Buhler patho

NT: Dopamine

Recognize the molecular targets at the DA synapse and predict the synaptic effects of drugs that may impact each of these targets.

Correctly recognize the symptoms of PD.

Correctly describe the change in dopaminergic neurons and DA levels in the motor pathway in PD.

Parkinson’s Neurodegeneration 

• Parkinson’s is a disease or neurodegeneration 

  • There is a physical damage to and loss of brain tissue 

  • No treatment for degeneration 

  • Symptomatic treatment only 

• Dopaminergic motor pathways are our focus 

SCAN theory: non-motor symptoms occur because a network links motor, cognitive, and ANS!

Don’t need to know in detail:

Molecular Pathophysiology 

• Defining feature of PD: intracellular Lewy body formation 

• Lewy bodies: deposits of misfolded alpha-synuclein and cell debris 

• What is alpha-synuclein?

  • Involved in docking and recycling vesicles

  • Regulates NT release 

• Aggregated misfolded a-synuclein is neurotoxic 

• Multiple mechanisms of toxicity:

  • Synaptic dysfunction - clustering of vesicles 

  • Membrane disruption 

  • Calcium dysregulation 

  • Oxidative stress and mitochondrial toxicity 

  • Defective protein degradation and clearance

Models of Parkinson’s disease 

• 1st step: misfolding 

  • GI bacteria, mitochondrial dysfunction, neuroinflammation 

• 2nd step: spread-Prion like spread

  • Gut-to-brain model: bacterial misfolding; transmission via vagal nerve

  • Brain-first model: begins in olfactory 

• Cause for misfolding/spread varies by person 

Patho of PD and AD

Explain the circuitry and effect of the Glutamate and DA/ACh&Adenosine balance on the target neuron in the striatum.

Normal: Healthy brain’s basal ganglia 

• In the stratum:

  • Target neurons are activated by glutamatergic inputs 

  • Output is modulated by balance of:

    • Dopamine receptors (focus on D2)

    • Muscarinic + Adenosine receptors 

Disease: Death of Dopamine neurons 

• Movement symptoms result from death of dopaminergic neurons within the basal ganglia 

• Death of the substantia nigra cell bodies decreases release of DA in the stratum 

How to rebalance NTs?

• Increase DA signaling 

• Decrease cholinergic or Ad signaling agents.

prodopinergic ade

Correctly describe the clinical barriers involving metabolism and kinetics of L-DOPA when given alone, and explain in detail how COMT inhibitors and LAADC inhibitors mitigate these difficulties. 

• Why can’t we just give dopamine? → Dopamine cannot cross BBB well

• Why can we use L-DOPA? → Crosses BBB

• But, PO L-DOPA:

  • DA extensively metabolized in GI 

  • Short DOA when given alone

  • Lots of ADEs

PO L-dopa and dopamine synthesis 

1. Encounters peripheral COMT + LAADC

2. GI ADEs 1-2% PO dose crosses BBB

3. Taken up by live neurons

4. Converted to DA within neurons by LAADC

5. DA released 

LAADC inhibitor Carbidopa is given with L-dopa because it:

1. Inhibits peripheral conversion of L-dopa to DA 

2. Reduces nausea and vomiting by reducing DA production in GI 

3. Decreases oral dose of L-dopa needed

4. Important that it not cross BBB

L-dopa

• Goal: increase synaptic DA levels

• Class MOA: 

  • precursor for DA synthesis 

  • increases synaptic DA release at EVERY DA synapse globally!

  • Boosts function of the basal ganglia motor control pathway

• Agents: Levodopa (aka L-dopa)

L-dopa + LAADC inhibitor 

• Carbi dopa→ inhibits decarboxylase for L-dopa

• MOA:

  • Inhibits LAADC in gut & blood, blocks peripheral L-dopa -> DA

  • Increases L-dopa in brain, increases synaptic DA levels in striatum

  • Boosts function of the basal ganglia motor control pathway

• Agents:

  • carbidopa/levodopa (Sinemet; CD/LD)

  • carbidopa/levodopa/entacapone PO (Stalevo)

COMT inhibitors 

• MOA:

  • Inhibits COMT in gut and blood, blocks L-dopa -> peripheral breakdown products 

  • Increases L-dopa in brain, increases synaptic DA levels in striatum

  • Boosts function of the basal ganglia motor control pathway

• Agents:

  • carbidopa/levodopa/entacapone (Stalevo)

  • entacapone (Comtan)

DA receptor direct agonist 

• MOA: 

  • DA receptor agonists (D_2-like + other subtypes)

  • Directly increases DA receptor activation

  • Boosts function of the basal ganglia motor control pathway

• Agents:

  • ropinirole (Requip) 

  • rotigotine (Neupro)

  • pramipexole (Mirapex)

  • apomorphine (Apokyn; Kynmobi) (*D1/D2 non-selective)

MAO-B inhibitors 

• MOA:

  • irreversible inhibitor of MAO-B (low-dose selective for MAO-B)

  • blocks breakdown, increases DA within synapse 

  • Boosts function of the basal ganglia motor control pathway

• Agents:

  • selegiline (Deprenyl; Zelapar)

  • rasagiline (Azilect)

  • safinamide (Xadago)

NMDA antagonist 

• Class: Amantadine (anktidyskinetic)

• Class Dual MOAs:

  • MOA 1. Multiple mechanisms to increase DA activity

    • DA effect treats motor symptoms 

  • MOA 2. Glu NMDA receptor antagonist (favors overactive channels)

    • NMDA effect decreases l-dopa dyskinesias

• Agents:

  • Amantadine  

  • Amantadine ER (Gocovri; Osmolex)

Identify the drugs with NMDA antagonism listed in the slide set

NMDA receptor mediated effects (Glutamate)

• Glu inputs drive this pathway

• Local alpha-synuclein increases Glu function and increases NMDA-induced excitotoxicity

• NMDA antagonists help regulate responses

Drugs with NMDA antagonism 

• Memantine

• Amantadine

• Dextromethorphan

• Ketamine

• Methadone

Antimuscarinic drugs 

• MOAs:

  • Muscarinic receptor antagonists

  • Counterbalances loss of DA inputs to GABA neurons

  • Boosts function of the basal ganglia motor control pathway

• Agents:

  • Benztropine (Cogentin) 

  • Trihexyphenidyl (Artane)

• Points of interest:

  • Bypasses DA circuits! Does NOT affect DA levels here

  • Know your antimuscarinic profile! DRY

Adenosine A2A antagonist 

• This region also has important adenosine inputs

• MOAs:

  • Adenosine receptor A_2A antagonist

  • Counterbalances loss of DA inputs to GABA neurons 

  • Boosts function of the basal ganglia motor control pathway

• Agent:

  • istradefylline (Nourianz)

• Point of interest:

  • Bypasses DA circuits! Does NOT affect DA levels here

  • Caffeine and theophylline are adenosine antagonists!