MadSci Network: Neuroscience |
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
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