptake inhibitor than the other three drugs; it inhibited the uptake in the frontal cortex and striatum without selectivity for either monoaminergic system. It is suggested that adafenoxate affects cognition through the involvement of central neurotransmission and particularly through the inhibition of monoamine uptake systems.     

Effect of cocaine and 5-HT3 receptor antagonists on 5-HT-induced [3H]dopamine release from rat striatal synaptosomes.

The effect of serotonin (5-HT) on the release of tritium from striatal synaptosomes previously loaded with [3H]dopamine ([3H]DA) was studied. 5-HT stimulated both the spontaneous and Ca(2+)-evoked efflux of tritium in a concentration-dependent manner. This effect was not mimicked by the non-selective 5-HT agonist, d-lysergic acid diethylamide. Further, the stimulatory effects of 5 muM 5-HT were unaffected by the selective 5-HT3 receptor antagonists, MDL-72222 and GR-38032F. On the other hand, cocaine and the selective DA uptake inhibitor, nomifensine completely antagonized the effect of 5 muM 5-HT on spontaneous tritium efflux with IC50 values of 0.2 and 0.09 muM, respectively. The effect of 5-HT on Ca(2+)-evoked tritium efflux was also blocked by these DA uptake inhibitors, albeit at somewhat higher concentrations. These data support the hypothesis that 5-HT induces the release of DA from striatal nerve terminals via a mechanism involving the transport of 5-HT into the dopaminergic terminal, rather than by activating 5-HT3 receptors as has been proposed to account for the effect of 5-HT observed in striatal slices.     

Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants

The peripheral administration of tetrabenazine (TBZ) induces rapid depletion of brain regional concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). With respect to both dosage and time, striatal DA was most sensitive to the effects of TBZ while hypothalamic NE was least affected. Pretreatment with the monoamine oxidase (MAO)-inhibitor, clorgyline (1-6 mg/kg) dose-dependently prevented the reduction of all three monoamines for up to 60 min after TBZ (3 mg/kg). The TBZ-induced depletion of cortical NE was also significantly antagonized by desmethylimipramine (DMI) but was of shorter duration (up to 30 min after TBZ). DMI, however, did not influence the effect of TBZ on striatal DA or hypothalamic 5-HT. The protective effects of both clorgyline and DMI were also evident under the conditions of the behavioral TBZ test utilizing high doses of TBZ (20 mg/kg).     

Time course of changes in nociception after 5,6-dihydroxytryptamine lesions of descending 5-HT pathways

Intrathecal injection of 5,6-dihydroxytryptamine (5,6-DHT) in rats produced selective lesions of the descending 5-HT pathways. Spinal 5-HT levels gradually fell to less than 10% of controls within 10 days of 5,6-DHT administration with no recovery evident within 4 weeks. The uptake of ¹⁴C-5-HT into crude spinal synaptosomes was similarly reduced. The uptake of ³H-NA into spinal synaptosomes was unaffected, as was the uptake of ¹⁴C-5-HT and ³H-NA into cortical synaptosomes. Following 5,6-DHT, tail-flick latencies were reduced by 20–30% during the first post-injection week, but returned to control levels during the second week. Intrathecal or systemic administration of the 5-HT receptor antagonist metergoline significantly reduced latencies of normal rats and of 5,6-DHT treated rats tested after the second week when the response was normalized. Metergoline did not, however, further reduce the latencies of lesioned rats during the first post-injection week. It is concluded that functional adaptation involving 5-HT neurotransmission compensated for the selective lesion of descending 5-HT pathways induced by 5,6-DHT.     

Changes induced by corticosterone and adrenalectomy in synaptosomal and platelet uptake and binding of 5-HT: The relationship to [3H]imipramine binding

A comparative study of the effect of adrenalectomy, treatment with corticosterone, and imipramine on platelet and synaptosomal uptake was undertaken. One day after adrenalectomy, uptake of 5-hydroxytryptamine (5-HT) in the platelet and the hypothalamus was significantly decreased with an increase in the apparent K_m, but the uptake of 5-HT of the cerebral synaptosomes was unchanged. In this group, the k_d) of low affinity binding of 5-HT was also increased in the hypothalamic synaptosomes and in the platelet preparations. Treatment with cortieosterone (5 $\text{mg}\text{kg}$, i.m.) restored the decrease in the uptake of 5-HT induced by adrenalectomy in the hypothalamic synaptosomes and in the platelets, and significantly increased the uptake of 5-HT of these fractions in sham-operated rats. The binding of 5-HT was unchanged by acute treatment with corticosterone. The effectiveness of imipramine varied with the preparation and treatment group. The IC₅₀ of the cerebral synaptosomal preparation was greater than that of the hypothalamic synaptosomal preparation. Using this latter preparation, the IC₅₀ for imipramine in adrenalectomised, sham-operated and corticosterone-treated rats were found to be 0.04, 0.09 and 0.25 μM, respectively. These changes in sensitivity to imipramine were not reflected in the binding of [³H]imipramine which was unchanged.     

