Amphetamines are psychostimulant substances; they cause an enhancement in alertness, energy and self-confidence, which are accompanied by an increase in the sense of euphoria and wellbeing, as well as a decrease in appetite (Green et al., 2003). Their use can trigger severe undesired effects, which range from cardiovascular complications to psychotic reactions, hallucinations and paranoia. Furthermore, if used frequently, most amphetamines have high abuse liability and can cause tolerance (Hoffman and Lefkowitz, 1996). 

Amphetamines, as suggested by their generic name (Alpha- MethylPHenEThylAMINE), are comprised of a phenyl ring connected to an amino group by a two-carbon side-chain with a methyl group on carbon-1 of the side chain (Fig. 1). Amphetamine, Methamphetamine and methylenedioxymethamphetamine (MDMA) are the most popular substances of this group among users.

 Dopamine Amphetamine Comparison


Generic mechanism of action of amphetamines:

Synaptic terminals are endowed with vesicles that store reserves of neurotransmitters, which, in physiological conditions, are released through exocytosis into the synaptic cleft at a controlled rate.

Amphetamines are, with few exceptions, psychostimulants of the releaser type. They increase extracellular neurotransmission by promoting the release of neurotransmitters found in presynaptic vesicles. Depending on their specific structure, these compounds can evoke an increase in dopamine, norepinephrine and serotonin, at different ratios and to different degrees. Nonetheless, the main psychostimulant and reinforcing effects of amphetamines are generally attributed to the release of dopamine (Gulley and Zahniser, 2003; Kuczenski et al., 1995; Sulzer et al., 2005).

Amphetamines enter the synaptic terminal through monoamine transporters, mainly the dopamine, norepinephrine and serotonin transporters (abbreviated DAT, NET and SERT, respectively), where they act as substrates (Liang and Rutledge, 1982; Zaczek et al., 1991). This high affinity for monoamine transporters is explained by the high homology between amphetamines and catecholamines, such as dopamine or norepinephrine.

Once they enter the synaptic terminal, amphetamines are capable of massively releasing neurotransmitters, which are contained in vesicles. Due to the high concentrations of cytoplasmic neurotransmitters, there is a shift in the gradient (i.e. there is a higher concentration of free monoamines inside the terminal), which, in turn, causes their release into the synaptic cleft by reverse transport, mediated by the monoamine transporters mentioned above (Leviel, 2001) (Fig. 2).

Vesicular Neurotransmitter Release by Amphetamines (MDMA, Amphetamine, Meth...)

There are two main hypotheses as to how vesicular content in released into the cytoplasm.

Weak base Hypothesis:

All sympathomimetic compounds are weak bases with amine moieties that are capable of accepting protons with pKs in the range of ~ 8 to 10. Thus, they can be protonated in acidic organelles including catecholamine vesicles (Sulzer and Rayport, 1990): once charged, they become less membrane-permeable and accumulate in the acidic structure.

The acidic pH gradient in secretory vesicles provides the energy to accumulate neurotransmitters against their concentration gradient. Secretory vesicles are acidic; vesicles maintain a pH of 5.0 – 5.7, depending on conditions (Markov et al., 2008) that provide the energy to accumulate monoamine transmitters.

Weak base compounds that are sufficiently membrane-permeable to enter secretory vesicles bind free protons, alkalinize the existing vesicular acidic pH gradient and thus decrease the energy that drives the accumulation of neurotransmitters (Markov et al., 2008; Sulzer and Rayport, 1990).

 Vesicular Release MDMA Amphetamine Meth

Several studies have tested the weak base hypothesis by comparing effects on vesicular pH and catecholamine redistribution. Interestingly, there is not a direct correlation between vesicular pH and neurotransmitter release (Floor and Meng, 1996). Furthermore, (S+)-amphetamine stereoisomer is several-fold more effective at blocking uptake than its (R−)isomer (Peter et al., 1994); these phenomena cannot be explained uniquely by the weak base hypothesis. Thus, data points to the existence of a complementary mechanism of action in the mediation of vesicular monoamine release.

Substrate hypothesis:

It has been demonstrated that amphetamine can bind to the vesicular monoamine transporter (VMAT), the protein whereby monoamines are taken into the vesicle for storage (Erickson et al., 1996). This would allow reuptake blockade, which, in turn, would cause a gradual increase in cytosolic monoamines due to leakage across the permeable vesicular membrane (Schonn et al., 2003). Additionally, amphetamine acts as a substrate, thus entering the vesicle through the transporter (Partilla et al., 2006); this would allow the release of intravesicular monoamines in the process (amphetamine/monoamine exchange). In agreement with this hypothesis is the observation initially made on isomer-driven preferential effect of amphetamine, as the (S+)-isomer exhibits preferential binding to the transporter (Peter et al., 1994).