Re: Amphetamine, a stimulant, was used to treat hyperactivity?

Thanks for the question, it is a very good question that is currently 
perplexing the scientific fields of molecular neurobiology, psychiatry, 
psychology and ancillary areas.

The best answer I can give at this time is that we don’t really have the 
answer.  We have some very good ideas on what may be occurring in the 
brain when administering these amphetamine treatments to our ADHD 
patients, but more work needs to be done.  However, I will give you all 
the information I have, and what I could find in the literature.

According to the Physician’s Desk Reference (or as we like to call it in 
the pharmacological sciences – PDR) there is no known mechanism for 
methylphenidate (brand name: Ritalin hydrochloride) or amphetamine (main 
ingredient, in several forms, in brand name: Adderall) [1].  

However, the literature suggests that amphetamines appear to mediate the 
release of dopamine in various nuclei of the brain [2] (the therapeutic 
effect most likely involved in the treatment of narcolepsy).  The 
literature also suggests that amphetamines stimulate the activity of 
autoreceptors on pre-synaptic inhibitory neurons (the theoretical holy 
grail in ADHD treatment).  The result of this increased activity in the 
pre-synaptic inhibitory neurons is decreased activity in the dopamine and 
norepinephrine pathways [3].

I’ll take a short departure from the ADHD discussion to give a basic 
review of dopamine and norepinephrine (norepi).  These two chemicals act 
as messengers that are released by a pre-synaptic neuron and which 
typically bind to receptors on the post-synaptic neuron (the synapse being 
the space between two neurons).  Under some circumstances, however (just 
to complicate things for undergrad neurobiology students) dopamine and 
norepi can bind to receptors on the pre-synaptic neuron and modulate their 
own release.  Once dopamine and norepi are in the synapse they typically 
bind to specific transport proteins and are taken into an interneuron 
(sometimes they re-enter the pre-synaptic neuron – no matter where the 
chemical is taken-up the process is called re-uptake) where they are 
processed into an inactive form, or constituents, and sent back to the pre-
synaptic neuron for reprocessing and repackaging.  Many psychological 
disorders involve problems with the re-uptake system.

Now then, we still do not know what is going on in the brain of the ADHD 
patient.  One possible explanation is that there may be a mutation in the 
dopamine transport gene [4].  Such a mutation would result in a patient 
who has an increased half-life of dopamine in the synaptic cleft (in 
English – dopamine is able to mediate its signal longer).  This could 
explain why a patient with ADHD shows hyperactivity.

So let’s put these things together.  Amphetamine drugs stimulate the pre-
synaptic inhibitory neurons.  By stimulating these inhibitory neurons, the 
drug in fact serves to hyperpolarize the post-synaptic neuron, which will 
prevent the post-synaptic neuron from firing and passing messages along.  
In other words, the amphetamine is acting as a message blockade/blocker of 
a dopamine or norepi releasing neuron.  By preventing the release of 
norepi and dopamine, or at least keeping it at low levels, the mutant/less 
effective re-uptake system can cope and act like a “normal” system.  For 
now, this is the best story that we can come up with.  As more data 
becomes available we'll be able to revamp and pin-down the story.

I hope we soon have more definite answers to your question in the future.  
I know there is a lot of research going on in this field, and that at a 
later date we might be able to say with some certainty the mechanisms at 
work.  However in the mean-time, this is the best we can do.  Thanks for 
your question.


Reference:

[1] 2000 Physician’s Desk Reference.  Medical Economics Company.  2000.

[2] Russell V, de Villiers A, Sagvolden T, Lamm M, Taljaard J.  
Differences between electrically-, ritalin- and D-amphetamine-stimulated 
release of [3H]dopamine from brain slices suggest impaired vesicular 
storage of dopamine in an animal model of Attention-Deficit Hyperactivity 
Disorder. Behav Brain Res 1998 Jul;94(1):163-71.

[3] Solanto MV.  Neuropsychopharmacological mechanisms of stimulant drug 
action in attention-deficit hyperactivity disorder: a review and 
integration.  Behav Brain Res 1998 Jul;94(1):127-52.

[4] Cook EH Jr, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, 
Leventhal BL.  Association of attention-deficit disorder and the dopamine 
transporter gene.  Am J Hum Genet 1995 Apr;56(4):993-8.

For more information on physiology (and some pharmacology) of neurons see:

[1] Levitan, IB; Kaczmarek, LK.  The Neuron: Cell and molecular biology.  
2nd Edition.  1997.  Oxford University Press.

[2] Shepherd, GM.  Neurobiology.  3rd Edition.  1994.  Oxford University 
Press.


Lyle D. Burgoon
Graduate Research Assistant
Department of Pharmacology and Toxicology
Michigan State University