Evidence for a role of transporter-mediated currents in the depletion of brain serotonin induced by serotonin transporter substrates.

Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions.

An efficient synthesis of 3-OBn-6β,14-epoxy-bridged opiates from naltrexone and identification of a related dual MOR inverse agonist/KOR agonist.

In an effort to better understand the conformational preferences that inform the biological activity of naltrexone and related naltrexol derivatives, a new synthesis of the restricted analog 3-OBn-6β,14-epoxymorphinan 4 is described. 4 was synthesized starting from naltrexone in 50% overall yield, proceeding through the OBn-6α-triflate intermediate 8. Key steps to the synthesis include benzylation (96% yield), reduction (90% yield, α:β:3:2), followed by a one-pot triflation/displacement sequence (96% yield) to yield the desired bridged epoxy derivative 4.

The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.

The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity.

Effects of MDMA and related analogs on plasma 5-HT: relevance to 5-HT transporters in blood and brain.

(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g.

Design, synthesis, and characterization of 6beta-naltrexol analogs, and their selectivity for in vitro opioid receptor subtypes.

Since the mu opioid receptor (MOR) is known to be involved in the therapeutically relevant pathways leading to the manifestation of pain and addiction, we are currently studying the specific structural characteristics that promote antagonism at the MOR. The opiates 6beta-naltrexol and 6beta-naltrexamide function as neutral antagonists in in vitro and in vivo systems previously exposed to morphine, and are under investigation as improved treatments for narcotic dependence. In this research, we synthesized and characterized carbamate and sulfonate ester derivates of 6beta-naltrexol that do not contain a protic group at C(6), and evaluated these compounds for opioid receptor affinity.

Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence.

Methamphetamine (METH) abuse is a growing health problem, and no treatments for METH dependence have been identified. The powerful addictive properties of METH are mediated by release of dopamine (DA) from nerve terminals in mesolimbic reward pathways. METH stimulates DA release by acting as a substrate for DA transporter (DAT) proteins, thereby triggering efflux of DA from cells into the synapse.

Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate.

Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins.

In Vivo Correlates of Central Serotonin Function after High-Dose Fenfluramine Administration.

High doses of fenfluramine (FEN) are known to deplete central serotonin (5-HT) in animals, but functional impairments associated with such 5-HT depletion have been difficult to identify. In the present work, we examined neuroendocrine responsiveness in rats exposed to repeated high-dose FEN treatment. Male rats fitted with indwelling catheters received FEN (20 mg/kg, subcutaneously, twice a day) or saline for 4 days.