Dopamine, often referred to as the "pleasure molecule", is a crucial neurotransmitter involved in a wide range of physiological functions. While it is widely recognised for its role in cognition, memory, learning, and motor movement, dopamine also regulates essential body processes like blood pressure, kidney activity, and gastrointestinal functions. In addition to its presence in the brain, dopamine exists in the gut, where it plays a critical role in intestinal motility, secretion, and the maintenance of the mucosal barrier.
This neurotransmitter's widespread influence extends beyond simple pleasure and reward systems. Disruptions in dopamine signalling are central to many psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, and its receptors play a significant role in how it affects the body.

Dopamine formation
Dopamine is synthesised primarily in areas of the brain like the hypothalamus and the ventral tegmental area. It originates from the amino acid tyrosine, which is converted into 3,4-dihydroxyphenylalanine (L-DOPA) through the action of the enzyme tyrosine hydroxylase. L-DOPA is then decarboxylated by DOPA decarboxylase to form dopamine. Once synthesised, dopamine is transported into vesicles via vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2), where it awaits release into the synaptic cleft.
Dopamine is metabolised mainly by monoamine oxidase (MAO), aldehyde dehydrogenase, and catechol-O-methyltransferase (COMT). Within the brain, dopamine is also regulated by reuptake into presynaptic nerve terminals through dopamine transporters. Despite these mechanisms, dopamine is not entirely contained within synaptic vesicles, leaking back into the cytoplasm, where enzymes like MAO and COMT play a role in its breakdown.

Dopamine receptors: Overview
Dopamine exerts its effects through five distinct types of G-protein coupled receptors (GPCRs), divided into two primary families: D1-like receptors (D1 and D5) and D2-like receptors (D2, D3, and D4). These receptor families differ not only in their distribution but also in the signalling pathways they activate. The D1-like receptors stimulate adenylate cyclase activity, while D2-like receptors inhibit it.

D1-Like receptors
The D1-like receptors (D1 and D5) are primarily associated with reward, reinforcement, and decision-making processes. Studies in rodents have demonstrated that blocking D1 receptors leads to reduced motivation to exert effort for a reward, choosing easier tasks over more rewarding but effortful ones. This is especially relevant in psychiatric conditions such as depression and schizophrenia, where effort-based decision-making is impaired. D5 receptors also play a crucial role in learning and memory, as shown by experiments in mice with D5 receptor knockouts, who exhibited impaired spatial and recognition memory.

D2-Like receptors
D2-like receptors (D2, D3 and D4), on the other hand, are involved in modulating motor control and cognitive functions. Antipsychotic medications primarily target D2 receptors, which are critical in regulating dopamine's activity in the brain. Excessive dopamine signalling through D2 receptors is linked to conditions like schizophrenia, characterised by delusions and hallucinations. By blocking these receptors, antipsychotics help reduce the overactive dopamine transmission associated with psychotic symptoms.

Dopamine and motor control
Dopamine's role in motor function is primarily mediated through its interactions with the basal ganglia, a group of structures in the brain responsible for movement control. Dopamine's influence on motor pathways depends on the type of receptor it binds to.
When dopamine binds to D1 receptors in the substantia nigra, it triggers the release of gamma-aminobutyric acid (GABA) from neurons, which inhibits the globus pallidus internal (GPi). This inhibition reduces the GPi's inhibitory effect on the thalamus, leading to increased excitation of the motor cortex and, consequently, movement.
On the other hand, when dopamine binds to D2 receptors, it suppresses GABA release from neurons projecting to the globus pallidus external (GPe). This action causes the GPe to inhibit the subthalamic nuclei, which, in turn, reduces excitation of the GPi. The net result of both pathways is an overall increase in motor activity, highlighting dopamine's critical role in promoting movement.

Dopamine signalling pathways
Dopamine signalling is complex and involves several pathways within cells. The two primary pathways activated by dopamine receptors are the cAMP pathway and the extracellular signal-regulated kinase (ERK) pathway.

cAMP pathway
When dopamine binds to its receptors on the postsynaptic neuron, it activates G proteins, which, in turn, stimulate or inhibit adenylyl cyclase depending on the receptor type. In the case of D1-like receptors, adenylyl cyclase activity is increased, leading to the production of cyclic AMP (cAMP), a crucial second messenger. cAMP activates protein kinase A (PKA), which phosphorylates various target proteins, ultimately altering neuronal excitability, gene expression, and synaptic plasticity.

ERK pathway
The ERK pathway is another crucial signalling mechanism, particularly in relation to D1-like receptors. Dopamine receptors activate extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) through the activation of Ras proteins and the mitogen-activated protein kinase (MAPK) cascade. ERK activation leads to phosphorylation of a wide array of proteins, influencing processes such as cell cycle progression, gene expression and cytoskeletal reorganisation.

Dopamine and calcium signalling
D1-like receptors also play a role in modulating calcium signalling through voltage-gated calcium channels (VGCCs). Activation of these receptors leads to an influx of calcium ions into the cell, triggering various calcium-mediated signalling pathways. Calcium ions act as secondary messengers, modulating numerous cellular functions, including neurotransmitter release, synaptic plasticity and gene expression.
Within the synapse, calcium signalling is essential for neurotransmitter release. Calcium influx into the presynaptic neuron triggers the fusion of synaptic vesicles containing neurotransmitters with the presynaptic membrane, facilitating their release into the synaptic cleft.

Desensitisation and internalisation of dopamine receptors
Prolonged exposure to dopamine can lead to receptor desensitisation, a process regulated by G protein-coupled receptor kinases (GRKs) and β-arrestins. Desensitisation occurs when GRKs phosphorylate the dopamine receptor, reducing its ability to activate G proteins and signal downstream pathways. β-arrestins then bind to the phosphorylated receptor, blocking further signalling and promoting receptor internalisation into the cell.
Once internalised, dopamine receptors can be either recycled back to the cell surface or degraded. Recycling allows the receptors to become reactivated and available for future signalling, while degradation reduces the number of active receptors, limiting the cell's response to dopamine.

Conclusion
Dopamine is a neurotransmitter of extraordinary significance, influencing not only pleasure and reward but also critical processes such as motor control, gastrointestinal function and immune responses. Its effects are mediated through five distinct dopamine receptors, each of which plays a unique role in regulating various physiological functions. The signalling pathways activated by dopamine receptors, including the cAMP and ERK pathways, contribute to its complex effects on the body.
Disruptions in dopamine signalling can lead to various psychiatric and neurological disorders, highlighting the importance of understanding its mechanisms. Continued research into dopamine and its receptors will offer new insights into potential therapies for conditions such as schizophrenia, Parkinson's disease and depression. As our understanding of dopamine's multifaceted role deepens, so too will our ability to target its pathways for therapeutic purposes.

Renald Blundell is a biochemist and biotechnologist with a special interest in Natural and Alternative Medicine. He is a professor at the Faculty of Medicine and Surgery, University of Malta.

Lara Arslan is currently a medical student at the University of Malta.

Photo: AI-generated image created by Prof. Blundell