L3 Clinical Pharmacology Parkinson's Disease

Overview

This lecture covers the neuropharmacology of Parkinson’s disease (PD): the dopaminergic pathways in the brain, PD as a nigrostriatal dopamine-deficiency state, dopamine receptor pharmacology, dopamine biosynthesis, and the core drug strategies used to restore striatal dopamine — increasing dopamine synthesis (L-DOPA with carbidopa), reducing dopamine breakdown (MAOB inhibitors such as selegiline), and directly stimulating dopamine receptors (agonists such as ropinirole) — together with each strategy’s side-effect profile and the reasons treatment efficacy declines over time. (Slide 3, the deck’s title card, and slide 30, a decorative closing image, carried no lecture content and are not covered further below.)

Dopaminergic neurons and pathways in the brain

Dopaminergic neurons are neurons that release dopamine. Two main dopaminergic regions are described:

• Substantia nigra — movement and sensing.
• Ventral tegmental area (VTA) — cognition, memory, learning; pleasure and reward.

Three named dopamine pathways project from these regions: the mesocortical pathway, the nigrostriatal pathway, and the mesolimbic pathway, running from substantia nigra/VTA to the striatum, prefrontal cortex, and nucleus accumbens respectively.

Reward pathway. VTA dopamine release into the nucleus accumbens increases in the presence of an unexpected reward. Neuronal recordings show a reward-prediction-error pattern across three conditions:

1. No conditioned stimulus: the neuron fires at the time of an unexpected reward.
2. After conditioning: the neuron fires both at the conditioned (predictive) stimulus and at reward.
3. Conditioned stimulus with reward withheld: the neuron fires at the stimulus only, with no firing at the time the reward would have occurred.

Slide flag: exact axis values on the raster-plot/histogram panels were not legible at render resolution, though the overall firing pattern and labels were clear.

Movement circuitry. Neurons in the substantia nigra and striatum modulate neurons connected to the motor cortex; dopamine release into the striatum promotes motor cortex activity, allowing increased movement. The direct basal ganglia pathway runs as a disinhibition sequence:

1. Cortex sends transient excitatory input to the striatum.
2. Striatum inhibits the globus pallidus.
3. Globus pallidus inhibits the VA/VL complex of the thalamus.
4. Thalamus (itself receiving excitatory input) excites the motor cortex.
5. Motor cortex projects onward to lower motor neurons.

Parkinson’s disease: clinical features, epidemiology and pathophysiology

Clinical features (idiopathic PD):

• Bradykinesia: slowness of movement (hypokinesia, akinesia), producing stooped posture and frozen/masked facial expression.
• Tremor at rest: approximately 6 Hz.
• Rigidity: increased muscle tone, leading to loss of movement and pain.
• Additional described features: forward tilt of trunk, flexed elbows and wrists, reduced arm swinging, slightly flexed hips and knees, trembling of extremities, shuffling short-stepped gait.

Pathophysiology:

• PD is a progressive neurodegenerative disorder affecting movement.
• Presynaptic dopaminergic neurons in the substantia nigra undergo cell death, causing less stimulation of postsynaptic neurons in the striatum — this substantia-nigra-to-striatum connection is the nigrostriatal pathway.
• Approximately 90% of dopamine disappears from the basal ganglia.
• This produces an imbalance between the inhibitory action of dopamine and the excitatory action of acetylcholine (ACh) on muscarinic ACh receptors.
• Symptoms progress gradually; pathology (protein aggregation) is depicted spreading within a cell, cell-to-cell, and brain region to region, paralleling worsening clinical gait/posture.
• Schematic comparison: in the normal state, substantia nigra sends dopamine to the striatum, which sends GABA onward; in parkinsonism, the substantia-nigra-to-striatum dopamine connection is markedly reduced.

Roughly 90% of basal ganglia dopamine is lost in PD, tipping the balance toward excess cholinergic (muscarinic ACh) activity. Treatment strategies either replace the missing dopamine or reduce ACh effects.