铅接触者单胺类神经生化的改变

铅接触者暴露于0.56±0.46 mg/m~3空气铅180d,血铅达到3.57～3.98μmol/L时,FEP含量超过正常值上限4～6倍。外周血淋巴细胞DA受体含量降低,尿液HVA排泄量增加以及血小板主动摄取[~3H]5-HT能力下降。提示铅可影响人体单胺类神经元的生化过程,干扰DA神经递质,可能是铅中毒某些神经行为异常的原因。     

Ceramide-induced alterations in dopamine transporter function

The purpose of this study was to determine the effects of ceramide on dopamine and serotonin (5-HT, 5-hydroxytryptamine) transporters. Exposure of rat striatal synaptosomes to C2-ceramide caused a reversible, concentration-dependent decrease in plasmalemmal dopamine uptake. In contrast, ceramide exposure increased striatal 5-HT synaptosomal uptake. This increase did not appear to be due to an increased uptake by the 5-HT transporter. Rather, the increase appeared to result from an increase in 5-HT transport through the dopamine transporter, an assertion evidenced by findings that this increase: (1) does not occur in hippocampal synaptosomes (i.e., a preparation largely devoid of dopamine transporters), (2) occurs in striatal synaptosomes prepared from para-chloroamphetamine-treated rats (i.e., a preparation lacking 5-HT transporters), (3) is attenuated by pretreatment with methylphenidate (i.e., a relatively selective dopamine reuptake inhibitor) and (4) is inhibited by exposure to exogenous dopamine (i.e., which presumably competes for uptake with 5-HT). Taken together, these results reveal that ceramide is a novel modulator of monoamine transporter function, and may alter the affinity of dopamine transporters for its primary substrate.     

Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats

We examined the effect of dietary selenium (Se) on the long-term effect of 3,4-methylenedioxymethamphetamine (MDMA) on dopamine (DA) and 5-hydroxytryptamine (5-HT) containing neurons in the brain of mice and rats. Animals were fed either a Se-deficient (<0.02 ppm) or Se-replete (0.2 ppm) diet for 8 weeks. On the seventh week mice received three injections of MDMA (15 mg/kg, i.p. 3 h apart) or saline and rats a single dose of MDMA (12.5 mg/kg i.p.) or saline. All animals were sacrificed 7 days later. MDMA administration to mice depleted striatal DA concentration in both dietary groups, although depletion was considerably larger in the Se-deficient mice (64%) than Se-replete mice (30%). In addition, a decrease in 5-HT (17-32%) occurred in brain regions of Se-deficient but not Se-replete mice. In rats, MDMA decreased cortical [(3)H]-paroxetine binding (62%) and 5-HT content, the depletion being similar in the Se-deficient and Se-replete groups. No DA loss occurred in either group. There was no difference in the hyperthermic response induced by MDMA in Se-deficient or Se-replete animals. The Se-deficient diet decreased glutathione peroxidase (GPx) activity by 30% in mouse striatum and cortex and increased the degree of lipid peroxidation in cortical synaptosomes. Se-deficient rats also showed a decrease in brain GPx activity compared with the Se-replete group, but the degree of lipid peroxidation in synaptosomes was similar in both dietary groups. These results suggest that the antioxidant capacity of rats and mice differ leading to a differential susceptibility to the oxidative stress caused by MDMA in situations of low dietary Se.     

Effects of taurine,homotaurine and GABA on hypothalamic and striatal dopamine metabolism

Summary To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of -aminobutyric acid (GABA) and homotaurine (a GABA_A-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 mol/rat, and rat were sacrificed 15 and 60 min later, respectively.Homotaurine (by 11010) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 mol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 mol the amino acids decreased striatal 3-MT by about 40%. At 36 mol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 mol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 mol but not at 36 mol slightly (20%) increased DA.These results show that taurine and homotaurine clearly alter the hypothalamic DA metabolism, and give further support to the suggestion that taurine and homotaurine similarly to GABA reduce the release of DA in the striatum. Homotaurine seems to alter the striatal DA metabolism more effectively than taurine or GABA. On the other hand, hypothalamic DA seems to be equally sensitive to taurine and homotaurine, and is clearly less sensitive to GABA. The pronounced elevation of hypothalamic DA and DOPAC after taurine and homotaurine could be related to changes in hypothalamic NA. Send offprint requests to L. Ahtee at the above address     

Neurotoxicity of the organochlorine insecticide heptachlor to murine striatal dopaminergic pathways.

