On the mechanism of the coronary dilator effect of serotonin in the dog.

In experiments designed to determine the nature of the coronary dilator effect of serotonin the influence of intracoronary administration of the amine on coronary perfusion pressure, heart rate and ventricular contractile force was assessed in anesthetized open-chest dogs in which the left coronary artery was perfused with blood at a constant rate. Serotonin elicited dose-related decreases in coronary perfusion pressure and increases in contractile force, and lowered heart rate slightly. The dilator response was antagonized by methysergide, slightly potentiated by practolol and unaffected by reserpine. The inotropic effect was partially antagonized by methysergide and completely blocked by practolol and reserpine. It is concluded that serotonin induces coronary dilatation by direct stimulation of specific receptors that this effect is independent of the cardiac stimulation produced by the amine, and the latter response is mediated through beta1-adrenoceptors activated by released norepinephrine.     

The effects of quipazine on 5-HT metabolism in the rat brain

Summary Since quipazine is a potent 5-HT agonist in peripheral organs, its possible stimulatory effects on serotoninergic receptors in the rat brain were investigated. Quipazine administration (10 mg/kg, i.p.) induced a significant decrease in the synthesis and turnover rates of serotonin in the brain stem as well as in the forebrain. It is not likely that these changes were mediated by a negative feed-back mechanism triggered by adirect action of quipazine on central 5-HT postsynaptic receptors. Indeed, in contrast to LSD and 5-methoxy-N,N-dimethyltryptamine, this compound failed to activate the 5-HT sensitive adenylate cyclase in colliculi homogenates of newborn rats. However, quipazine exerted direct effects on serotoninergic terminals. It inhibited competitively the reuptake process in synaptosomes (Ki =1.38×10^–7 M) and stimulated the K⁺ evoked release of newly synthesized³H-5-HT in slices of the brain stem. Injected in vivo in a dose which affected 5-HT uptake and release, quipazine did not modify MAO activity. However, this activity was noncompetitively inhibited by high concentration of the drug in vitro (Ki=3.0×10^–5 M). These actions are very likelyindirectly responsible for the stimulation of central 5-HT receptors.     

Cyclic AMP and cyclic GMP in the rat gastric mucosa

Summary Mice were given various 7-day treatments designed to reduce cerebral noradrenergic function. Following these treatments, alterations in the sensitivity of limbic forebrain adenylate cyclase to noradrenaline (NA), and in the locomotor response of the mice to dopaminergic and noradrenergic agonists were studied. An enhanced response of the NA-sensitive adenylate cyclase to 1-NA (10^–5 M), in comparison to control mice, was demonstrated after treatments producing a chronic reduction in stimulation of -adrenergic receptors (phenoxybenzamine 10 mg/kg per day), -adrenergic receptors (propranolol, 0.05% diet), all noradrenergic receptors (reserpine 5 mg/kg, followed by FLA-63, 25 mg/kg per day), and dopaminergic as well as noradrenergic receptors (chlorpromazine, 5 mg/kg per day). Sensitivity of the NA-stimulated adenylate cyclase was not altered by chronic treatment with FLA-63 alone as a 0.05% diet. However, none of the chronic treatments except chlorpromazine administration increased the locomotor activity recorded for 2 h following apomorphine (1 mg/kg, s.c.) and none of the treatments altered the locomotor activity recorded in the 2 h following administration of the -adrenergic agonist clonidine (1 mg/kg, i.p.), or a combination of apomorphine (1 mg/kg, s.c.) plus clonidine (1 mg/kg, i.p.) The results support the hypothesis that noradrenergic stimulation plays a role secondary to that of dopamine in the production of locomotor activity.     