Epidemiology and causes:

• Typical onset over 60 years old; affects approximately 3% of people over 65.
• Cause largely unknown:
  • Genetic predisposition (15%).
  • Environmental factors: MPTP (an impurity from illicit synthesis of the synthetic opioid MPPP); increased risk after exposure to the natural pesticide rotenone (shown in rats); traumatic brain injury.

Imaging evidence:

• Gross brain sections show visibly less pigmented (neuromelanin-containing) tissue in the substantia nigra in PD compared with unaffected brain.
• PET imaging with tracers such as [18F]FDOPA (dopamine synthesis capacity), [11C]raclopride (receptor availability), and [11C]WIN 35,428/[18F]FP-CIT (transporter availability) shows reduced striatal dopamine handling in PD.
• 18F-DOPA PET specifically shows less dopamine production in PD patients: normal scans show bright, elongated bilateral striatal signal near the substantia nigra, while PD scans show visibly reduced signal in the same regions.

Dopamine receptor families

• D1 receptor family (D1 and D5 receptors):
  • Increase cAMP production.
  • K+ channel inhibition and Ca2+ channel activation/inhibition, depending on subtype.
  • Enhancement of NMDA receptor responses.
  • D1 located in striatum and neocortex; D5 in hippocampus and striatum.
  • Gs-coupled GPCRs — stimulate adenylyl cyclase (AC) to raise cAMP and activate PKA.
• D2 receptor family (D2, D3, D4 receptors):
  • Decrease cAMP production.
  • Decreased excitability via K+ channels.
  • Increased presynaptic inhibition via Ca2+ channels.
  • D2 located in striatum, hippocampus and cortex; D3 in striatum, hippocampus and nucleus accumbens; D4 in cortex, striatum and hippocampus.
  • Gi-coupled GPCRs — inhibit AC.

Dopamine handling at the synapse:

• Synthesis occurs presynaptically (tyrosine → L-DOPA → dopamine), with dopamine packaged into vesicles and released into the synaptic cleft.
• Reuptake: the dopamine transporter (DAT) removes dopamine from the cleft back into the presynaptic terminal.
• Breakdown: monoamine oxidase (MAO); the MAOB subtype breaks down dopamine and noradrenaline.

Dopamine biosynthesis

Ordered biosynthetic pathway:

$\text{L-Tyrosine}\stackrel{\text{tyrosine hydroxylase}}{\to }\text{L-DOPA}\stackrel{\text{DOPA decarboxylase}}{\to }\text{Dopamine}\stackrel{\text{dopamine }\beta \text{-hydroxylase}}{\to }\text{Noradrenaline}\stackrel{\text{norepinephrine N-methyltransferase}}{\to }\text{Adrenaline}$

The L-DOPA → dopamine step, via DOPA decarboxylase, is highlighted as the key step exploited in PD drug treatment.

Dopamine imbalance: Parkinson’s disease vs schizophrenia

• Parkinson’s disease: not enough dopamine released from the substantia nigra to activate the striatum. Drugs increase dopamine (increase production, e.g. L-DOPA; decrease breakdown, e.g. selegiline). Side effect of treatment: psychosis-like symptoms.
• Schizophrenia: too much dopamine released from the VTA, activating the nucleus accumbens. Drugs decrease dopamine (dopamine receptor antagonists). Side effect of treatment: Parkinson’s-like symptoms.

This dichotomy explains why treating one condition’s dopamine imbalance tends to produce side effects resembling the other condition.

Drug treatment strategies for Parkinson’s disease

All strategies aim to increase dopamine levels in the striatum:

1. Increase dopamine synthesis — L-DOPA.
2. Increase dopamine release — selegiline.
3. Activate dopamine receptors directly — dopamine agonists (bromocriptine and other D2 receptor agonists, e.g. ropinirole, a D2/D3/D4 receptor agonist).
4. Prevent dopamine metabolism — MAOB inhibitors (e.g. selegiline) or COMT inhibitors (e.g. entacapone)
5. Reinstate the DA/ACh balance — antimuscarinics, e.g. trihexyphenidyl

The core drug list drugs specifically named are L-DOPA (with carbidopa) and ropinirole.

