Effect of (+)-Amphetamine on the Retention of 3H-Catecholamines in Slices of Normal and Reserpinized Rat Brain and Heart

Abstract The effect of reserpine on the inhibition by (+)-amphetamine and cocaine of the accumulation of ³H-dopamine (DA) in striatal slices and ³H-noradrenaline (NA) in slices of cerebral occipital cortex and heart atrium of rats and the release of the ³H-amines from these tissues were examined. Reserpine (5 mg/kg intraperitoneally) was injected 18 hours before the experiments. It was found that reserpine markedly enhanced the in vitro potency of amphetamine in the striatum and heart but only slightly in the cortex. After administration in vivo (+)-amphetamine was about 10 times more potent in reducing the amine accumulation in the cortex as in the striatum. Reserpine enhanced the effect in both regions. The inhibitory potency of cocaine in vitro was unchanged by reserpine in the striatum but was reduced in the cortex and heart. Reserpine did not change the inhibitory potency of desipramine in the cortex and heart. The release of the ³H-amines by (+)-amphetamine was enhanced by reserpine in the striatum and heart but the small release produced in the cortex was not increased. The release produced by cocaine was similarly enhanced by reserpine but cocaine was much less active than (+)-amphetamine. The results indicate that (+)-amphetamine and cocaine inhibit the amine accumulation by different mechanisms.     

A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying agents

1. Effects on 5-HT function of sibutramine and its active metabolites, BTS 54 354 and BTS 54 505, were compared with fluoxetine, (+)-fenfluramine and (+)-amphetamine.
2. In vitro sibutramine weakly inhibited [³H]-5-HT uptake into brain synaptosomes. BTS 54 354, BTS 54 505 and fluoxetine were powerful [³H]-5-HT uptake inhibitors, whereas (+)-fenfluramine and (+)-amphetamine were very much weaker. Conversely, whilst sibutramine, its metabolites and fluoxetine did not release [³H]-5-HT from brain slices at ?10^?5M, (+)-fenfluramine and (+)-amphetamine concentration-dependently increased [³H]-5-HT release.
3. Sibutramine and fluoxetine had no effect on 5-hydroxytryptophan (5-HTP) accumulation in either frontal cortex or hypothalamus at doses <10 mg kg^?1. In contrast, (+)-amphetamine (?3 mg kg^?1) reduced 5-HTP in hypothalamus, whilst (+)-fenfluramine (?1 mg kg^?1) decreased 5-HTP in both regions.
4. Sibutramine (10 mg kg^?1 i.p.) and fluoxetine (10 mg kg^?1 i.p.) produced slow, prolonged increases of extracellular 5-HT in the anterior hypothalamus. In contrast, (+)-fenfluramine (3 mg kg^?1 i.p.) and (+)-amphetamine (4 mg kg^?1 i.p.) induced rapid, short-lasting increases in extracellular 5-HT.
5. Only (+)-fenfluramine (10 mg kg^?1) altered 5-HT_2A receptors in rat frontal cortex when given for 14 days, producing a 61% reduction in receptor number and a 18% decrease in radioligand affinity.
6. These results show that sibutramine powerfully enhances central 5-HT function via its secondary and primary amine metabolites; this effect, like that of fluoxetine, is almost certainly mediated through 5-HT uptake inhibition. By contrast, (+)-fenfluramine enhances 5-HT function predominantly by increasing 5-HT release. (+)-Amphetamine, though weaker than (+)-fenfluramine, also enhances 5-HT function by release.

     

Dissociating effects of cocaine and <Emphasis Type="Italic">d</Emphasis>-amphetamine on dopamine and serotonin in the perirhinal,entorhinal, and prefrontal cortex of freely moving rats

Rationale Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. Objective The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). Materials and methods We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). Results Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. Conclusions We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.     

Tetrahydro-β-carbolines and Corresponding Tryptamines: In Vitro Inhibition of Serotonin and Dopamine Uptake by Human Blood Platelets

Abstract Tetrahydro-β-carbolines (THBCs), 6-methoxyharmalan and norharman and the corresponding open chain tryptamines studied inhibited 5-hydroxytryptamine (5-HT) and dopamine (DA) uptake in human blood platelets. 1-methyl-THBCs were better inhibitors of DA than 5-HT uptake but THBCs generally were far more potent inhibitors of 5-HT uptake than of DA uptake. 6-methoxy-1,2,3,4-tetrahydro-β-carboline was as potent as 5-HT itself in ³H-5-HT uptake inhibition in platelets and the inhibition was competitive. All the β-carbolines studied were more potent inhibitors of ³H-DA uptake than DA itself. Contrary to results in rat brain synaptosomes, THBCs were more potent in platelets than the corresponding tryptamines with the freely rotating ethylamine side chain. Unsaturated β-carbolines were weaker inhibitors than THBCs. The clear difference in the rank order of potencies of these compounds in human platelets and rat brain synaptosomes demonstrates that these different model systems for amine uptake studies do not always give comparable results. The results also suggest that there are differences in the uptake systems for 5-HT and DA in human platelets.     