Changes in biochemical status of nerve terminals in the corpus striatum, one of the primary brain regions affected in Parkinson's disease, were studied in groups of C57BL/6 mice treated by ip injection three times over a 2-week period with 3--100 mg/kg heptachlor. On average, the maximal rate of striatal dopamine uptake increased > 2-fold in mice treated at doses of 6 mg/kg heptachlor and 1.7-fold at 12 mg/kg heptachlor. Increases in maximal rate of striatal dopamine uptake were attributed to induction of the dopamine transporter (DAT) and a compensatory response to elevated synaptic levels of dopamine. Significant increase in V(max) of striatal DAT was not observed at doses > 12 mg/kg, which suggested that toxic effects of heptachlor epoxide may be responsible for loss of maximal dopamine uptake observed at higher doses of heptachlor. In support of this conclusion, polarigraphic measurements of basal synaptosomal respiration rates from mice treated with doses of heptachlor > 25 mg/kg indicated marked, dose-dependent depression of basal tissue respiration. At doses of 6 and 12 mg/kg heptachlor, which increased expression of striatal DAT, uptake of 5-hydroxytryptamine into cortical synaptosomes was unaffected. Thus, striatal dopaminergic nerve terminals were found to be differentially sensitive to heptachlor. This reduced sensitivity of serotonergic pathways was mirrored in the greater potency of heptachlor epoxide to cause release of dopamine from preloaded striatal synaptosomes in vitro compared to release of serotonin from cortical membranes. These results suggest that heptachlor, and perhaps other organochlorine insecticides, exert selective effects on striatal dopaminergic neurons and may play a role in the etiology of idiopathic Parkinson's disease.     

Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue

There is increasing evidence linking dopamine (DA) to the long-term serotonergic (5-HT) neurotoxic effects of certain substituted amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA). The present study was undertaken to examine the importance of DA metabolism, uptake inhibition and release in the long-term effects of these drugs by combining various dopaminergic agents with an analogue of MDMA that had low neurotoxic liability, namely 5,6-methylenedioxy-2-aminoindan (MDAI). Monoamine and metabolite levels and the number of 5-HT uptake sites (using [³H]paroxetine binding) were determined 3 hours or 1 week after treatments. Combining the monoamine oxidase inhibitors, clorgyline (MAO_A selective) or deprenyl (MAO_B selective) with MDAI did not result in any long-term reductions of serotonergic markers. Similarly, combining the DA uptake inhibitor GBR-12909 with MDAI did not result in any long-term changes in monoamine levels at 1 week. In contrast, a single pretreatment or posttreatment with the nonvesicular DA releaser S-amphetamine and MDAI resulted in small but significant long-term changes in monoamine levels. More importantly, if a subacute dosing regimen (every 12 hours for 4 days) was utilized, the combination of S-amphetamine with MDAI resulted in a marked long-term decrease in the levels of cortical, hippocampal and striatal 5-HT, 5-HIAA and the number of 5-HT uptake sites. The results are discussed in terms of the significance of DA and especially nonvesicular DA release in the long-term effects of MDMA-like drugs.     

Effects of DM-9384, a pyrrolidone derivative, on ischemia-induced changes in the central monoamine systems.

Alterations in brain tissue levels of monoamines and monoamine metabolites were studied in gerbils 60 min after cerebral ischemia induced by 10 min carotid ligation after pretreatment with the antiischemic drug DM-9384 (1, 3, 10, 30 mg/kg, PO). The DA levels decreased in striatum after the ischemia, while cortical and hippocampal DA levels increased. The DOPAC levels increased in cortex, but were essentially unaffected in other regions. The HVA levels increased in all forebrain regions studied. NA levels decreased in hippocampus and superior colliculus, while a general increase in MHPG levels was seen. Decreases in 5-HT levels were seen in all forebrain regions except cortex. The 10 mg/kg and 30 mg/kg doses of DM-9384 counteracted the decrease in striatal 5-HT and hypothalamic MHPG/NA ratio, respectively. Thus pretreatment with DM-9384 exerted minor protective effects on the alterations induced in monoamine systems by transient forebrain ischemia.     

Tetrahydro-β-carbolines and Corresponding Tryptamines: In Vitro Inhibition of Serotonin,Dopamine and Noradrenaline Uptake in Rat Brain Synaptosomes

Abstract The structure activity relationships of tryptolines and some other β-carbolines and tryptamines as inhibitors of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) uptake were studied in rat brain synaptosomes. All β-carbolines inhibited to higher degree the uptake of 5-HT than that of DA or NA (IC50's 5–100 times lower). The most potent tryptoline derivative was 6-hydroxy-tetrahydro-β-carboline (5-hydroxytryptoline, 6-OH-THBC) with an IC50 of 5.0× 10^-7M at a 5-HT concentration of 10^-7M. 6-Methoxy-tetrahydro-β-carboline (5-methoxytryptoline) was slightly weaker; the inhibition of 5-HT uptake and DA uptake being competitive. Also tetrahydro-β-carboline (tryptoline) was more potent than its 1-methylderivative, tetrahydroharmane (methtryptoline) or norharmane (β-carboline). All of them were, however, weaker inhibitors of 5-HT uptake than the freely rotating indoleamines N-methyl-tryptamine (N-Me-T) or 5-HT itself. N-Me-T and 5-HT were also more potent inhibitors of DA and NA uptake than most of the β-carbolines, DA uptake, however, was inhibited better by 6-OH-THBC than by 5-HT or N-Me-T. Tetrahydro-β-carbolines may inhibit 5-HT uptake also in vivo but it is unlikely that catecholamine uptake is affected.