29 research outputs found
In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates
3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings
RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. OBJECTIVE: The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of “interspecies scaling” to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. RESULTS: MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1–2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10–20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. CONCLUSIONS: MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks
Adenylate cyclase of human fat cells. Expression of epinephrrine-sensitive activation revealed by 5'guanylyl-imidodiphosphate.
Salts promote activation of fat cell adenylate cyclase by GTP: special role for sodium ion.
Studies of the Biogenic Amine Transporters. 12. Identification of Novel Partial Inhibitors of Amphetamine-Induced Dopamine Release
Structural Modification of the Designer Stimulant α-Pyrrolidinovalerophenone (α-PVP) Influences Potency at Dopamine Transporters
Stereoselective Actions of Methylenedioxypyrovalerone (MDPV) To Inhibit Dopamine and Norepinephrine Transporters and Facilitate Intracranial Self-Stimulation in Rats
The
designer stimulant methylenedioxypyrovalerone (MDPV) is a potent reuptake
inhibitor at transporters for dopamine (DAT) and norepinephrine (NET)
that produces a constellation of abuse-related behavioral effects.
MDPV possesses a chiral center, and the abused formulation of the
drug is a racemic mixture, but no data are available on the pharmacology
of its isomers. Here, the individual optical isomers of MDPV were
prepared and examined with respect to their neurochemical actions
on neurotransmitter reuptake and behavioral effects in an assay of
intracranial self-stimulation (ICSS) in rats. In assays of DAT uptake
inhibition, <i>S</i>(+)MDPV (EC<sub>50</sub> = 2.13 nM)
was more potent than either (±)MDPV (EC<sub>50</sub> = 4.85 nM)
or <i>R</i>(−)MDPV (EC<sub>50</sub> = 382.80 nM);
the three drugs were less potent at NET uptake inhibition, with the
same rank order of potency. Neither racemic MDPV nor its optical isomers
inhibited the reuptake of serotonin at concentrations up to 10 μM. <i>S</i>(+)MDPV produced an abuse-related and dose-dependent facilitation
of ICSS, and the potency of <i>S</i>(+)MDPV (significant
facilitation at doses ≥ 0.1 mg/kg) was greater than that of
the racemate (significant facilitation at doses ≥ 0.32 mg/kg). <i>R</i>(−)MDPV failed to alter ICSS at doses up to 100
times greater than the lowest effective dose of <i>S</i>(+)MDPV. The results indicate that abuse-related neurochemical and
behavioral effects of racemic MDPV reside primarily with its <i>S</i>(+) isomer
British Journal of Pharmacology / Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
BACKGROUND AND PURPOSE 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1)) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.W 1232-B24(VLID)310834