Levodopa (L-DOPA) and carbidopa

Dopamine cannot be given directly, as it does not cross the blood-brain barrier (BBB).

L-DOPA:

• Precursor molecule for dopamine synthesis.
• Introduced as a new therapy in the 1960s; remains the “gold standard” PD therapy even today — the most effective drug.
• Best for bradykinesia and rigidity; not as effective for tremor.
• Rapid breakdown after oral dosing; large systemic side effects.
• Given alone, only 1–3% reaches the brain, because peripheral DOPA decarboxylase converts 97–99% to dopamine peripherally, which cannot cross the BBB.

Carbidopa (given in combination with L-DOPA):

• Inhibits DOPA decarboxylase (the enzyme that converts L-DOPA to dopamine), preventing peripheral breakdown of L-DOPA to dopamine.
• Does not cross the blood-brain barrier itself.
• Decreases systemic side effects of L-DOPA and increases the concentration of L-DOPA reaching the brain.
• With carbidopa: ~10% of L-DOPA crosses into the brain, and ~90% of the dopamine formed from that fraction forms in the brain (peripheral DOPA decarboxylase is blocked).
• Without carbidopa (L-DOPA alone): only 1–3% of L-DOPA reaches the brain, as unopposed peripheral DOPA decarboxylase converts 97–99% to dopamine peripherally.

Combining L-DOPA with carbidopa increases the brain-available fraction roughly ten-fold (1–3% alone vs ~10% combined) while reducing peripheral dopamine-mediated side effects.

Acute side effects of L-DOPA:

• Nausea and vomiting (requiring dose adjustment) — via the chemoreceptor trigger zone (CTZ), per the integrated summary.
• Cardiovascular disturbances (arrhythmias, postural hypotension, per the integrated summary).
• Psychiatric disturbances: vivid dreams, hallucinations, psychotic states, confusion; impulse control disorders.
• Dyskinesia.

Problems with long-term L-DOPA use:

• Decrease in efficacy after about 5 years.
• Onset of the “on-off phenomenon” — no fully satisfactory treatment (partly pharmacokinetic in origin); continuous infusions or direct agonists may help, but efficacy ultimately diminishes.
• Reduced effectiveness over time results from:
  1. Narrowing of the therapeutic window (the upper “dyskinesia” toxicity threshold falls while the lower “akinesia/rigidity” efficacy threshold rises with years of disease).
  2. “Off” periods when plasma L-DOPA concentrations are too low.
  3. Decreased effectiveness with PD progression, i.e. ongoing neuron cell death.
• Adjunctive therapies may improve activities of daily living and motor function by reducing fluctuations/wearing-off and minimising dyskinesias (abnormal involuntary movements).

Enzyme inhibitors: MAOB inhibitors

Selegiline (a MAOB inhibitor):

• Reduces breakdown of dopamine; increases levels of dopamine and noradrenaline.
• Can be given alone at early stages of disease.
• Used in combination with L-DOPA to reduce the therapeutic dose of L-DOPA required.
• Can offer some antidepressant effects.
• Side effects: twitching, twisting, uncontrolled repetitive movements; insomnia; loss of appetite; severe drug interactions with reuptake inhibitors (NDRIs, SNRIs, SSRIs).

Dopamine receptor agonists

Non-selective or selective dopamine agonists are a second-line treatment after L-DOPA.

Ropinirole:

• Selective agonist at D2, D3 and D4 receptors.
• Directly activates receptors in the striatum.
• Can be used to reduce “off time” from L-DOPA therapy.
• Side effects: somnolence, syncope, hypotension, hallucinations and psychotic behaviour, dyskinesias.

Other D2 receptor agonists named (in the integrated summary diagram): bromocriptine, pramipexole.

Side effects of dopamine agonists more broadly:

• Hallucinations.
• Nausea and vomiting, via activation of dopamine receptors in the chemoreceptor trigger zone.
• Disruption of natural pleasure/reward pathways, increasing the risk of gambling addiction and impulse control disorder.

Imaging correlate: compulsive gamblers show enhanced dopamine synthesis capacity in the VTA, leading to excess stimulation of nucleus accumbens neurons; PET scans show a more intense striatal signal in gamblers than in controls.