Effect of a specific 5-HT uptake inhibitor,citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro

The uptake of ³H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of ³H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of ³H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with ³H-5-HT is specific for 5-HT neurons.The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of ¹⁴C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain.When rats were treated orally with citalopram or chlorimipramine, the inhibition of ³H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.     

The transport of (+)-amphetamine by the neuronal noradrenaline carrier

Summary PC-12 cells (a clonal line of rat phaeochromocytoma cells) take up noradrenaline by a transport system which is identical with the neuronal amine transport system (uptake₁). The uptake of ³H-noradrenaline into reserpine-pretreated PC-12 cells (monoamine oxidase inhibited) was saturable (K_m=0.6±0.1 mol/l), dependent on sodium and chloride, and competitively inhibited by (+)-amphetamine (K_i=0.18±0.04 mol/l), cocaine (K_i=0.55±0.15 mol/l) and desipramine (K_i=4.3±0.6 nmol/l). The uptake and accumulation of ³H (+)-amphetamine showed characteristics comparable to those of ³H-noradrenaline, since the uptake of ³H (+)-amphetamine (0.1 mol/l) was reduced by omission of sodium or chloride from the incubation medium. The sodium-sensitive component of uptake and accumulation of ³H (+)-amphetamine was fully inhibited by cocaine and desipramine. The IC₅₀ of desipramine for inhibition of the sodium-sensitive component of the 1-min uptake of ³H (+)-amphetamine (20 nmol/l) was about 2 nmol/l, i.e., identical with the K_i for inhibition of uptake of ³H-noradrenaline. At concentrations above 1 mol/l, desipramine additionally caused an inhibition of the sodium-independent permeation of ³H (+)-amphetamine into PC-12 cells.Hence, by using a homogeneous population of cells endowed with uptake₁, it is possible to demonstrate — besides a pronounced lipophilic entry — a carrier-mediated uptake of ³H (+)-amphetamine.Some of the results were communicated to the German Pharmacological Society (Bönisch 1981). This study was supported by the Deutsche Forschungsgemeinschaft (Bo 521)     

The Uptake of 6-Methoxy-1,2,3,4-Tetrahydro-β-carboline and its Effect on 5-Hydroxytryptamine Uptake and Release in Blood Platelets

Abstract The uptake of 6-methoxy-1,2,3,4-tetrahydro-β-carboline (6-MeOTHBC, 5-methoxytryptoline) by rabbit blood platelets was studied by using ³H-labelled compound. A high rate active uptake (Km 6.6 μM), which was inhibited by 5-hydroxytryptamine (5-HT) and cinnanserine, and a slow rate uptake, not inhibited by 5-HT were observed. The intracellular distribution of ³H-6-McOTHBC in platelets clearly differed from that of ¹⁴C-5-HT. 6-MeOTHBC also competitively inhibited the high-rate active (but not the slow passive) uptake of ¹⁴C-5-HT, being more active than 5-HT itself. The spontaneous release of the newly taken-up ¹⁴C-5-HT from platelets was increased only with high concentrations of 6-MeOTHBC.     

Effect of sympathomimetic amines on the synaptosomal transport of noradrenaline,dopamine and 5-hydroxytryptamine

The interaction of sympathomimetic amines with the transport of ³H-noradrenaline (³H-NE), ³H-dopamine (³H-DA) and ³H-5-hydroxytriptamine (³H-5-HT) were investigated in rat hypothalamic (³H-NE) and striatal (³H-DA and ³H-5-HT) synaptosomes. Modifications in the phenylethylamine structure led to changes in activity towards biogenic amine uptake and release: (a) the introduction of a β-OH group led to compounds less active in inhibiting uptake and stimulating release of ³H-NE, ³H-DA and ³H-5-HT, with the exception of ³H-NE release which was stimulated more by unlabeled 1-NE than by DA; (b) the introduction of phenolic -OH groups always led to compounds which were stronger uptake inhibitors and releasers of the three biogenic amines; (c) the α-methylation increased the potency towards uptake inhibition and release stimulation, with the exception of ³H-NE release: in fact, the releasing activity of phenylethylamine was suppressed by α-methylation; (d) the introduction of a -Cl group in the para position selectively potentiated the effects on ³H-5-HT uptake and release and generally depressed those on catecholamine transport.     

