Dopamine

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Dopamine (DA) is a monoamine neurotransmitter found in the brain and body of many animals, including humans. It is a catecholamine and phenethylamine. Dopamine plays several important roles in the brain and body. In the brain, it is crucial for reward, motivation, pleasure, motor control, learning, and attention. In the body, it acts as a local paracrine messenger and also has effects on the kidney, heart, and blood vessels.

Dopamine is synthesized in the brain in the Substantia nigra and Ventral tegmental area (VTA), and in the periphery in the adrenal gland and kidneys. It is released into the synapse to transmit signals between neurons.

Dopamine dysfunction is implicated in several neurological and psychiatric disorders, including Parkinson's disease, addiction, schizophrenia, attention deficit hyperactivity disorder (ADHD), and restless legs syndrome.

Chemistry and Production

Dopamine is chemically known as 3,4-dihydroxyphenethylamine. It is synthesized from the amino acid tyrosine through a two-step process:

1. Tyrosine is converted to L-DOPA (L-3,4-dihydroxyphenylalanine) by the enzyme tyrosine hydroxylase. This is often the rate-limiting step in dopamine synthesis.
2. L-DOPA is converted to dopamine by the enzyme DOPA decarboxylase.

In the brain, dopamine is primarily produced by neurons in the Substantia nigra (specifically the pars compacta) and the Ventral tegmental area (VTA). These neurons project to various brain regions, forming the major dopaminergic pathways.

In the periphery, dopamine can be synthesized in the adrenal medulla (as a precursor to epinephrine and norepinephrine), the kidneys, and other tissues.

Mechanism of Action

Dopamine exerts its effects by binding to and activating specific G protein-coupled receptors called dopamine receptors. There are five main types of dopamine receptors, broadly divided into two families:

• D1-like receptors (D1 and D5): These receptors are typically coupled to G_s proteins and stimulate adenylyl cyclase, leading to an increase in cyclic AMP (cAMP) levels. They are generally considered excitatory or facilitatory.
• D2-like receptors (D2, D3, and D4): These receptors are typically coupled to G_i/o proteins and inhibit adenylyl cyclase, leading to a decrease in cAMP levels. They are generally considered inhibitory.

After being released into the synaptic cleft, dopamine's action is terminated primarily by reuptake into the presynaptic neuron via the dopamine transporter (DAT). Once inside the neuron, dopamine can be repackaged into vesicles or metabolized by enzymes such as monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).

Dopaminergic Pathways in the Brain

There are four major dopaminergic pathways in the brain:

• Mesolimbic pathway: Projects from the VTA to the nucleus accumbens, amygdala, and hippocampus. This pathway is critically involved in reward, motivation, and pleasure. It is heavily implicated in addiction.
• Mesocortical pathway: Projects from the VTA to the prefrontal cortex. This pathway is involved in cognition, memory, attention, and executive functions. Dysfunction is linked to the negative and cognitive symptoms of schizophrenia.
• Nigrostriatal pathway: Projects from the Substantia nigra to the striatum (caudate nucleus and putamen). This pathway is essential for the control of voluntary movement. Degeneration of these neurons leads to Parkinson's disease.
• Tuberoinfundibular pathway: Projects from the hypothalamus (arcuate nucleus and periventricular nucleus) to the pituitary gland (specifically the anterior pituitary). Dopamine released here inhibits the secretion of prolactin.

Functions

Dopamine is involved in a wide range of physiological and cognitive processes:

• Reward and Motivation: Dopamine is a key component of the brain's reward system. Its release signals that an activity is pleasurable or rewarding, reinforcing the behavior and motivating future actions to obtain similar rewards. This includes natural rewards like food, water, and social interaction, as well as artificial rewards like drugs of abuse.
• Motor Control: The nigrostriatal pathway's role in movement is well-established. Adequate dopamine levels in the striatum are necessary for smooth, coordinated voluntary movement.
• Cognition and Executive Functions: The mesocortical pathway influences cognitive processes such as working memory, planning, decision-making, and attention.
• Hormonal Regulation: The tuberoinfundibular pathway inhibits prolactin release from the pituitary gland. Dopamine also influences the release of other hormones.
• Nausea and Vomiting: Dopamine receptors in the chemoreceptor trigger zone of the brainstem are involved in triggering nausea and vomiting.
• Sleep and Arousal: Dopamine contributes to regulating wakefulness and sleep cycles.

Role in Disease

Dysregulation of the dopaminergic system is implicated in numerous disorders:

• Parkinson's Disease: Characterized by the progressive degeneration of dopaminergic neurons in the Substantia nigra, leading to motor symptoms like tremor, rigidity, bradykinesia (slow movement), and postural instability.
• Addiction: Most drugs of abuse increase dopamine signaling in the mesolimbic reward pathway, either by promoting release, blocking reuptake, or inhibiting metabolism. This leads to the intense pleasure and reinforcement that drives compulsive drug seeking.
• Schizophrenia: The dopamine hypothesis of schizophrenia suggests that the disorder is related to excessive dopamine activity in the mesolimbic pathway (positive symptoms like hallucinations and delusions) and potentially reduced activity in the mesocortical pathway (negative and cognitive symptoms).
• Attention Deficit Hyperactivity Disorder (ADHD): Some theories suggest that altered dopamine signaling, particularly in pathways related to motivation and executive function, contributes to ADHD symptoms.
• Restless Legs Syndrome (RLS): Linked to dysfunction in the dopaminergic pathways involved in motor control.
• Tourette Syndrome: Thought to involve abnormalities in dopaminergic signaling in the basal ganglia.

Pharmacology

Many drugs affect the dopaminergic system and are used therapeutically or are substances of abuse:

• L-DOPA: A precursor to dopamine, used to treat Parkinson's disease by increasing dopamine synthesis.
• Dopamine receptor agonists: Drugs that mimic dopamine and activate dopamine receptors (e.g., pramipexole, ropinirole, used for Parkinson's and RLS).
• Dopamine receptor antagonists: Drugs that block dopamine receptors (e.g., antipsychotics like haloperidol, risperidone, used for schizophrenia and other psychotic disorders).
• Dopamine reuptake inhibitors (DRIs): Drugs that block the dopamine transporter, increasing dopamine levels in the synapse (e.g., cocaine, methylphenidate, amphetamine, some antidepressants like bupropion).
• Enzyme inhibitors: Drugs that inhibit the enzymes that break down dopamine (e.g., MAO-B inhibitors like selegiline, COMT inhibitors like entacapone, used for Parkinson's).

History

Dopamine was first synthesized in 1910 by George Barger and James Ewers at King's College, London. Its role as a neurotransmitter was definitively established in 1958 by Arvid Carlsson and Nils-Åke Hillarp at the National Heart Institute in Sweden. Carlsson was awarded the Nobel Prize in Physiology or Medicine in 2000 for his findings regarding dopamine as a neurotransmitter.

Conclusion

Dopamine is a fundamental neurotransmitter and hormone with diverse and critical functions throughout the brain and body. Its intricate involvement in reward, movement, motivation, and cognition makes it central to understanding both normal physiological processes and the pathophysiology of numerous neurological and psychiatric conditions. Research continues to uncover the complexities of dopamine signaling and its potential as a target for therapeutic interventions.

See Also

• Dopaminergic pathways
• Dopamine hypothesis of schizophrenia
• Reward system
• Parkinson's disease
• Neurotransmitter