The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra,striatum and limbic forebrain in vivo

Summary The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT_1A receptor agonist 8-OH-DPAT, the 5-HT_1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066B and RU 24969, the 5-HT_1A/1B antagonist (±)pindolol, the 5-HT_2/1C receptor antagonist ritanserin, the 5-HT_2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI), the 5-HT₃ receptor antagonist BRL 43 694, the unselective 5-HT₁ receptor antagonist methiothepin, and carbidopa+L-5-hydroxytryptophan (L5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT_1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT₁ receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethylphenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%–220% of controls. In the limbic forebrain also the highest dose of RU 24 969 (15 mg/kg) increased the 3-MT accumulation (78%), whereas in the striatum the lowest does of the drug (1.5 mg/kg) decreased it by 30%. The trifluoromethylphenylpiperazine-induced stimulation of 3-MT accumulation was not blocked by ritanserin. In the limbic forebrain, also DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and carbidopa+Lr5-HTP treatment increased the 3-MT concentrations to 120% and 150% of controls, respectively. Paradoxically, methiothepin also induced an increase of the 3-MT accumulation in these brain regions, probably due to its DA receptor antagonism. None of the other serotoninergic drugs induced any pronounced effects on the 3-MT accumulation in these brain parts. The results may overall support the hypothesis that 5-HT₁ does modulate the DA activity in the striatum and limbic forebrain, tentatively via 5-HT_1B receptors in the striatum and 5-HT_1B and 5-HT₂ or 5-HT_1C receptors in the limbic forebrain. It may be speculated therefore, that clinical application of 5-HT₁ receptor-modulating drugs to influence central dopaminergic activity might be of therapeutical benefit, for example, in motor disorders like Parkinson's disease. Send offprint requests to H. Nissbrandt at the above address     

Dopamine D-2 receptors inhibit D-1 stimulated cyclic AMP accumulation in striatum but not limbic forebrain

Summary The effect of dopamine D-2 receptor activtion on dopamine D-1 stimulated cyclic AMP accumulation was investigated in slices of rat striatum and limbic forebrain (nucleus accumbens and tuberculum olfactorium). In striatal slices the dose-dependent increase in cyclic AMP accumulation due to dopamine (3–100 mol/1) was enhanced by selective D-2 receptor blockade using (–)-sulpiride (30 mol/1). In limbic slices the increase in cyclic AMP due to dopamine (3–50 mol/l) was unaffected by selective D-2 receptor blockade. The enhancement of cyclic AMP accumulation due to the selective D-1 agonist SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 1 gmol/1) in striatal slices was attenuated in the presence of the selective D-2 receptor agonist LY 171555 (quinpirole hydrochloride; 10 mol/l). This attenuation was in turn blocked by (–)-sulpiride (10 mol/1). In limbic slices LY 171555 (10 mol/l) had no effect on SKF 38393 (1 mol/l) stimulated cyclic AMP accumulation. Conversely muscarine receptor activation, using carbachol (10 mol/l), attenuated D-1 stimulated cyclic AMP accumulation in both striatum and limbic forebrain. Dopamine D-2 or muscarine receptor stimulation in either striatal or limbic slices did not attenuate cyclic AMP accumulation due to VIP (vasoactive intestinal polypeptide; 0.5 mol/l), isoprenaline (10 mol/l) or 2-chloroadenosine (100 mol/l). This suggests that in striatal slices, D-2 receptors mediate a selective inhibition of D-1 stimulated cyclic AMP accumulation, but that in the limbic forebrain D-2 receptors are unlikely to be coupled to D-1 receptor-linked adenylate cyclase. These data indicate a fundamental difference in the properties of D-2 receptor-effector coupling in these brain regions. Send offprint requests to S. R. Nahorski at the above address     

Simultaneous determination of femtomole quantities of 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid in brain using HPLC with electrochemical detection

A simple rapid method for the determination of 5-hydroxytryptophan, serotonin (5-hydroxytryptamine), and 5-hydroxyindoleacetic acid in brain is presented. Brain proteins are precipitated with Zn(OH)2. The indoles in the supernatant are separated by HPLC in less than than 8 min on a reverse phase column and detected electrochemically. As little as 38 fmol of hydroxyindole compound can be detected and quantitated. Because the method is rapid and uncomplicated many samples can be processed in a day.     

