How can dopamine be increased in the central nervous system?

Increasing Central Nervous System Dopamine

Dopamine levels in the CNS can be increased through pharmacological agents that either enhance dopamine synthesis, block its reuptake, inhibit its breakdown, or directly stimulate dopamine receptors.

Pharmacological Strategies to Increase CNS Dopamine

Dopamine Precursor Supplementation

• Levodopa (L-DOPA) is the most effective method to increase CNS dopamine synthesis, as it crosses the blood-brain barrier and is converted to dopamine by aromatic amino acid decarboxylase in dopaminergic neurons 1.
• Levodopa must be combined with a peripheral decarboxylase inhibitor (carbidopa) to prevent premature conversion to dopamine outside the CNS, which would cause peripheral side effects and reduce CNS availability 1.
• This approach is the cornerstone of Parkinson's disease treatment, directly addressing the striatal dopamine deficiency caused by degeneration of substantia nigra neurons 2, 1.

Monoamine Oxidase Inhibitors (MAOIs)

• Selegiline selectively inhibits MAO-B at doses ≤10 mg/day, blocking the catabolism of dopamine and thereby increasing the net amount of dopamine available in the synaptic pool 1.
• MAO-B inhibition is irreversible, so the recovery of enzyme activity depends on de novo protein synthesis rather than drug clearance; platelet MAO-B activity returns to normal 5–7 days after discontinuation 1.
• Selegiline may also increase dopaminergic activity through additional mechanisms, including interference with dopamine reuptake at the synapse 1.
• The drug's metabolites—amphetamine and methamphetamine—interfere with neuronal uptake and enhance release of dopamine, norepinephrine, and serotonin, though their contribution to therapeutic effects remains unclear 1.

Dopamine Reuptake Inhibitors

• Methylphenidate blocks the dopamine transporter (DAT), raising resting extracellular dopamine levels several-fold while paradoxically reducing the amplitude of impulse-triggered dopamine release 3.
• At therapeutic doses (0.2–0.5 mg/kg), methylphenidate reduces locomotion in hyperactive individuals by elevating baseline dopamine, which dampens the phasic dopamine surges that drive psychomotor activity 3.
• This mechanism explains how "stimulants" reduce hyperactivity: the elevated tonic dopamine activates presynaptic autoreceptors that inhibit further dopamine release, resulting in smaller phasic responses to neural impulses 3.
• Psychostimulants (methylphenidate, dexmethylphenidate, dexamphetamine) act as dopamine and norepinephrine reuptake inhibitors, increasing dopamine levels in the CNS 4.

Dopamine Receptor Agonists

• Bromocriptine, pergolide, lisuride, quinpirole, and carmoxirole are DA₂ receptor agonists used in Parkinson's disease to directly stimulate dopaminergic receptors in the nigrostriatal system, bypassing the need for endogenous dopamine synthesis 5.
• Fenoldopam, piribedil, ibopamine, and SKF 3893 are DA₁ receptor agonists that activate dopaminergic signaling, though their primary clinical use is outside the CNS (e.g., cardiovascular effects) 5.
• Dopamine receptor agonists are particularly useful when dopaminergic neurons are severely depleted and cannot synthesize adequate dopamine even with levodopa supplementation 1.

Amphetamine-Class Stimulants

• Dexamphetamine enhances dopamine release from presynaptic terminals and blocks dopamine reuptake, producing a dual mechanism that substantially increases synaptic dopamine concentrations 3.
• Amphetamines also interfere with vesicular monoamine transporter (VMAT), causing dopamine to leak from storage vesicles into the cytoplasm, where it is then released into the synapse 1.
• At higher doses, amphetamines produce generalized CNS stimulation due to very high resting and pulsatile dopamine levels that overcome presynaptic inhibition 3.

Physiological Context and Mechanisms

Dopamine Synthesis Pathway

• Dopamine is synthesized from the dietary amino acid phenylalanine, which is converted to tyrosine and then to L-DOPA by tyrosine hydroxylase (the rate-limiting step), followed by decarboxylation to dopamine 6.
• This synthesis occurs in dopaminergic neurons of the substantia nigra, ventral tegmental area, and hypothalamus, as well as in peripheral tissues 7.

Major Dopaminergic Pathways

• The nigrostriatal pathway (substantia nigra → striatum) controls motor function; motor symptoms appear only after 40–50% of dopaminergic neurons are lost 2.
• The mesolimbic pathway (ventral tegmental area → nucleus accumbens) mediates reward and motivation 2.
• The mesocortical pathway (ventral tegmental area → prefrontal cortex) regulates executive function, working memory, and attention 2.
• The tuberoinfundibular pathway (hypothalamus → pituitary) inhibits prolactin secretion 5.

Receptor-Mediated Effects

• Dopamine acts through five G-protein-coupled receptor subtypes (D₁–D₅) that are expressed both synaptically and extra-synaptically in neurons and non-neuronal cells throughout the body 6, 8.
• D₁-like receptors (D₁, D₅) are excitatory and coupled to Gs proteins, while D₂-like receptors (D₂, D₃, D₄) are inhibitory and coupled to Gi proteins 8.
• Dopamine receptors are found not only in the CNS but also in the kidney, pancreas, lungs, blood vessels, and immune cells, where dopamine acts as an autocrine or paracrine agent 6, 7.

Clinical Applications and Disease States

Parkinson's Disease

• Parkinson's disease results from progressive degeneration of dopaminergic neurons in the substantia nigra, causing striatal dopamine deficiency 2, 1.
• Early in the disease, levodopa effectively compensates for reduced dopamine synthesis, but over time the response deteriorates due to continued neuronal loss 1.
• Selegiline is used as an adjunct to levodopa/carbidopa to prolong dopamine availability by blocking its breakdown 1.

ADHD

• Stimulants (methylphenidate, amphetamines) enhance dopamine and norepinephrine in mesocortical pathways, improving frontal lobe function and ameliorating deficits in inhibitory control and working memory 2.
• The therapeutic effect relies on increasing tonic dopamine levels, which paradoxically reduces phasic dopamine release and decreases hyperactivity 3.

Schizophrenia

• Antipsychotic efficacy is mediated through antagonism of dopamine D₂ receptors, reducing excessive dopaminergic activity in mesolimbic pathways 2.
• This highlights that dopamine modulation can be bidirectional—increasing dopamine treats Parkinson's and ADHD, while blocking dopamine treats psychosis 2, 8.

Important Caveats and Contraindications

Dietary Restrictions with Non-Selective MAOIs

• Non-selective MAO inhibitors (which block both MAO-A and MAO-B) require strict dietary restrictions to avoid the "cheese reaction"—hypertensive crisis from tyramine-containing foods 1.
• Selegiline at doses ≤10 mg/day selectively inhibits MAO-B and can ordinarily be used without dietary restrictions, though rare hypertensive reactions have occurred even at recommended doses 1.

Combination Therapy Risks

• Attempts to combine levodopa with non-selective MAOIs were abandoned due to hypertension, increased involuntary movements, and toxic delirium 1.
• Selegiline's benefit in Parkinson's disease has only been documented as an adjunct to levodopa/carbidopa; its efficacy as monotherapy is unknown 1.

Peripheral Dopamine Effects

• Dopamine synthesized peripherally (e.g., in the kidney) regulates sodium excretion and blood pressure; defective renal dopamine function may contribute to hypertension 7.
• Dopamine receptors in immune cells regulate antigen presentation, T-cell activation, and inflammation, suggesting broader therapeutic applications beyond neurology 6.