p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent.

p-Methylthioamphetamine (MTA), was compared to p-chloroamphetamine (PCA) in a number of pharmacological assays. MTA was about 2-fold more potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and about 7-fold and 10-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]dopamine and [3H]norepinephrine, respectively. In drug discrimination assays, MTA was nearly equipotent to PCA in animals trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA), or two related analogues S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-MBDB) or 5-methoxy-6-methyl-2-aminoindan (MMAI). MTA caused dose-dependent increases of tritium efflux from superfused rat frontal cortex slices preloaded with [3H]5-HT, comparable to that induced by an equal molar concentration of PCA. The potential neurotoxicity of MTA was examined by measuring monoamine and metabolite levels at one week following an acute dose. A 10 mg/kg dose of PCA caused a 70-90% decrease of cortical, hippocampal and striatal 5-HT and 5-hydoxyindoleacetic acid (5-HIAA) levels, while twice the molar dose of MTA (21.3 mg/kg) had no effect. Thus, MTA is a potent, selective, serotonin releaser, apparently devoid of serotonin neurotoxic effects. This work also supports the idea that catecholamine systems may play a critical role in the neurotoxicity of PCA-like compounds.     

Effects of trimethyltin on dopaminergic and serotonergic function in the central nervous system

The effects of trimethyltin (TMT) administration on regional concentrations of dopamine (DA), serotonin (5-HT), and their metabolites were determined. Acute administration of 3 or 7 mg/kg TMT (as the chloride) to adult male Long-Evans rats caused alterations in both dopaminergic and serotonergic function in brain at 7 days posttreatment. Dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were decreased in the nucleus accumbens of rats treated with 7 mg/kg, with a trend occurring with the 3-mg/kg dose group. Conversely, concentrations of DA or DOPAC were not altered in striatum, olfactory tubercle, septum, or amygdala/pyriform cortex. Administration of 3 mg/kg TMT decreased the concentration of serotonin in striatum and nucleus accumbens, and increased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus. The 7-mg/kg dose resulted in increased concentrations of 5-HIAA in striatum, nucleus accumbens, septum, amygdala/pyriform cortex, and hippocampus, and also decreased the concentration of 5-HT only in amygdala/pyriform cortex. The ratio of 5-HIAA to 5-HT (an indirect estimate of serotonin turnover) was increased in all brain regions of rats treated with 7 mg/kg, and in nucleus accumbens and amygdala/pyriform cortex of rats treated with 3 mg/kg. Conversely, no alteration in the DOPAC to DA ratio was found in any region of brain in rats killed at 7 days, nor was there a change in dopamine receptors (as measured by [³H]spiperone binding) in rats treated with 7 mg/kg TMT and killed 7 days following exposure. Thus, the acute sequelae of TMT neurotoxicity appears to involve primarily serotonergic systems, and these effects may be related to the behavioral effects resulting from TMT administration.     

Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered methylenedioxymethamphetamine (MDMA)

MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50-60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50-60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19-33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA (n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Neurotoxic effects of the alpha-ethyl homologue of MDMA following subacute administration

The possible neurotoxic effects of the alpha-ethyl homologue of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), were examined following a regimen of twice daily dosing for four days. The levels of norepinephrine, serotonin and its metabolite 5-HIAA were quantitated by standard HPLC-EC techniques. In addition, the number of 5-HT uptake sites was estimated by examining the binding of [3H]-paroxetine to rat cortex homogenate. With 20 mg/kg (IP) subacute dosing of MDMA, a nearly 60% reduction in 5-HT, 5-HIAA, and 5-HT uptake sites was found, with no change in NE, two weeks posttreatment. A behaviorally equipotent dose of MBDB (25 mg/kg, IP) also produced a significant decrease in the serotonergic markers; 5-HT, 5-HIAA and [3H]-paroxetine binding sites. However, a comparison of the relative toxic effects of MDMA and MBDB indicates that MBDB may be slightly less neurotoxic. It was also found that MDMA but not MBDB caused a significant increase in dopamine levels at 3 hours following a single IP injection. The results are discussed in relation to the therapeutic index of MBDB and the relative importance of dopamine release in the neurotoxicity of MDMA.     

5-Iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine.