The effect of nomifensine on the depletion of brain serotonin and catecholamines induced respectively by fenfluramine and 6-hydroxydopamine in rats.

Nomifensine, at a dose of 10 mg/kg i.p., completely antagonized the decrease of brain dopamine induced by an intraventricular injection of 6-hydroxydopamine. The decrease of brain noradrenaline was also significantly antagonized by nomifensine. Desipramine antagonized the effect of 6-hydroxydopamine on noradrenaline but not on dopamine. The decrease of brain serotonin induced by fenfluramine was antagonized by chlorimipramine but not by nomifensine. The findings indicate that nomifensine specifically blocks the uptake mechanism for catecholamines in the brain without significant effects on serotonin.     

Increased brain serotonin metabolism during rebound sleep in sleep-deprived rats

Adult male Wistar rats were almost totally deprived of sleep by handling for 24 hr. 5-Hydroxyindolacetic acid concentrations in the dorsal raphe nucleus area and thalamus increased by 140-180%, immediately after sleep deprivation and when the rats had a 3- or 30-min rebound sleep. The higher levels of 5-hydroxyindolacetic acid were still observed after the rats were awakening from a 4-hr sleep. The concentrations of 5-hydroxytryptamine (serotonin) decreased after sleep deprivation and increased during and after sleep, but the differences were not significant. Tryptophan accumulated in the dorsal raphe area and thalamus after sleep deprivation, and an elevated level did not return to baseline concentrations until the rats were awakening. Tryptophan hydroxylase activity did not change in the dorsal raphe area during and after sleep deprivation. These results suggest that the release and synthesis of 5-hydroxytryptamine in the dorsal raphe area and thalamus increased when the rats had a sleep pressure or a rebound sleep after total sleep deprivation. An increased transport of tryptophan into the brain may be closely involved in sleep-inducing mechanisms.     

高效液相色谱法AtlantisC18反相色谱柱检测生物样品中儿茶酚胺的研究

采用了AtlantisC18反相色谱柱（适用于分离极性分子的反相色谱柱），成功地分离了去甲肾上腺素（NA），肾上腺素（A），多巴胺（DA）等儿茶酚胺（CAs）类物质，研究了CAs在AtlantisC18和NovlepakC18柱的保留特性，比较了流动相中离子对试剂辛烷基磺酸钠（B8）浓度对CAs容量因子k’的作用，确认采用AtlantisC18柱分离CAs，色谱条件优化空间更大，更适于复杂生物样品分析。色谱条件：AtlantisC18柱，电化检测，流动相：NaH2PO4 50mmol／L、柠檬酸钠50mmol／L缓冲液-乙腈（体积比（75：25），检测限（S／N=2）在0．93—2．43pg，绝对回收率均在98．02％以上，样品日内RSD1．5％以下。方法精密、准确。     

Chronic antidepressant treatments increase basic fibroblast growth factor and fibroblast growth factor-binding protein in neurons

One of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic connections and plasticity in the hippocampus and cerebral cortex. Fibroblast growth factor 2 (FGF2) is a growth factor essential for the proper formation of synaptic connections in the cerebral cortex, maturation and survival of catecholamine neurons, and neurogenesis. In this report, we attempted to establish a correlation between antidepressant treatments and FGF2 expression in the cerebral cortex and hippocampus, two brain areas relevant for depression. Desipramine (DMI, 10 mg/kg) or fluoxetine (FLU, 5 mg/kg) was injected acutely (single injection) or chronically (daily injection for two weeks) in adult rats. Chronic, but not acute, antidepressant treatments increase FGF2 immunoreactivity in neurons of the cerebral cortex and in both astrocytes and neurons of the hippocampus. FGF2 immunoreactivity in the cortex was increased mainly in the cytoplasm of neurons of layer V. Western blot analyses of nuclear and cytosolic extracts from the cortex revealed that both antidepressants increase FGF2 isoforms in the cytosolic extracts and decrease accumulation of FGF2 immunoreactivity in the nucleus. To characterize the anatomical and cellular specificity of antidepressants, we examined FGF-binding protein (FBP), a secreted protein that acts as an extracellular chaperone for FGF2 and enhances its activity. DMI and FLU increased FBP immunoreactivity in both cortical and hippocampal neurons. Our data suggest that FGF2 and FBP may participate in the plastic responses underlying the clinical efficacy of antidepressants.     