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.     

Effect of two non tricyclic antidepressant drugs on [14C]5-hydroxytryptamine uptake by rat platelets

The uptake of ¹⁴C-5-HT by rat blood platelets was examined in vitro in experimental conditions which allowed measurement of the initial velocity and excluded other passive processes across the cell membrane. In these conditions, the effect of two non tricyclic antidepressant drugs (Lilly 110140 and trazodone) was investigated. Lilly 110140 was as active as chlorimipramine and several times more active than imipramine as an inhibitor of ¹⁴C-5-HT uptake. Like chlorimipramine, Lilly 110140 appeared to be either a non-competitive or an uncompetitive inhibitor, according to the concentration of drug used. Trazodone also inhibited ¹⁴C-5-HT uptake by platelets but to a lesser extent than chlorimipramine, imipramine or Lilly 110140. m-Chlorophenylpiperazine, a possible metabolite of trazodone, was about 3 times more potent an inhibitor than the parent molecule. Both compounds acted non-competitively. Compared with published data on the effect of Lilly 110140 and trazodone on brain 5-HT, the present results support the suggestion that rat platelets are a useful pharmacological model of serotoninergic nerve endings.     

Uptake of 14C-5-hydroxytryptamine by human and rat platelets and its pharmacological inhibition

Summary In order to approach the uptake of ¹⁴C-5HT by platelets as a first-order process, experimental conditions were selected in which accumulation of the amine either by diffusion or by other passive nonsaturable processes could be excluded. These conditions included an incubation period of ¹⁴C-5HT with human or rat platelets of 4 min or 30 s, respectively and the use of substrate concentrations around the calculated apparent K _m values (0.25–2.0 M). While the apparent K _m values were rather similar for human and rat platelets, V _max was about 5 times higher in rat than in human platelets.The kinetic model adopted in this study was used to evaluate the relative potency and the type of inhibition of ¹⁴C-5HT uptake exhibited by imipramine, chlorimipramine and (+)-fenfluramine. All 3 compounds inhibited ¹⁴C-5HT uptake by platelets. Chlorimipramine was about 10 times more effective than imipramine both in rat and in human platelets. Both drugs were more potent inhibitors on human than on rat platelets. (+)-Fenfluramine was almost as active as imipramine on rat but 30 times less potent than imipramine on human platelets. Both imipramine and chlorimipramine inhibited ¹⁴C-5HT uptake by an apparent non-competitive mechanism, whereas (+)-fenfluramine appeared to act as a competitive inhibitor. No differences were found in this respect between human and rat platelets.Pharmacological or therapeutic doses of these drugs usually result in plasma concentrations similar to those found in this study to effectively inhibit platelet ¹⁴C-5HT uptake.     

Effect of Heavy Metals on Dopamine,Noradrenaline and Serotonin Uptake and Release in Rat Brain Synaptosomes

Abstract: The effects of some heavy metals on the initial high affinity uptake and spontaneous release of tritiated dopamine (³H-DA), noradrenaline (³H-NA) and 5-hydroxytryptamine (³H-5-HT) were studied in vitro in rat striatal, cortical and hypothalamic synaptosomes, respectively. As uptake inhibitors, metals were quite inactive in these conditions. At 10 μM Cu²⁺ was most potent, inhibiting ³H-DA and ³H-5-HT uptake nearly completely while inhibition of ³H-NA uptake varied. ³H-DA uptake was in addition inhibited slightly by Zn²⁺, sometimes by Sn²⁺ but never by Co²⁺, Hg²⁺ or Mn²⁺. Unexpectedly Pb²⁺ and Cd²⁺ tended to increase the synaptosomal ³H-DA uptake. ³H-5-HT uptake was affected least while that of ³H-NA showed some diversity. Zn²⁺, Pb²⁺ and Sn²⁺ induced inhibition of ³H-NA uptake possibly by direct interference with ³H-NA. As to the spontaneous release of tritiated amines during short incubation from preloaded synaptosomes, Cd²⁺ decreased that of ³H-DA at high concentrations but Hg²⁺, Pb²⁺, Sn²⁺ and Zn²⁺ were ineffective. The results suggest that in vitro the uptake and the release of ³H-DA are more affected than those of other amines. The inhibitory mechanisms of monoamine uptake may include both direct effects on synaptosomes and indirect ones by interference with the amines themselves.     

