How does cocaine's mechanism of action differ from that of amphetamine in the central nervous system?

Cocaine's mechanism of action differs from that of amphetamine primarily because cocaine acts as a reuptake inhibitor, while amphetamine acts as a releasing agent and reuptake inhibitor with a reversal mechanism. Cocaine primarily blocks the reuptake of dopamine, norepinephrine, and serotonin by binding to and inhibiting the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), respectively. These transporters are responsible for removing the neurotransmitters from the synapse back into the presynaptic neuron. By blocking these transporters, cocaine prevents the reuptake of these neurotransmitters, leading to an accumulation of dopamine, norepinephrine, and serotonin in the synapse. Amphetamine, on the other hand, not only blocks the reuptake of dopamine and norepinephrine but also acts as a substrate for the DAT and NET, meaning it is transported into the presynaptic neuron. Once inside, amphetamine disrupts the vesicular monoamine transporter 2 (VMAT2), which normally packages dopamine into vesicles. This results in increased dopamine concentrations in the cytoplasm, leading to the reversal of DAT, causing it to pump dopamine out of the neuron and into the synapse. Therefore, cocaine primarily increases neurotransmitter levels by blocking their reuptake, while amphetamine increases neurotransmitter levels both by blocking reuptake and by actively releasing neurotransmitters from the presynaptic neuron through a transporter reversal mechanism. This difference in mechanism contributes to the distinct pharmacological profiles of the two drugs.