What is the mechanism of dopamine (DA) release?

From the Guidelines

Dopamine release is triggered by the activation of the μ opioid receptor, which results in an increase in dopamine release in the brain's reward circuitry, primarily in response to rewarding or pleasurable stimuli, such as opioid use 1. The mechanism of dopamine release involves the synthesis of dopamine from the amino acid tyrosine through a two-step process involving tyrosine hydroxylase and DOPA decarboxylase, and its storage in vesicles until an action potential causes calcium influx, triggering vesicle fusion with the cell membrane and dopamine release into the synapse. Some key points to consider about dopamine release include:

• Dopamine is synthesized in dopaminergic neurons, mainly in the ventral tegmental area and substantia nigra
• Dopamine release is influenced by various substances, including opioids, which activate the μ opioid receptor to trigger a cascade of intracellular activity that results in an increase in dopamine release
• The effects of dopamine release are mediated by its binding to receptors on neighboring neurons, activating signaling pathways that influence mood, motivation, pleasure, and motor control
• After activation, dopamine is either reabsorbed by the releasing neuron through dopamine transporters (DAT) or broken down by enzymes like monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), as noted in the context of opioid use and addiction 1. Understanding dopamine release is crucial for treating conditions like addiction, which involves dopamine system dysregulation, and for developing effective strategies for managing opioid use and preventing addiction, particularly in vulnerable populations such as adolescents 1.

From the FDA Drug Label

Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain.

The mechanism of dopamine (DA) release is not directly described in the provided drug labels. However, it is mentioned that levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is presumably converted to dopamine in the brain. This suggests that dopamine release is indirectly related to the administration of levodopa.

• The exact mechanism of dopamine release is not explicitly stated in the drug labels 2 3.
• Therefore, no conclusion can be drawn about the mechanism of dopamine release.

From the Research

Mechanism of Dopamine Release

The mechanism of dopamine (DA) release is complex and involves multiple processes.

• Dopamine release can be categorized into two types: phasic and tonic release. Phasic release refers to high-amplitude, burst-like release of dopamine, while tonic release refers to a low-level, background release of dopamine 4.
• The release of dopamine is regulated by various mechanisms, including the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, and the dopamine transporter, which regulates the reuptake of dopamine 5.
• Dopamine release is also influenced by autoreceptors, which provide feedback inhibition of dopamine release, and by the firing rate of dopaminergic neurons 5.
• Recent studies suggest that dopamine release is a fast process that generates small signaling hotspots, rather than a slow process that influences many target cells via widespread receptors 6.

Regulation of Dopamine Release

The regulation of dopamine release is crucial for maintaining proper dopamine signaling.

• The dopamine release apparatus is regulated by various mechanisms, including the activity of tyrosine hydroxylase, the dopamine transporter, and autoreceptors 5, 6.
• The striatal architecture for dopamine signaling may have evolved to support rapid dopamine coding, and the regulation of dopamine release may act through this machinery 6.
• Dopamine receptors are expressed in many types of mammalian cells, inside and outside the central nervous system, and dopamine regulates various processes, including antigen presentation, T-cell activation, and inflammation 7.

Dopamine Signaling

Dopamine signaling plays a crucial role in various physiological functions, including motor control, modulation of affective and emotional states, reward mechanisms, and selected higher cognitive functions.

• Dopamine is involved in the modulation of synaptic dynamics through different pathways, and it plays a role in the regulation of long-term synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD) 8.
• The effect of dopamine on dendritic spines places this molecule at the interface between the motor and the cognitive systems, and dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders 8.