Tricyclic Antidepressant Agents. II. Effect of Oral Administration on the Uptake of 3H-Noradrenaline and 14C-5-Hydroxytryptamine in Slices of the Midbrain-Hypothalamus Region of the Rat

Abstract: The inhibition of the simultaneous uptake of ³H-l-noradrenaline (NA) and ¹⁴C-5-hydroxytryptamine (5-HT) in slices of the midbrain-hypothalamus region of the rat brain after oral administration of desipramine, imipramine, nortriptyline, amitriptyline, chlordesipramine and chlorimipramine was determined. All compounds were more active in inhibiting the NA uptake than the 5-HT uptake. This difference was very marked for desipramine, imipramine, nortriptyline and chlordesipramine. Chlorimipramine was almost as active on the 5-HT uptake (ED₅₀ = 35 mg/kg orally) as on the NA uptake (ED₆₀ = 20 mg/kg orally) and amitriptyline had low activity on both uptake mechanisms (ED₅₀ > 50 mg/kg orally). Desipramine and imipramine were the most active compounds on the NA uptake (ED₅₀ = 8 mg/kg orally for both compounds) and the duration of the action was very long. The ED₅₀ values for nortriptyline and chlordesipramine in inhibiting the NA uptake were about 20 mg/kg orally for both compounds. The inhibition of the 5-HT uptake was less than 50% at 50 mg/kg orally for all compounds except for imipramine (ED₅₀ = 50 mg/kg orally) and for chlorimipramine. The role of the biotransformation for the inhibitory activities of imipramine, chlorimipramine and amitriptyline was investigated in animals pre-treated with SKF 525 A. The inhibitory potency of imipramine was increased by the same factor for both uptake mechanisms probably due to the large increase in the concentration of imipramine in the rat brain, which was demonstrated after the administration of ¹⁴C-imipramine. The inhibitory activity of chlorimipramine was somewhat more increased for the 5-HT uptake than for the NA uptake. The low activity of amitriptyline seems to be mainly due to poor resorption, since pretreatment of the animals with SKF 525 A only slightly increased the potency whereas intraperitoneal injection of amitriptyline had a rather marked effect on the NA uptake (ED₅₀ = 11 mg/kg intraperitoneally).     

Investigation of possible interactions between substance P and transmitter mechanisms in the substantia nigra and corpus striatum of the rat

The effect of substance P (SP) on the uptake and release of radiolabelled dopamine (³H-DA), 5-hydroxytryptamine (³H-5-HT) and γ-aminobutyric acid (³H-GABA) was studied in slices of rat substantia nigra and corpus striatum. SP, 10^?9 to 10^?5m , failed to modify the uptakes of these compounds during incubations (10–90 min) with slices of either brain region. SP, 10^?6m , had no apparent effect on the spontaneous output of any of these compounds in either substantia nigra or corpus striatum. In the corpus striatum, SP seemed to potentiate the potassium-stimulated outflow of ³H-DA and ³H-5-HT, but not ³H-GABA, while the releases from substantia nigra were unaffected. Morphine (10^?3m ), but not met-enkephalin (5 × 10^?6m ), weakly antagonized K⁺-evoked release of ³H-DA in the corpus striatum. These results are discussed with reference to the possible interaction of SP with transmitter mechanisms at presynaptic sites in the central nervous system.     

Effect of fenfluramine on 5-hydroxytryptamine uptake and release by rat blood platelets.

1. (+)-Flenfluramine reduces the central stores of 5-hydroxytryptamine (5-HT) by a poorly understood mechanism. 2. Rat blood platelets have been used in this study as a simple model for serotoninergic nerve endings. 3. (+)-Fenfluramine shows a dual effect: it inhibits the uptake of (14C)-5-HT by platelets and it releases newly absorbed (14C)-5-HT from platelets. 4. The inhibition of (14C)-5-HT uptake induced by (+)-fenfluramine appears very rapidly, is concentration-dependent and seems not to be competitive. (+)-Fenfluramine is ten times less effective than chloroimipramine but tem times more effective than (+)-amphetamine; (+)-fenfluramine is more active than its (-)isomer or its metabolite norfenfluramine ((+)- or (-)-form). 5. The release of (14C)-5-HT from platelets induced by (+)-fenfluramine is concentration-dependent but increases wtih increased incubation time. Both chloroimipramine and (+)-amphetamine are in comparison very poor release inducers; (+)-fenfluramine is more active than its (-)-isomer or its metabolites. 6. The effect on (14C)-5-HT uptake exerted by (+)-fenfluramine and chloroimipramine in vitro could not be observed in vivo. 7. The observed effect on fenfluramine on the uptake and release of 5-HT may explain the lowering action of fenfluramine on the brain 5-HT level, an effect considered of importance for the anoretic effect on this drug.     