The selective adenosine A2A receptor antagonist SCH 58261 discriminates between two different binding sites for [3H]-CGS 21680 in the rat brain

We have used quantitative autoradiography to further examine two previously described binding sites for [³H]-CGS 21680 in cortical regions and in striatum, respectively. The striatal binding sites largely represent classical adenosine A_2A receptors whereas the cortical sites show characteristics that differ from those of recognised adenosine receptors. A recently developed non-xanthine A_2A receptor antagonist SCH 58261 displaced the binding of [³H]-CGS 21680 from the A_2A receptors in striatum with an estimated K_i value of 2.4 nM, but was more than 1000-fold less potent in displacing its binding from cortex. Conversely, the adenosine analogue 2-chloro-NECA was found to be some 10 times more potent in displacing CGS 21680 from the cortical binding sites than from A_2A receptors. The results provide additional evidence that CGS 21680 binds not only to classical A_2A receptors, but also to sites that differ from defined adenosine receptors. They also suggest that effects of CGS 21680 observed in the presence of SCH 58261 might reveal the functional significance (if any) of these sites.     

Antidepressant activity of Asparagus racemosus in rodent models

Asparagus racemosus Linn. (AR) is an Ayurvedic rasayana used as an adaptogen. Adaptogenic drugs are those which are useful as anti-stress agents by promoting non-specific resistance of the body. Although, the adaptogenic effect of AR is well documented, its use in psychological disorders like depression is not scientifically evaluated. Hence, the present investigation evaluates the antidepressant effect of methanolic extract of roots of AR (MAR) standardized to saponins (62.2% w/w). Rats were given MAR in the doses of 100, 200 and 400 mg/kg daily for 7 days and then subjected to forced swim test (FST) and learned helplessness test (LH). The results show that MAR decreases immobility in FST and increases avoidance response in LH indicating antidepressant activity. In behavioral experiments, MAR increased the number of head twitches produced by 5-HTP and increased clonidine-induced aggressive behavior indicating facilitatory effect on both serotonergic and adrenergic systems respectively. However, MAR had insignificant effect on l-DOPA-induced aggressive behavior indicating absence of activity on dopaminergic system. MAR also reversed changes to the endogenous antioxidant system induced by FST. Thus, MAR has significant antidepressant activity and this effect is probably mediated through the serotonergic and the noradrenergic systems and augmentation of antioxidant defenses.     

The uptake of dopamine and serotonin in rat brain during progesterone decline

A possible relevant animal model for the hormone-triggered emotional disturbances of premenstruum, post-partum, and the menopause was investigated. The common characteristic situation of progesterone decline was simulated in ovariectomised rats, studied 12, 24, 36, and 48 h after the last of a week-long 12-hourly series of progesterone injections. In vitro uptake of ³H-dopmine and ³H-serotonin in slices from cortex, preoptic—hypothalamus, thalamus, midbrain and striatum was measured. Serotonin uptake was reduced in progesterone treated slices from the preoptic-hypothalamus 24 h, from the thalamus 36 h after the last injection, whereas no change in dopamine uptake in any region was noted. Dopamine uptake was found to increase with time after the last injection (a possible effect of the particular stress situation of chronic injection), and was also significantly higher at 8 h than at 20 h in cortex, midbrain, and striatum. Serotonin uptake did not vary with the time of day.     

