Answer by Jens Mowatt:

Amphetamines like Adderall (L-amphetamine), Ritalin (Methylphendiate) and Dexedrin (D-amphetamine) are all slightly different. Keep in mind that almost all the studies I’ll cite use D-amphetamine, the mirror molecule of Adderall. All of the amphetamines act to increase dopaminergic transmission, so it is quite likely that they have similar effects on acetylcholine (but I’m not entirely certain about this).

Administration of amphetamines reverses dopamine transporters, leading to increased dopamine release by neurons of the mesolimbic, mesocortical, and nigrostriatal pathways. By acting on areas such as the nucleus accumbens (in the limbic system), cerebral cortex, and striatum (part of the basal ganglia), dopamine exerts its effects.

Downstream, there are many different types of neurons that are affected by dopamine, including ones that utilize acetylcholine (called “cholinergic” neurons). In general, amphetamine administration leads to an increase in cholinergic activity. I’ll give you a few examples:

The striatum

Dopaminergic neruons synapse on cholinergic neurons in the striatum, as you can see from the diagram below. The cholinergic neurons then activate GABAergic neurons, which act to inhibit the substantia nigra in an effort to return dopamine levels to baseline.

When you administer an amphetamine, this nigrostriatal pathway can be activated. Indeed, one study found a substantial increase in actylcholine transmission within the caudate nucleus (part of the striatum) following amphetamine administration [1].

Nucleus Accumbens

The main dopaminergic reward pathway you will always hear about is the mesolimbic pathway. Dopaminergic cells in the ventral tegmental area release dopamine onto the nuleus accumbens (Nacc). There are acetylcholine-containing neurons in the Nacc that are activated when amphetamine activates this pathway. Indeed, amphetamine administration generally increases ACh release within the nucleus accumbens, although this depends on the dosage [2].

Other areas

Another area that experiences an increase in ACh transmission following amphetamine administration is the hippocampus [1]. Cholinergic neurons in the basal forebrain of the cerebral cortex also increase their level of ACh release.

One last caveat…

I’d be careful in generalizing these results to amphetamines other than D-amphetamine. Also, note that all of these studies used rats as their subjects, not humans. Generalize these results to humans at your own peril.

[1] Effects of cocaine and amphetamine on acetylcholine release in the hippocampus and caudate nucleus.
[2] D1 and D2 dopamine receptor mediation of amphetamine-induced acetylcholine release in nucleus accumbens.
[3] Page on ohio-state.edu

How do dopaminergic stimulants like Adderall/Ritalin affect acetylcholine signalling?

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