A rigid analogue, 5-iodo-2-aminoindan (5-IAI), of the serotonin neurotoxic halogenated amphetamine p-iodoamphetamine (PIA) was pharmacologically evaluated for production of serotonin neurotoxicity. A comparison was also made between 5-IAI and PIA in the two-lever drug discrimination paradigm in rats trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA) or saline from the alpha-ethyl homologue of MDMA, MBDB. PIA and 5-IAI were both behaviorally active, and fully substituted in both groups of animals, but were considerably less potent than p-chloroamphetamine (PCA). PIA had about twice the potency of PCA as an inhibitor of [3H]-5-HT uptake in rat brain cortical synaptosomes, while 5-IAI was only about 75% as potent as PCA in this assay. A single 40 mg/kg dose of PIA resulted in a 40% reduction of 5-HT and 5-HIAA levels and in the number of 5-HT uptake sites in rat cortex at one week sacrifice. The same dose of 5-IAI with one week sacrifice led to about a 15% decrease in 5-HIAA levels and number of 5-HT uptake sites, but only the latter was statistically significant. In rat hippocampus, PIA gave significant decreases in all serotonin markers examined, while 5-IAI slightly but significantly decreased only 5-HT levels. Neither compound produced any change in catecholamine or catecholamine metabolite levels. The results confirm earlier reports of the selective serotonin neurotoxicity of PIA, which is less severe than that of PCA, and also demonstrate that its rigid analogue 5-IAI does not appear to cause significant serotonin deficits in the rat.     

Effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on central serotonergic and dopaminergic systems of the rat

The influence of N-ethyl-3,4-methylenedioxyamphetamine (MDE) on the central serotonergic and dopaminergic systems of the rat after a single or multiple injections was studied. MDE (10 mg/kg) produced a significant decrease in the concentration of 5-hydroxytryptamine (5-HT) 1 hr later in the frontal cortex and the hippocampus without affecting the concentration of 5-hydroxyindoleacetic acid (5-HIAA) or tryptophan hydroxylase (TPH) activity. Hypothalamic and neostriatal concentrations of 5-HT, 5-HIAA, dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remained unaffected, as well as the neostriatal TPH and tyrosine hydroxylase (TH) activities. However, 3 hr after the MDE injection, the serotonergic variables including TPH activity were decreased in most of the brain areas examined. The dopaminergic system remained unaffected, except for a significant reduction in neostriatal DOPAC concentrations. The changes in transmitter concentrations after a single injection were dose dependent; the maximum depletion in TPH activity was reached with a 10 mg/kg dose. The administration of multiple doses of MDE caused greater decreases in TPH activity and 5-HT concentrations 3 hr after the treatment than did a single injection; in addition, a partial recovery from multiple administrations occurred by 18 hr. The effects of MDE on DA and its metabolites were transient, and neostriatal TH activity was not altered. This study demonstrates that MDE primarily affects the central serotonergic system, as reported for its congeners 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. It does, however, produce less neurotoxicity as judged by its lower potency on the dopaminergic and the serotonergic systems as well as the recovery occurring in these systems.     

Tryptophan pretreatment augmentation of p-chloroamphetamine-induced serotonin and dopamine release and reduction of long-term neurotoxicity

The impact of tryptophan (TRP) pretreatment on the neurochemical effects of p-chloroamphetamine (PCA) was investigated. The neurotoxic effects of PCA on serotonin (5-HT) neurons, the acute effects of PCA on extracellular 5-HT and dopamine (DA), and the displacement by PCA of whole blood 5-HT were examined. TRP pretreatment (400 mg/kg of the methyl ester) significantly reduced the long-term (1 week) decrease in tissue 5-HT resulting from PCA (2 mg/kg, i.p., of the hydrochloride salt) in the prefrontal cortex and striatum, but not in the dorsal hippocampus. Microdialysis studies in awake animals showed that this pretreatment regimen resulted in augmented PCA-induced increases in extracellular 5-HT (4-fold) and DA (2-fold). TRP pretreatment also resulted in increased displacement of 5-HT from whole blood. The implications of these results toward possible mechanisms of action of PCA-induced neurotoxicity are discussed.     

Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.

The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.     

Differential effects of d-fenfluramine and p-chloroamphetamine on H75/12-induced depletion of 5-hydroxytryptamine and dopamine in the rat brain.