强啡肽A（1－17）所致大鼠运动障碍及对脊髓组织AC－cAMP水平的影响

大鼠蛛网膜下腔注射强啡肽Ａ（１－１７），观察其所引起的行为变化及对脊髓组织ＡＣ－ｃＡＭＰ系统的影响。强啡肽Ａ（１－１７）５、１０、２０ｎｍｏｌ可引起大鼠双后肢弛缓性瘫痪，并在给药１０ｍｉｎ强啡肽Ａ（１－１７）１０、２０ｎｍｏｌ显著抑制脊髓组织ｃＡＭＰ含量和ＡＣ活性，呈量效关系，２ｈ后均有不同程度的恢复。选择性ｋ型阿片受体拮抗剂ｎｏｒ－ＢＮＩ３０ｎｍｏｌ可明显对抗强啡肽Ａ（１－１７）２０ｎｍｏｌ所致的后肢瘫痪并完全阻断其对ＡＣ、ｃＡＭＰ的抑制作用；Ｌ型Ｃａ２＋通道阻断剂异搏定１００ｎｍｏｌ亦可部分阻断强啡肽Ａ（１－１７）对脊髓的影响；而兴奋性氨基酸ＮＭＤＡ受体特异性拮抗剂ＡＰＶ１０ｎｍｏｌ则无效。提示ｋ型阿片受体和Ｌ型Ｃａ２＋通道参与了强啡肽Ａ（１－１７）所引起的大鼠运动障碍及对脊髓组织ＡＣ、ｃＡＭＰ水平的调控。     

Alterations of second messenger systems in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle

We studied the sequential changes in second messenger systems in the striatum and substantia nigra (SN) after 6-hydroxydopamine lesions of the medial forebrain bundle in rats. The animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. [³H]Phorbol-12,13-dibutyrate (PDBu), [³H]forskolin and [³H]rolipram were used to label protein kinase C (PKC), adenylyl cyclase and calcium/calmodulin-independent cyclic-AMP phosphodiesterase, respectively. The degeneration of nigrostriatal pathway produced a significant increase in [³H]PDBu binding in the ventromedial part of the ipsilateral striatum from 2 to 8 weeks postlesion. In the contralateral side, [³H]PDBu binding showed a transient increase in the SN only 4 weeks after lesioning. [³H]Forskolin binding showed a significant increase in the ipsilateral and contralateral striatum from 2 to 4 weeks postlesion. In the ipsilateral SN, a significant increase in [³H]forskolin binding was observed at 4 weeks after lesioning. However, no significant change in [³H]forskolin binding was observed in the contralateral SN during postlesion. On the other hand, [³H]rolipram binding showed no conspicuous alteration in the brain during postlesion. These results demonstrate that rats made hemiparkinsonism by unilateral 6-hydroxydopamine injection have a significant increase in [³H]PDBu and [³H]forskolin binding in the striatum and/or SN, whereas no significant change in [³H]rolipram binding is observed in these areas during postlesion. Our findings also suggest that the increase in [³H]forskolin binding is more pronounced than that in [³H]PDBu binding in the brain after unilateral 6-hydroxydopamine injection. Thus, our studies may provide valuable information concerning degeneration of the nigrostriatal pathway such as Parkinson’s disease.     

Biochemical evidence for the 5-HT agonist properties of PAT (8-hydroxy-2-(di-n-propylamino)tetralin) in the rat brain