Integrated pathway and overall summary

The lecture’s composite pathway diagram maps each drug class onto its specific site of action:

• Peripherally (below the BBB): DOPA decarboxylase converts DOPA to dopamine in the blood; carbidopa inhibits this enzyme. When unopposed, this peripheral conversion produces the peripheral side effects (nausea/vomiting via CTZ, arrhythmias, postural hypotension).
• Centrally (above the BBB): L-DOPA crosses via the L-amino acid transporter, then is converted either to 3-OMD or, via DOPA decarboxylase (also inhibited by carbidopa), to dopamine.
• Brain dopamine is then either:
  • Taken up by dopamine receptors, directly activated by bromocriptine, pramipexole, or ropinirole; or
  • Metabolised by MAO-B (inhibited by selegiline or rasagiline) to DOPAC, or converted to 3-MT.

Overall conclusions:

• Parkinson’s disease is caused by a lack of dopamine production due to neuron cell death in the substantia nigra.
• L-DOPA remains the most common treatment for Parkinson’s disease.
• Other treatments include dopamine receptor agonists (ropinirole) and MAOB inhibitors.
• All drug treatment for PD is symptomatic and does not last; novel therapies are urgently needed.

Self-test

1. Define the three cardinal motor features of idiopathic Parkinson’s disease.
2. What proportion of dopamine is lost from the basal ganglia in Parkinson’s disease, and what neurochemical imbalance does this cause?
3. List the two main dopaminergic brain regions described and the function associated with each.
4. Describe the pattern of VTA neuron firing across the three reward-conditioning scenarios shown (no conditioned stimulus, conditioned stimulus with reward, conditioned stimulus with reward withheld).
5. Describe, in order, the steps of the direct basal ganglia motor pathway from cortical input to motor cortex output.
6. List the known genetic and environmental risk factors for Parkinson’s disease mentioned in the lecture.
7. Distinguish the D1 and D2 dopamine receptor families in terms of G-protein coupling and effect on cAMP.
8. Describe the dopamine biosynthesis pathway from L-tyrosine, naming each enzyme.
9. Distinguish the dopamine abnormality (and its brain location) in Parkinson’s disease from that in schizophrenia, and explain why treating one can produce symptoms resembling the other.
10. List the five drug strategies for treating Parkinson’s disease, with one example drug for each.
11. Explain why L-DOPA is co-administered with carbidopa, and how this changes the proportion of L-DOPA reaching the brain.
12. Explain, using the concept of a narrowing therapeutic window, why L-DOPA becomes less reliably effective after several years of treatment.
13. Describe the mechanism of action and side effects of selegiline.
14. A patient started on ropinirole for early Parkinson’s disease develops a new compulsive gambling habit. Explain the mechanism linking the drug to this behaviour.
15. A patient with 8 years of Parkinson’s disease on L-DOPA reports unpredictable swings between severe stiffness and abnormal involuntary movements over the course of the day. Explain this using the therapeutic window and “on-off phenomenon” concepts.
16. Integrative: explain, using the dopamine synthesis/receptor pathway, how three different drug classes (L-DOPA, selegiline, ropinirole) each raise effective dopamine signalling in the striatum by a different mechanism.

