Molecular Mechanisms of Amphetamines

Reith, Maarten E. A.; Gnegy, Margaret E.

doi:10.1007/164_2019_251

Cited by 30 publications

(16 citation statements)

References 195 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As substrates of these transporters, they interact with the proton-driven vesicular monoamine transporters (VMATs) and are translocated into vesicles, dissipating their proton gradient and redistributing the vesicle content [ 32 ] ( Figure 1A ). Concomitantly, amphetamines inhibit the activity of monoamine oxidases (MAO) [ 33 ], catechol-O-methyl-transferase (COMT), and activate different kinases (e.g., alpha-CamKII or protein kinase C [ 34 ]). The combined actions on the VMAT, MAO, and COMT determine the cytosolic increase in the endogenous neurotransmitter (e.g., dopamine).…”

Section: Neurotransmitter Transporters – Key Regulators Of Synaptic Transmissionmentioning

confidence: 99%

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Niello

Gradisch

Løland

et al. 2020

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

Neurotransmitter transporters (NTTs) are involved in the fine-tuning of brain neurotransmitter homeostasis. As such, they are implicated in a plethora of complex behaviors, including reward, movement, and cognition. During recent decades, compounds that modulate NTT functions have been developed. Some of them are in clinical use for the management of different neuropsychiatric conditions. The majority of these compounds have been found to selectively interact with the orthosteric site of NTTs. Recently, diverse allosteric sites have been described in a number of NTTs, modulating their function. A more complex NTT pharmacology may be useful in the development of novel therapeutics. Here, we summarize current knowledge on such modulatory allosteric sites, with specific focus on their pharmacological and therapeutic potential.

show abstract

Section: Neurotransmitter Transporters – Key Regulators Of Synaptic Transmissionmentioning

confidence: 99%

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Niello

Gradisch

Løland

et al. 2020

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

show abstract

“…They function as indirect sympathomimetics by raising synaptic concentrations of monoamine neurotransmitters through stimulating their release from presynaptic vesicles and/or inhibiting reuptake. Psychostimulants can also interfere with monoaminergic neurotransmitter metabolism and interact with monoaminergic receptors and other targets (Luethi and Liechti, 2020;Reith and Gnegy, 2020). Amphetamine and other phenylethylamine derivatives (Figure 1 top) form a large group of such indirect sympathomimetics.…”

Section: Introductionmentioning

confidence: 99%

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

et al. 2021

View full text Add to dashboard Cite

Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a Km of 24.3 µM and a vmax of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with Km values in the range of 7.9–46.0 µM and vmax values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the vmax 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.

show abstract

“…The psychostimulant amphetamine modulates neurotransmission in striatal and limbic brain areas that increases locomotion and reward-related behaviours (Bamford et al, 2004(Bamford et al, , 2018Reith & Gnegy, 2019;Wang et al, 2013). We tested whether CB 1 R expression in MSNs would be sufficient to rescue the reduced amphetamine-triggered hyperlocomotion measured in CB 1 R KO mice (Corbillé et al, 2007).…”

Section: Cb 1 R (Msn) Rescues As Without Rescuing Impaired Amphetamin...mentioning

confidence: 99%

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB₁ receptors expressed in medium spiny neurons

Bonm

Elezgarai

Gremel

et al. 2021

Eur J of Neuroscience

View full text Add to dashboard Cite

Activation of cannabinoid 1 receptors (CB1R) modulates multiple behaviours, including exploration, motor coordination and response to psychostimulants. It is known that CB1R expressed by either excitatory or inhibitory neurons mediates different behavioural responses to CB1R activation, yet the involvement of CB1R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB1R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB1R in MSN on a CB1R knockout (KO) background (CB1R(MSN) mice). The absence of cannabimimetic responses measured in CB1R KO mice was not rescued in CB1R(MSN) mice, nor was decreased spontaneous locomotion, impaired instrumental behaviour or reduced amphetamine‐triggered hyperlocomotion measured in CB1R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB1R KO mice were fully rescued in CB1R(MSN) mice. Impaired motor coordination in CB1R KO mice measured on the Rotarod was partially rescued in CB1R(MSN) mice. Thus, CB1R expressed by MSN control exploration, motor coordination, and AS. Our study demonstrates a new functional roles for cell specific CB1R expression and their causal link in the control of specific behaviors.

show abstract

Molecular Mechanisms of Amphetamines

Cited by 30 publications

References 195 publications

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB₁ receptors expressed in medium spiny neurons

Contact Info

Product

Resources

About

Molecular Mechanisms of Amphetamines

Cited by 30 publications

References 195 publications

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB1 receptors expressed in medium spiny neurons

Contact Info

Product

Resources

About

Control of exploration, motor coordination and amphetamine sensitization by cannabinoid CB₁ receptors expressed in medium spiny neurons