In vitro investigations revealed that PAT (8-hydroxy-2-(n-dipropylamino)tetralin) interacted with postsynaptic 5-HT receptors in the rat brain: the drug stimulated 5-HT-sensitive adenylate cyclase in homogenates of colliculi from new-born rats (K_Aapp 8.6 μM) and inhibited the specific binding of [³H]5-HT to 5-HT₁ sites. The PAT-induced inhibition of [³H]5-HT binding showed marked regional differences compatible with a preferential interaction of PAT (IC₅₀ 2 nM) with the 5-HT_1A subclass. As previously seen with 5-HT agonists, the efficacy of PAT for displacing [³H]5-HT bound to hippocampal membranes was markedly increased by Mn²⁺ (1 nM) and reduced by GTP (0.1 nM). PAT also affected presynaptic 5-HT metabolism since it inhibited competitively (K_i 1.4 μM) [³H]5-HT uptake into cortical synaptosomes and reduced (in the presence of the 5-HT uptake inhibitor fluoxetine) the K⁺-evoked release of [³H]5-HT previously taken up or newly synthesized from [³H]tryptophan in cortical or striatal slices. This latter effect was prevented by 5-HT antagonists (methiothepin, metergoline) suggesting that it was mediated by the stimulation of presynaptic 5-HT autoreceptors by PAT. Like 5-HT, PAT counteracted the stimulatory effect of K⁺-induced depolarization on the synthesis of [³H]5-HT from [³H]tryptophan in cortical slices. It is concluded that PAT is a potent 5-HT agonist acting on both post- and presynaptic 5-HT receptors in the rat brain.     

Role of phosphodiesterase and adenylate cyclase isozymes in murine colonic glucagon-like peptide 1 secreting cells

BACKGROUND AND PURPOSE

Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L-cells after food intake. Increasing GLP-1 signalling either through inhibition of the GLP-1 degrading enzyme dipeptidyl-peptidase IV or injection of GLP-1-mimetics has recently been successfully introduced for the treatment of type 2 diabetes. Boosting secretion from the L-cell has so far not been exploited, due to our incomplete understanding of L-cell physiology. Elevation of cyclic adenosine monophosphate (cAMP) has been shown to be a strong stimulus for GLP-1 secretion and here we investigate the activities of adenylate cyclase (AC) and phosphodiesterase (PDE) isozymes likely to shape cAMP responses in L-cells.

EXPERIMENTAL APPROACH

Expression of AC and PDE isoforms was quantified by RT-PCR. Single cell responses to stimulation or inhibition of AC and PDE isoforms were monitored with real-time cAMP probes. GLP-1 secretion was assessed by elisa.

KEY RESULTS

Quantitative PCR identified expression of protein kinase C- and Ca²⁺-activated ACs, corresponding with phorbolester and cytosolic Ca²⁺-stimulated cAMP elevation. Inhibition of PDE2, 3 and 4 were found to stimulate GLP-1 secretion from murine L-cells in primary culture. This corresponded with cAMP elevations monitored with a plasma membrane targeted cAMP probe. Inhibition of PDE3 but not PDE2 was further shown to prevent GLP-1 secretion in response to guanylin, a peptide secreted into the gut lumen, which had not previously been implicated in L-cell secretion.

CONCLUSIONS AND IMPLICATIONS

Our results reveal several mechanisms shaping cAMP responses in GLP-1 secreting cells, with some of the molecular components specifically expressed in L-cells when compared with their epithelial neighbours, thus opening new strategies for targeting these cells therapeutically.     

Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice

Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/-) and knockout (-/-) mice. In SERT -/- mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1mg/kg) or the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/- mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT -/- mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/- and -/- mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT -/- mice.     

The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls

Rationale 3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental.Objectives To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function.Methods We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR.Results We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task.Conclusions The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR.     

Protopine inhibits serotonin transporter and noradrenaline transporter and has the antidepressant-like effect in mice models

The protopine isolated from a Chinese herb Dactylicapnos scandens Hutch was identified as an inhibitor of both serotonin transporter and noradrenaline transporter in vitro assays. 5-hydroxy-DL-tryptophan(5-HTP)-induced head twitch response (HTR) and tail suspension test were adopted to study whether protopine has anti-depression effect in mice using reference antidepressant fluoxetine and desipramine as positive controls. In HTR test, protopine at doses of 5, 10, 20 mg/kg dose dependently increase the number of 5-HTP-induced HTR. Protopine at doses of 3.75 mg/kg, 7.5 mg/kg and 30 mg/kg also produces a dose-dependent reduction in immobility in the tail suspension test. The present results open up new possibilities for the use of protopine in the treatment of mood disorders, such as mild and moderate states of depression.