Answers

Reveal answers

1. Bradykinesia (slowness of movement — hypokinesia/akinesia, producing stooped posture and masked facial expression), tremor at rest (~6 Hz), and rigidity (increased muscle tone causing loss of movement and pain).
2. Approximately 90% of dopamine is lost from the basal ganglia, producing an imbalance between the inhibitory action of dopamine and the excitatory action of acetylcholine on muscarinic ACh receptors.
3. Substantia nigra (movement and sensing) and the ventral tegmental area (cognition, memory, learning; pleasure and reward).
4. With no conditioned stimulus, the neuron fires at the time of an unexpected reward. After conditioning, it fires at both the conditioned stimulus and the reward. When reward is withheld after a conditioned stimulus, it fires at the stimulus only, with no firing at the time reward would have occurred.
5. Cortex sends transient excitatory input to the striatum → striatum inhibits the globus pallidus → globus pallidus inhibits the VA/VL complex of the thalamus → thalamus (also receiving excitatory input) excites the motor cortex → motor cortex projects to lower motor neurons.
6. Genetic predisposition (15% of cases); environmental factors including MPTP (an impurity in illicit synthesis of the opioid MPPP), the natural pesticide rotenone (shown in rats), and traumatic brain injury.
7. D1 receptors are Gs-coupled and increase cAMP production; D2 receptors are Gi-coupled and decrease cAMP production. (D1/D5 also modulate K+/Ca2+ channels and enhance NMDA responses; D2/D3/D4 decrease excitability via K+ channels and increase presynaptic inhibition via Ca2+ channels.)
8. L-Tyrosine → L-DOPA (via tyrosine hydroxylase) → Dopamine (via DOPA decarboxylase) → Noradrenaline (via dopamine β-hydroxylase) → Adrenaline (via norepinephrine N-methyltransferase).
9. In Parkinson’s disease, too little dopamine is released from the substantia nigra to activate the striatum; in schizophrenia, too much dopamine is released from the VTA, activating the nucleus accumbens. Because PD drugs increase dopamine, they can cause psychosis-like symptoms; because schizophrenia drugs (dopamine antagonists) decrease dopamine, they can cause Parkinson’s-like symptoms.
10. Increase dopamine synthesis (L-DOPA); increase dopamine release (selegiline); activate dopamine receptors directly (ropinirole/bromocriptine); prevent dopamine metabolism (MAOB inhibitor selegiline, or COMT inhibitor entacapone); reinstate the DA/ACh balance (antimuscarinic trihexyphenidyl).
11. Carbidopa inhibits peripheral DOPA decarboxylase, the enzyme that converts L-DOPA to dopamine, and does not itself cross the blood-brain barrier. Given alone, L-DOPA has only 1–3% reach the brain because unopposed peripheral DOPA decarboxylase converts 97–99% to dopamine peripherally (which cannot cross the BBB). With carbidopa, peripheral conversion is blocked, so about 10% of the L-DOPA dose reaches the brain, and about 90% of the dopamine formed from what crosses does so within the brain — while systemic side effects are also reduced.
12. Over years of disease, the upper toxicity threshold (dyskinesia) falls and the lower efficacy threshold (akinesia/rigidity) rises, narrowing the therapeutic window between them. The same oscillating dose-to-dose plasma concentration pattern therefore increasingly strays into either the dyskinesia zone or the akinesia/rigidity zone as the window narrows.
13. Selegiline is a MAOB inhibitor: it reduces breakdown of dopamine, increasing dopamine and noradrenaline levels. It can be used alone early in disease or combined with L-DOPA to reduce the L-DOPA dose needed, and has some antidepressant effect. Side effects include twitching/twisting/uncontrolled repetitive movements, insomnia, loss of appetite, and severe interactions with reuptake inhibitors (NDRIs, SNRIs, SSRIs).
14. Ropinirole is a dopamine agonist that disrupts the natural pleasure/reward pathways (mediated via VTA/nucleus accumbens dopamine signalling), and this disruption carries an increased risk of gambling addiction and impulse control disorder as a described side effect of dopamine agonists.
15. After years of L-DOPA treatment, the therapeutic window between the akinesia/rigidity (too-low) threshold and the dyskinesia (too-high) threshold narrows. The same fluctuating plasma L-DOPA level that once stayed within the window now crosses above it (causing abnormal involuntary movements/dyskinesia) or below it (causing stiffness/akinesia) at different points in the dosing cycle — the “on-off phenomenon.”
16. L-DOPA increases dopamine synthesis (as the metabolic precursor converted to dopamine via DOPA decarboxylase); selegiline (a MAOB inhibitor) reduces the breakdown of dopamine that has already been made, raising the amount available at the synapse; ropinirole bypasses dopamine synthesis and breakdown altogether by directly activating postsynaptic D2/D3/D4 receptors as an agonist. All three raise net dopaminergic signalling in the striatum, but by acting at different points — production, degradation, and the receptor itself.