(Z)-Dimethylamino-l-(4-bromophenyl)-l-(3-pyridyl) propene (H 102/09), a New Selective Inhibitor of the Neuronal 5-Hydroxytryptamine Uptake

Abstract The inhibition of the uptake of ³H–(–)–noradrenaline (NA), ³H–dopamine and ¹⁴C–5–hydroxytryptamine (5–HT) in mouse brain slices by (Z)–3–dimethylamino–l–(4–bromophenyl)–l–(3–pyridyl)propene (H 102/09), desipramine and chlorimipramine and their releasing effect on the ³H–amines previously accumulated in the slices were examined. The interactions with reserpine produced hypothermia and sedation and the 5–hydroxytryptophan (5–HTP) syndrome in mice were also studied. Due to the poor inhibitory activity on the NA uptake H 102/09 was a more selective inhibitor of the 5–HT uptake than was chlorimipramine, particularly after administration in vivo, where it was as potent as chlorimipramine (ED50 = 19 μmol/kg intraperitoneally). In vitro chlorimipramine was 6 to 12 times more active than H 102/09. Desipramine was a very selective inhibitor of the NA uptake in vitro and in vivo. The compounds were generally more potent in inhibiting the uptake than in releasing the amines. However, in striatal slices the inhibition of DA uptake could be due to the releasing effect since the difference in potencies were small. The effect of desipramine on 5–HT uptake and that of H 102/09 on NA uptake could also involve a release component. The 5–HTP syndrome was potentiated by H 102/09 and chlorimipramine but not by desipramine. The reserpine hypothermia but not the sedation was potently antagonized and reversed by desipramine and by chlorimipramine at high doses but not by H 102/09, suggesting that NA but not 5–HT is involved in the hypothermic action of reserpine.     

Effect of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) on the uptake and release of 14C-5-hydroxytryptamine by rabbit blood platelets

The uptake of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) into rabbit blood platelets and the effect of DOM on uptake and release of 5-hydroxytryptamine (5-HT) from platelets have been investigated. Tritium labeled DOM was taken up slightly against the concentration gradient. DOM in concentrations ranging from 5 × 10^?5 to 1 × 10^?3 M did not affect ¹⁴C-5-HT uptake into platelets. However, it increased the ¹⁴C-5-HT release from platelets by 100 and 300% at 2 × 10^?4 and 1 × 10^?3 M respectively when platelets were incubated in Krebs-Ringer phosphate buffer, but exerted no effect on the release of ¹⁴C-5-HT from the platelets when incubated in 0.9% saline. The mechanism and significance of the increase of ¹⁴C-5-HT release from platelets by DOM were discussed.     

Interactions between reserpine and various compounds on the accumulation of [14C] 5-hydroxytryptamine and [3H]noradrenaline in homogenates from rat hypothalamus.

The effect of reserpine, 5 mg/kg i.p., on the potencies of various compounds in inhibiting the accumulation of [¹⁴C] 15-hydroxytryptamine (5-HT) and [³H] (?)-noradrenaline (NA) in synaptosome-rich homogenates from rat hypothalamus was examined. It was found that some compounds, e.g. tryptamine, α-methyltryptamine, (+)-amphetamine and 4-chloroamphetamine, were considerably more potent in inhibiting the 5-HT accumulation in the reserpinized preparation than in the control preparation, whereas other compounds, e.g. chlorimipramine, zimelidine, norzimelidine, fluoxetine, alaproclate and desipramine, had the same activities in the two preparations. The inhibitory potencies of the same compounds on the [³H] NA accumulation was, on the other hand, not influenced by reserpine. The results indicate that tryptamines and amphetamines inhibit the 5-HT accumulation by releasing 5-HT rather than inhibiting its uptake. The same conclusion cannot be drawn for the inhibitors of the NA accumulation.     

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.     

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED₅₀ of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substututions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.Portions of this research were presented at the Ninth Annual Meeting of the Society for Neuroscience Atlanta, Georgia, November 2–6, 1979