Dextroamphetamine's Mechanism: Dopamine Reuptake Inhibition and Release
Dextroamphetamine primarily affects dopamine reuptake by binding to the dopamine transporter (DAT) and stimulating reverse transport, which causes dopamine release into the synaptic cleft rather than simply blocking reuptake—this dual mechanism distinguishes it from pure reuptake inhibitors. 1
Primary Mechanism of Action
Dextroamphetamine acts at the dopamine transporter to increase synaptic dopamine through two complementary mechanisms:
- Stimulation of reverse transport (dopamine release): Dextroamphetamine binds to DAT and causes dopamine to be transported out of the presynaptic terminal into the extracellular space, actively increasing dopamine efflux 1, 2
- Inhibition of dopamine reuptake: At higher doses, dextroamphetamine also blocks the normal reuptake function of DAT, preventing dopamine from being cleared from the synapse 3
The American Academy of Child and Adolescent Psychiatry describes this as stimulants binding to the dopamine transporter in the striatum, resulting in increased synaptic dopamine that enhances executive control processes in the prefrontal cortex 1.
Dose-Dependent Effects
The mechanism shows biphasic characteristics depending on dose:
- Lower doses (therapeutic range): Primarily facilitate neuronal release of dopamine through reverse transport, producing dose-linear increases in extracellular dopamine 2, 3
- Higher doses: Combine both facilitated release and inhibition of neuronal reuptake, though this can trigger compensatory negative feedback mechanisms that limit further dopamine increases 2, 3
Research demonstrates that in both rats and nonhuman primates, dextroamphetamine stimulation of dopamine outflow through reverse transport via DAT is primarily responsible for the dose-linear increase in dopamine 2.
Regional Brain Effects
Dextroamphetamine increases dopamine and norepinephrine in pathways crucial for frontal lobe function:
- Striatum: Primary site of action where dextroamphetamine binds to dopamine transporters, producing the most pronounced effects 1, 4
- Prefrontal cortex: Enhanced dopaminergic activity ameliorates deficits in inhibitory control and working memory characteristic of ADHD 1, 5
- Nucleus accumbens and olfactory tubercle (mesolimbic terminals): Effects similar to striatum but less pronounced 3, 6
The acute administration reduces functional connectivity in cortico-striatal-thalamic networks, with dextroamphetamine-induced dopamine release (not D2/3 receptor binding) positively associated with these connectivity changes 4.
Important Clinical Distinction
Dextroamphetamine does NOT increase dopamine production or synthesis—it redistributes existing dopamine:
- Studies measuring DOPA accumulation (marker of dopamine synthesis rate) show that higher doses of dextroamphetamine actually decrease the rate of dopamine synthesis in the striatum 3
- The drug works by mobilizing and releasing dopamine that is already present in presynaptic terminals, not by increasing the enzymatic production of new dopamine 7, 3
This contrasts with the drug's effect on dopamine availability in the synapse, which increases dramatically through the release and reuptake inhibition mechanisms described above 1, 2.
Acute Tolerance and Feedback Mechanisms
A critical caveat in understanding dextroamphetamine's effects:
- Acute tolerance develops: Even with sustained dextroamphetamine exposure in brain extracellular fluid, there is a loss of dopamine response, suggesting compensatory negative feedback to limit dopamine increases 2
- Species differences: Nonhuman primates show a 10-fold faster return to baseline dopamine compared to rats, indicating faster system response to tolerate dopamine increases 2
- Sensitization with chronic use: Repeated escalating doses can produce persistent hypersensitivity, with elevated dopamine release in the ventral striatum persisting 15-30 days after drug cessation 6
Human PET studies confirm that oral dextroamphetamine occupies a high proportion of dopamine transporter sites in the striatum 1.