The effects of the two 5-HT-releasing drugs, p-chloroamphetamine and d-fenfluramine, on central serotoninergic and dopaminergic systems were compared in adult rats. Both drugs (0.5-5.0 mg/kg i.p., 2 hr before death) produced a dose-dependent reduction in levels of 5-HT, but only p-chloroamphetamine decreased the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus, striatum and cerebral cortex. Within the dose range tested, d-fenfluramine did not affect the levels of DA and of its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in brain. By contrast, p-chloroamphetamine significantly increased the levels of DA and HVA and decreased the levels of DOPAC, notably in the striatum. As expected of a 5-HT uptake inhibitor, d-fenfluramine at small doses (0.2-0.5 mg/kg) prevented the depletion of 5-HT due to 4-methyl-alpha-ethyl-meta-tyramine (H75/12, 40 mg/kg i.p.), whereas at large doses (1.0-5.0 mg/kg) d-fenfluramine, like p-chloroamphetamine (0.2-1.0 mg/kg), slightly enhanced the effect of H75/12. Neither d-fenfluramine (0.5 mg/kg) nor p-chloroamphetamine (0.5 mg/kg) affected the depletion of DA due to H75/12. These data indicate that p-chloroamphetamine is a 5-HT-releasing drug, at any dose between 0.2 and 5.0 mg/kg, whereas d-fenfluramine acts as a 5-HT uptake inhibitor at 0.2-0.5 mg/kg and as a 5-HT releasing drug at larger doses. On account of the potential neurotoxicity of 5-HT-releasing drugs but not 5-HT uptake inhibitors, it can be inferred that d-fenfluramine is very probably devoid of any neurotoxic action in the dose range (less than 1.0 mg/kg) required for its anorectic action.     

Reduction in brain serotonin markers by alpha-ethyltryptamine (Monase).

alpha-Ethyltryptamine (Monase) is both an inhibitor of monoamine oxidase and a monoamine releasing agent. To determine whether alpha-ethyltryptamine induces serotonergic deficits similar to that of other monoamine releasing agents such as 3,4-methyl-enedioxymethamphetamine (MDMA) and para-chloroamphetamine (PCA), rats were given multiple doses (8 x 30 mg/kg s.c.) of alpha-ethyltryptamine acetate. Serotonin and 5-hydroxyindole acetic acid (5-HIAA) levels and the number of 5-HT uptake sites (determined from [3H]paroxetine binding) were significantly decreased in frontal cortex samples at one week killing. A significant decrease in 5-HT and 5-HIAA levels was also observed in rat hippocampal samples. The results provide evidence that alpha-ethyltryptamine may induce serotonin neurotoxicity similar to that of MDMA and PCA.     

Dopamine receptor subsensitivity in the substantia nigra after chronic morphine treatment in rats

Several classes of 5-HT and dopamine (DA) receptor binding sites, and the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), DA and dihydroxyphenylacetic acid (DOPAC) were examined in various brain regions 24 h after a 10-day treatment with morphine (2 X 15 mg/kg s.c. daily) in adult rats. Quantitative autoradiography of receptor binding sites revealed only a significant reduction of [3H]SCH-23390 and [3H]spiperone binding to D-1 and D-2 sites, respectively, in the substantia nigra pars compacta of morphine-treated rats. 5-HT and 5-HIAA levels remained unchanged in the substantia nigra and striatum, but the nigral levels of DA and DOPAC and the levels of DOPAC in the striatum were reduced significantly by morphine treatment. Apomorphine, at a dose (0.05 mg/kg s.c.) known to stimulate DA autoreceptors, decreased nigral and striatal DOPAC levels in controls but not in morphine-treated rats. It is concluded that chronic morphine treatment probably induces a down regulation of nigral D-1 and D-2 binding sites and reduces the negative feed-back mechanisms triggered by DA autoreceptors.     

Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists

Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined administration of a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue with amphetamine produces serotonin neurotoxicity in rats.

In the present study, a central serotonin neurotoxicity was induced by combining a non-neurotoxic 3,4-methylenedioxymethamphetamine analogue, 5-methoxy-6-methyl-2-aminoindan (MMAI), with the non-vesicular dopamine (DA) releaser, S-(+)-amphetamine (Amp). With the multiple dosing regimen utilized neither drug alone resulted in any changes in serotonergic parameters, including 5-HT, 5-HIAA and the number of 5-HT uptake sites. However, MMAI (10 mg/kg) in combination with Amp (2 x 2.5 mg/kg) did result in a long-term 20% decrease in cortical serotonergic parameters. The same dose of Amp plus 20 mg/kg MMAI resulted in a 50 to 60% reduction. Effects in the hippocampus and caudate nucleus were similar. These data support the hypothesis that DA release plays a critical role in the serotonin neurotoxicity of substituted amphetamines.     

