Template talk:Amphetamine pharmacodynamics

Synaptic vesicles

Hi, new to editing Wikipedia sorry for not logging in. There's a vesicle opening into the outside of the cell (synapse) at the bottom of the diagram. Should this vesicle be containing blue dots (amphetamine) as well?

If not, it would appear to show why extended release formulations and redosing in illicit consumers are associated with exponentially more neurotoxicity than subjects taking it once per day: the limited DAT and other transporters which still are working normally get clogged with amphetamine which has a higher affinity, leaving all the monoamines in the synapse trapped. — Preceding unsigned comment added by 108.56.194.48 (talk) 14:29, 5 November 2018 (UTC)

Hmm. The short answer is yes, but it doesn't particularly matter that much for the purpose of this diagram. If amphetamine has already entered a DA neuron and entered synaptic vesicles, any vesicles that fuse to the membrane and exocytotically release DA will also release amphetamine; however, amphetamine doesn't significantly modulate the release of DA (or itself) into the synaptic cleft via vesicular fusion (i.e., exocytosis) – it does it by collapsing the vesicular pH gradient, releasing DA into the cytosol in the process. Dopamine in the cytosol is then subsequently released via reverse transport through DAT (given that it is also a DAT substrate, the reverse transport of amphetamine should occur as well).

That said, I think if amphetamine (blue dots) were added to the vesicular contents, it might cause some people who view it to incorrectly conclude that amphetamine increases synaptic dopamine concentrations in part via exocytotic mechanisms.

Caveat

This review states: Due to this ability to collapse vesicular pH gradients, amphetamine provided a first instance of pharmacological manipulation of DA quantal size, as measured in PC12 cells [25]. Subsequent work showed that two classes of DA vesicles present in the giant DA neuron of Planorbis corneus were differentially depleted by amphetamine [92]. In dopamine axons of the striatum, electrochemical recordings in acute striatal slices suggest similar actions of amphetamine in intact tissue [93,94], although contradictory findings have yet to be resolved. For example, Paul Garris and colleagues have shown that amphetamines indeed can enhance synaptic vesicle fusion in DA neurons in vivo, perhaps via a circuit mechanism [95]. Moreover, some of the decrease in evoked DA release may also be due to activation of a striatal circuit in the striatum (Jose Lizardi-Ortiz et al., ms. in preparation). In a nutshell, amphetamine apparently can promote vesicular fusion in rat DA neurons in vivo; however, the concentration of DA in synaptic vesicles that contain amphetamine and undergo exocytosis would necessarily be smaller than that of vesicles with no amphetamine molecules within them. So, even if amphetamine does promote vesicular fusion in human DA neurons, that's not really a notable mode of DA release due to low vesicular concentrations of DA.

Seppi333 (Insert 2¢) 22:05, 5 November 2018 (UTC)

No need for "enantiomers" & suggestions

In the table header, I assert: Pharmacodynamics of amphetamine enantiomers in a dopamine neuron. Enantiomers is superfluous since amphetamine is its enantiomers. Both may be assumed to have these properties since no distinction is made in the graphic or caption.

The graphic would be easier to understand if amphetamine were red like the trafficking paths. Same with the others. If using the same color makes the substance units somewhat indistinguishable the path, path thickness can be reduced or path color lightened.

Why is the vesicle wall (line) thickness different in the internal vesicle than the fused vesicle?

I wonder if "trace amine or amphetamine (in)" might graphically read better "trace amine (in) amphetamine (in)".

I muse over ways this schematic could keep the content but allow ordinary readers to grasp the basic mechanism without being daunted by the details. One consideration is altering the layout so the paths could be uncrossed as much as possible.

I'll leave it there for now. Box73 (talk) 11:02, 18 November 2015 (UTC)

The thickness varies because it's hard to draw in inkscape.

I'll take your suggestions into account the next time that I update the graphic, but that really depends on how long it takes for researchers to identify the CAMKII phosphorylation pathway. Seppi333 (Insert 2¢) 22:03, 22 November 2015 (UTC)