Amphetamine

🧬 Receptor activity

Mechanism of action

Amphetamine's structure closely resembles catecholamine neurotransmitters, characterized primarily by a long planar conformation, an aromatic ring, and nitrogen in the aryl side chain. Like endogenous catecholamines, amphetamine is actively transported into presynaptic nerve terminals via monoamine reuptake transporters, which require association with two sodium ions and one chloride ion. Because amphetamine acts as a competitive substrate, increased concentrations lead to greater internalization of amphetamine. Once in the presynaptic terminal, amphetamine competes for storage in VMAT2 (Vesicular Monoamine Transporter 2), displacing other monoamines. This action induces the release of neurotransmitters into the synapse through a process known as reverse transport. The d-isomer is approximately fourfold more potent than the $l$-isomer in promoting dopamine release via this mechanism. The mechanism of action is further complemented by the inhibition of both monoamine reuptake and monoamine oxidase (MAO), which act synergistically to significantly elevate monoamine concentrations. Amphetamine does not act as a direct inhibitor but rather as a competitive substrate, classifying it as a weak dopamine reuptake inhibitor, a moderate noradrenaline reuptake inhibitor, and a very weak serotonin reuptake inhibitor. Consequently, the l-isomer exhibits significantly lower potency in this specific action. Amphetamine acts as a weak inhibitor of the mitochondrial-bound enzyme MAO, the catalytic enzyme responsible for degrading excess neurotransmitters. Although this mechanism is often considered minor due to its weak inhibitory nature, it remains a component of amphetamine's overall action. Amphetamine is a modulator of glutamatergic neurotransmission, primarily via its action on the dopamine system. The mass release of dopamine caused by amphetamine subsequently signals to the glutamatergic system, leading to long-lasting changes in synaptic plasticity. Amphetamine's entry into dopamine neurons triggers the endocytosis of the excitatory amino acid transporter EAAT3, reducing glutamate clearance and potentiating excitatory synaptic responses mediated by ionotropic receptors. Chronic exposure also alters receptor composition, such as the downregulation of the NMDA receptor NR2B subunit in the striatum, which is a key molecular change underlying behavioral sensitization to the drug.
Inactivation of sympathomimetic noncatecholamines largely depends on breakdown by monoamine oxidase and since substitution of an alkyl group for hydrogen on the a-carbon atom blocks enzymatic inactivation of the amino group, the duration of action of noncatecholamines (but not of catecholamines, which are inactivated largely by a different mechanism) is prolonged by a-substitution. The absence of a hydroxyl group on the aromatic ring of amphetamine reduces inactivation of the drug in the GI tract and the amphetamines are active following oral administration.

Pharmacodynamics

From its mechanism of action, it has been demonstrated that amphetamine augments the concentration of noradrenaline in the prefrontal cortex and dopamine in the striatum on a dose and time-dependent manner. The indistinct release of neurotransmitters which include adrenaline is known to produce cardiovascular side effects. There are old reports of a cognitive enhancement related to the administration of amphetamine in which improvements in intelligence test scores were reported. In ADHD, amphetamine has been largely showed to produce remarkable improvements in school performance, behavior, and demeanor. The effect was shown to be produced through both racemic forms and to this date, the use of racemic forms 3:1 (D:L) is very common. The therapeutic effect of amphetamine on serotonin does not seem to have a significant clinical effect on ADHD as observed on comparative studies with amphetamine and fenfluramine, a powerful serotonin releasing factor. However, the indirect effect on serotonin might have an effect on the depression and anxiety profile of ADHD. Studies regarding the illicit use of amphetamine in which heavy consumers were studied proved the generation of a paranoid state which flagged this drug as a psychiatric danger compound. This observation was supported by the continuous reports of misuse in patients under depression.

Pharmacokinetics

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