Differences between rats and mice in MDMA (methylenedioxymethylamphetamine) neurotoxicity

In both rats and mice a single large dose of methylenedioxymethylamphetamine (MDMA; 25 mg/kg i.p.) caused a fall 3 h after injection in the content of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in cortex, a fall in noradrenaline in hippocampus and cerebellum, and a rise in dopamine (DA) but fall in dihydroxyphenylacetic acid (DOPAC) in striatum. These effects were transient, levels being essentially back to normal by 24 h after injection. Repeated large doses (3 x 25 mg/kg in 24 h) of MDMA caused a large long-lasting fall in the content of 5-HT and 5-HIAA in cortex in rats but had only a slight effect in mice. Increasing the dose to 3 x 50 mg/kg in mice produced a large long-lasting fall in striatal DA. The analogue MDEA(3,4-methylenedioxyethylamphetamine) caused a similar slight fall in 5-HT but in contrast to MDMA caused a slight rise in DA content in mice. The nature and degree of neurotoxicity with methylenedioxyamphetamines appears to be drug and species-specific.     

Role of serotonergic input in the down-regulation of beta-adrenoceptors following long-term clorgyline treatment

Administration of the selective monoamine oxidase (MAO) type A-inhibiting antidepressant clorgyline (1 mg/kg per day) to rats for 21 days caused a significant decrease in cortical [3H]dihydroalprenolol binding. Selective lesioning of central serotonergic axons by 5,7-dihydroxytryptamine (5,7-DHT; confirmed by the presence of the serotonin syndrome in response to a 40 mg/kg dose of 5-hydroxytryptophan (5-HTP) or inhibition of 5-HT synthesis by parachlorophenylalanine (PCPA) caused significant 5-HT and 5-HIAA depletions in the cortex without much effect on NE and DA concentrations, but did not have any significant effect on beta-adrenoceptor density, and furthermore failed to attenuate clorgyline-induced decreases in beta-adrenoceptor density. Clorgyline treatment partially antagonized 5-HT depletion by the 5,7-DHT lesion or PCPA treatment. These findings suggest that due to their ability to raise 5-HT concentrations, MAO-inhibiting antidepressants may be a better alternative than the tricyclics in treating depressed patients with reduced 5-HT if down-regulation of beta-adrenoceptors is critical for antidepressant efficacy.     

Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neurotoxicity in mice

Amphetamine analogs such as p-chloroamphetamine (PCA) cause serotonergic and dopaminergic neurotoxicity. The behavioral consequences and the responsiveness to psychostimulants following the neurotoxic insult are unclear. The present study was undertaken to investigate the outcome of neurotoxic and non-neurotoxic PCA pre-treatments on the sensitivity of Swiss Webster mice to the psychomotor stimulating effects of PCA, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. PCA (15 mg/kg x 2; i.p.) caused 37-70% depletion of dopaminergic and serotonergic markers in mouse brain. Saline and PCA (15 mg/kg x 2) mice were challenged on days 5, 12, 40 and 74 with one of the following drugs: PCA (5 mg/kg), MDMA (10 mg/kg) and cocaine (20 mg/kg). The PCA pre-exposed mice showed marked locomotor sensitization from days 5-74 to all three drugs tested. The time course of the sensitized response coincided with the time course of the neurotoxic insult as determined by reduced densities of striatal dopamine transporter and frontal cortex serotonin transporter binding sites. A single injection of PCA (5 mg/kg) caused neither neurotoxicity nor sensitization to the locomotor stimulating effects of PCA, MDMA and cocaine. Repeated administration of a low non-neurotoxic dose of PCA (5 mg/kg/day; 6 days) caused a transient locomotor sensitization to PCA that dissipated after one month. Results of the present study suggest that PCA-induced serotonergic and dopaminergic neurotoxicity coincides with long-lasting locomotor sensitization to psychostimulants. These findings may be relevant to the psychopathology of amphetamines-induced neurotoxicity.     

Antagonism of 3,4-methylenedioxymethamphetamine-induced neurotoxicity in rat brain by 1-piperonylpiperazine.

