Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Baumann, Michael H.; Bulling, Simon; Benaderet, Tova S; Saha, Kusumika; Ayestas, Mario A.; Partilla, John S.; Ali, Syed F.; Stockner, Thomas; Rothman, Richard B.; Sandtner, Walter; Sitte, Harald H.

doi:10.1038/npp.2013.331

Cited by 36 publications

(40 citation statements)

References 62 publications

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“…27 Acutely, substrates can account for higher concentrations of extracellular neurotransmitter than blockers, and substrate-induced inward current are correlated with long-term depletion of neurotransmitters in the brain. 28 …”

Section: Discussionmentioning

confidence: 99%

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

Battisti

Sitta

Harris

et al. 2018

ACS Chem. Neurosci.

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4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), thereby causing non-exocytotic release of monoamine transmitters via reverse transport. Prior studies by us showed that increasing the N-alkyl chain length of N-substituted 4-MA analogs converts 4-MA from a transportable substrate (i.e., releaser) at DAT and NET to a non-transported blocker at these sites. Here we studied the effects of the individual optical isomers of N-methyl-, N-ethyl-, and N-n-propyl 4-MA on monoamine transporters and abuse-related behavior in rats because action/function might be related to stereochemistry. Uptake inhibition and release assays were conducted in rat brain synaptosomes whereas electrophysiological assessments of drug-transporter interactions were examined using cell-based biosensors. Intracranial-self stimulation (ICSS) in rats was employed to assess abuse potential in vivo. The experimental evidence demonstrates that S(+)N-methyl 4-MA is a potent and efficacious releaser at DAT, NET, and SERT with the highest abuse potential among the test drugs whereas R(−)N-methyl 4-MA, is a less potent releaser with reduced abuse potential. The S(+)ethyl analog displays decreased efficacy as a releaser at DAT but retains full release activity at NET and SERT with a reduction in abuse-related effects; the R(−)ethyl analog has a similar profile but is less potent. S(+)N-Propyl 4-MA is a non-transported blocker at DAT and NET, but an efficacious releaser at SERT, whereas the R enantiomer is almost inactive. In conclusion, the S enantiomers of the N-alkyl 4-MA analogs are most potent. Lengthening the N-alkyl chain converts compounds from potent non-selective releasers showing abuse-related effects, to more selective SERT releasers with no apparent abuse potential.

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Section: Discussionmentioning

confidence: 99%

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

Battisti

Sitta

Harris

et al. 2018

ACS Chem. Neurosci.

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“…[14][15][16][17][18] Serotonin (5-hydroxytryptamine, 5-HT) antagonists enhance the susceptibility of DBA mice to S-IRA. 20,21 Recent clinical studies found fenfluramine to be effective as an add-on agent in the control of seizures in patients with Dravet syndrome, 22,23 which is difficult to treat and has a tragically high risk of SUDEP. 14,19 Fenfluramine is a drug that is known to enhance serotonergic neurotransmission by augmenting carrier-mediated synaptic release of 5-HT and by preventing reuptake.…”

Section: Introductionmentioning

confidence: 99%

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Tupal

Faingold

2019

Epilepsia

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Summary Objective Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure‐induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure‐induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure‐induced respiratory arrest (S‐IRA) in DBA/1 mice. Methods The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz‐induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi‐square test. Results Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S‐IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20‐40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S‐IRA susceptibility occurred, which were long‐lasting (≥48 hours). The median effective dose (ED50) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. Significance This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S‐IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S‐IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

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“…Although substrate-induced currents through monoamine transporters are widely accepted [12–15] and they have been implicated in neurotransmitter depletion in the brain [16], the physiological significance of such currents are still under debate [17, 18]. Recently, we showed that depolarization induced by serotonin (5HT) or S(+)3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in skeletal muscle cells engineered to express the human serotonin transporter (hSERT) activates the L-type Ca 2+ channel Ca V 1.1 [19].…”

Section: Introductionmentioning

confidence: 99%

Amphetamine activates calcium channels through dopamine transporter-mediated depolarization

et al. 2015

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Amphetamine (AMPH) and its more potent enantiomer S(+)AMPH are psychostimulants used therapeutically to treat attention deficit hyperactivity disorder and have significant abuse liability. AMPH is a dopamine transporter (DAT) substrate that inhibits dopamine (DA) uptake and is implicated in DA release. Furthermore, AMPH activates ionic currents through DAT that modify cell excitability presumably by modulating voltage-gated channel activity. Indeed, several studies suggest that monoamine transporter-induced depolarization opens voltage-gated Ca2+ channels (CaV), which would constitute an additional AMPH mechanism of action. In this study we co-express human DAT (hDAT) with Ca2+ channels that have decreasing sensitivity to membrane depolarization (CaV1.3, CaV1.2 or CaV2.2). Although S(+)AMPH is more potent than DA in transport-competition assays and inward-current generation, at saturating concentrations both substrates indirectly activate voltage-gated L-type Ca2+ channels (CaV1.3 and CaV1.2) but not the N-type Ca2+ channel (CaV2.2). Furthermore, the potency to achieve hDAT-CaV electrical coupling is dominated by the substrate affinity on hDAT, with negligible influence of L-type channel voltage sensitivity. In contrast, the maximal coupling-strength (defined as Ca2+ signal change per unit hDAT current) is influenced by CaV voltage sensitivity, which is greater in CaV1.3- than in CaV1.2-expressing cells. Moreover, relative to DA, S(+)AMPH showed greater coupling-strength at concentrations that induced relatively small hDAT-mediated currents. Therefore S(+)AMPH is not only more potent than DA at inducing hDAT-mediated L-type Ca2+ channel currents but is a better depolarizing agent since it produces tighter electrical coupling between hDAT-mediated depolarization and L-type Ca2+ channel activation.

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Evidence for a Role of Transporter-Mediated Currents in the Depletion of Brain Serotonin Induced by Serotonin Transporter Substrates

Cited by 36 publications

References 62 publications

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Amphetamine activates calcium channels through dopamine transporter-mediated depolarization

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