Does cocaine block neurotransmitter (neurotransmitter) uptake at the presynaptic (presynaptic) nerve terminal?

From the Guidelines

Cocaine blocks neurotransmitter uptake at the presynaptic nerve terminal, primarily affecting dopamine, norepinephrine, and serotonin. This action is supported by the most recent and highest quality study, which explains that cocaine produces a sympathomimetic toxidrome by blocking the reuptake of norepinephrine, epinephrine, dopamine, and serotonin, leading to excess concentrations at the postsynaptic receptors and resulting in sympathetic activation and stimulation of dopaminergic neurons 1. The blockade of these neurotransmitters leads to prolonged and intensified stimulation of the receiving neurons, resulting in cocaine's characteristic euphoric effects, increased energy, and alertness.

Key Mechanisms

• Cocaine binds to transporters on the presynaptic neuron, preventing the reuptake of dopamine, norepinephrine, and serotonin
• This blockade causes an accumulation of catecholamines at the postsynaptic receptor, acting as a powerful sympathomimetic agent
• The chronotropic effects of cocaine use are intensified in the setting of alcohol use, and cocaine administration can reduce left ventricular function and increase end-systolic wall stress 1

Clinical Implications

• Cocaine use can lead to increased myocardial demand, vasoconstriction of coronary arteries, and a prothrombotic state, increasing the risk of myocardial ischemia and myocardial infarction
• The combination of cocaine and cigarette use results in greater increases in heart rate and vasoconstriction than either cocaine use or cigarette smoking alone 1
• Cocaine users have elevated levels of C-reactive protein, von Willebrand factor, and fibrinogen, which may contribute to thrombosis and accelerate atherosclerosis 1

From the Research

Mechanism of Cocaine

• Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses, which is the primary mechanism for its effects on the central nervous system (CNS) 2.
• This blockade leads to an increase in the levels of monoamines, such as dopamine, serotonin, and norepinephrine, in the extracellular space, resulting in the positively reinforcing effects that cocaine users seek 3.
• Cocaine possesses high affinity for the transporters of dopamine, serotonin, and noradrenaline, and blocks the reuptake of these monoamines 4.

Effects on Neurotransmitter Uptake

• The plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons, and cocaine interferes with this process by blocking the reuptake of these neurotransmitters 5.
• Cocaine's blockade of neurotransmitter uptake leads to a transient inhibition of transmitter biosynthesis in dopamine and serotonin neurons, which may represent a compensatory mechanism for the increased synaptic transmitter levels 6.

Presynaptic Nerve Terminal

• Cocaine acts at monoaminergic neurotransmitter transporters to block the uptake of monoamines at the presynaptic nerve terminal, leading to an increase in the levels of these neurotransmitters in the synaptic cleft 3.
• The increase in monoamine levels in the synaptic cleft is responsible for the euphoric and rewarding effects of cocaine, as well as its potential for addiction 2, 4.