The effects of 1-piperonylpiperazine and N,alpha-dimethylpiperonylamine, which are weak inhibitors for [3H]5-hydroxytryptamine (5-HT) uptake, on 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity were examined. The reductions of serotonergic parameters in the rat cerebral cortex produced by multiple administration of MDMA (10 mg/kg) were attenuated significantly by coadministration of 6-nitroquipazine (10 mg/kg), paroxetine (10 mg/kg) or 1-piperonylpiperazine (20 mg/kg), but not by N,alpha-dimethylpiperonylamine (20 mg/kg). The present data suggest that 1-piperonylpiperazine might inhibit the MDMA-induced neurotoxicity by effect(s) other than 5-HT uptake inhibition.     

N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy').

3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') is an illicit drug that stimulates the release of serotonin (5-HT) and dopamine (DA) from neurons. Recent evidence reveals that drug users are ingesting piperazine analogs, like 1-benzylpiperazine (BZP, or 'A2') and 1-(m-trifluoromethylphenyl)piperazine (TFMPP, or 'Molly'), to mimic psychoactive effects of MDMA. In the present study, we compared the neurochemistry of MDMA, BZP, and TFMPP in rats. The effects of MDMA, BZP, and TFMPP on transporter-mediated efflux of [3H]5-HT and [3H]MPP+ (DA transporter substrate) were determined in synaptosomes. The effects of drugs on extracellular levels of 5-HT and DA were examined using in vivo microdialysis in conscious rats. MDMA evoked transporter-mediated release of [3H]5-HT and [3H]MPP+. BZP released [3H]MPP+, whereas TFMPP was a selective releaser of [3H]5-HT. MDMA (1-3 mg/kg, i.v.) increased dialysate 5-HT and DA in a dose-related fashion, with actions on 5-HT being predominant. BZP (3-10 mg/kg, i.v.) elevated dialysate DA and 5-HT, while TFMPP (3-10 mg/kg, i.v.) elevated 5-HT. Administration of BZP plus TFMPP at a 1:1 ratio (BZP/TFMPP) produced parallel increases in dialysate 5-HT and DA; a 3 mg/kg dose of BZP/TFMPP mirrored the effects of MDMA. At a 10 mg/kg dose, BZP/TFMPP increased dialysate DA more than the summed effects of each drug alone, and some rats developed seizures. Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug-drug synergism may occur when piperazines are coadministered at high doses.     

Chloroamphetamine did not prevent the effects of chronic antidepressants on 5-hydroxytryptamine inhibition of forskolin-stimulated adenylate cyclase in rat hippocampus.

Administration of p-chloroamphetamine (PCA, 10 mg/kg i.p. on two occasions) to rats resulted in a severe depletion of [3H]paroxetine binding sites, a measure of presynaptic serotonergic terminals, in both cortex and hippocampus, but did not affect [3H]8-hydroxy-2-(di-n-propylamino)tetralin [( 3H]8-OH-DPAT) binding or 5-hydroxytryptamine (5-HT)-induced inhibition of forskolin-stimulated adenylate cyclase in hippocampal membranes. Administration of either imipramine (15 mg/kg i.p. for 2 weeks) or lithium (0.2% for 2 weeks) to PCA-treated rats did not affect [3H]8-OH-DPAT binding but reduced the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes. It is concluded that the effects of imipramine and Li+ on 5-HT1A receptor-mediated responses in the hippocampus are exerted postsynaptically, possibly at a level distal to the receptor.     

Mechanisms of orphenadrine-induced antinociception in mice: a role for serotonergic pathways

The possible involvement of central serotonergic pathways in the mechanism of action of orphenadrine citrate was investigated in male albino mice. Orphenadrine (20 mg/kg) did not alter the concentration of 5-hydroxytryptamine (5-HT) or its metabolite 5-hydroxyindole acetic acid in the frontal cortex or spinal cord, nor did it, in moderate concentrations, inhibit the uptake of [14C]5-HT, [3H]noradrenaline ([3H]NA) or [3H]dopamine ([3H]DA) into crude synaptosomal preparations from the cortex. The antinociceptive effect of orphenadrine was studied in the formalin test and in the increasing temperature hot plate test. No sensorimotor impairment was observed for doses of 30 mg/kg or lower. A general depletion of serotonin by means of p-chlorophenylalanine significantly reduced the effect of orphenadrine in both tests, while lesion of the ascending serotonergic systems by means of p-chloroamphetamine did not affect the analgesia. It is concluded that the antinociceptive effect of orphenadrine may be mediated in part via the raphe-spinal serotonergic systems.