Amphetamine
![Signaling cascade in the nucleus accumbens that results in amphetamine addiction
Note: colored text contains article links.
Nuclear pore
Nuclear membrane
Plasma membrane
Cav1.2
NMDAR
AMPAR
DRD1
DRD5
DRD2
DRD3
DRD4
Gs
Gi/o
cAMP
cAMP
PKA
CaM
CaMKII
DARPP-32
PP1
PP2B
CREB
ΔFosB
JunD
c-Fos
SIRT1
HDAC1
[Color legend 1]
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[111][112] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[113][114] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[114] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[115] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[103][116] ΔFosB functions as](/uploads/202502/11/ΔFosB.svg4444.png)
![Pharmacodynamics of amphetamine in a dopamine neuron
via AADC
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[36] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[36][144] When amphetamine enters the synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow-orange area).[144] When amphetamine binds to TAAR1, it reduces postsynaptic neuron firing rate via potassium channels and triggers protein kinase A (PKA) and protein kinase C (PKC) signaling, resulting in DAT phosphorylation.[36][145][146] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[36] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[36] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[147][148][149]](/uploads/202502/11/TAAR1_Dopamine.svg4444.png)
Amphetamine (contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, the term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.