• stored in presynaptic terminal
• released from presynaptic terminal after depolarization
• receptors are present on the postsynaptic cell

Glutamate depolarizes (excitatory)

GABA hyperpolarizes (inhibitory)

• Direct pathways result in excitatory input to the cerebral cortex
• Indirect pathways result in inhibitory input to the cerebral cortex
• They are both pathways that connect the striatum to the thalamus

1. tyrosine is transported along with Na+ by a symporter
2. tyrosine is converted to L-DOPA by tyrosine hydroxylase (rate-limiting step)
3. L-DOPA is converted to Dopamine by Amino Acid Decarboxylase
4. Dopamine is packaged into intracellular vesicles by VMAT, an antiporter dependent on hydrogen ion gradient
5. Action potential stimulates Dopamine release
6. Dopamine binds to post- and pre-synaptic receptors
7. Dopamine can reenter the neuron via a Dopamine transporter (DAT) - a symporter requiring a Na+ gradient
8. Dopamine can be recycled and stored in vesicles or metabolized by MAO and COMT

• Excitatory (activated direct pathway)
• Gs or Gq coupled
• Found in striatum and neocortex

Inhibitory (activates indirect pathway)

Gi coupled

Can increase K+ efflux or decrease Ca2+ influx

Found in striatum, substantia nigra, and pituitary gland

• it competes with dietary AA for AA transporters
• It is converted to Dopamine in the intestinal mucosa and the periphery -- Dopamine cannot cross BBB
• It undergoes extensive first pass metabolism

• Administered with L-DOPA
• Inhibits AADC
• Inhibits conversion of levodopa to dopamine in the periphery
• Decreases peripheral side effects of dopamine

• Dopamine in periphery causes nausea and vomiting (by stimulating chemoreceptor trigger zone)
• Conversion of levodopa to NE in the CNS results in cardiac side effects (tachycardia, Afib)
• Increased levels of dopamine in the CNS results in:

hallucinations

confusion

schizophrenia-like symptoms

dystonia

dyskinesia

• Inhibits COMT in periphery and CNS
• Risk of acute hepatic failure -- monitor live enzymes
• Since COMT is ubiquitous, can increase NE levels

• Inhibits COMT in periphery ONLY -- does not cross BBB
• No hepatic failure association
• Since COMT is ubiquitous, can increase NE levels

• Irreversible Inhibitor of MAO-B
• Blocks conversion of dopamine to DOPAC and H2O2
• Thought to decrease free radical generation

• Irreversible Inhibitor of MAO-B
• Blocks conversion of dopamine to DOPAC and H2O2
• Thought to decrease free radical generation

• Mechanism uncertain
• Thought to increase synaptic dopamine by enhancing vesicle release and/or inhibiting dopamine reuptake
• Effective for mild PD cases

• Dopamine Receptor Agonist
• Strong D2 agonist with some D1 antagonist activity
• However, non-selective and has alpha adrenergic and serotonin receptor activity

Side Effects:

• Inhibits prolactin secretion of ant. pituitary
• causes emesis through activation of CTZ
• Mental disturbances (hallucinations, delusions, confusion) mediated through mesolimbic system
• Orthostatic hypotension

D1 and D2 Receptor Agonist

Withdrawn due to associated risk of heart valve damage

D2 and D2 receptor agonist

more selective for dopamine receptors compared to ergot alkaldoids (bromocriptine, pergolide)

D2 and D2 receptor agonist

more selective for dopamine receptors compared to ergot alkaldoids (bromocriptine, pergolide)

High D4 receptor affinity

Moderate affinity for other dopamine receptor subtypes, except D1

Affinity for alpha adrenergic receptors

Used to treat "off" (akinetic) periods in PD

Side Effects:

• very strong emetic activity due to D2 receptor activation in the CTZ
• Hallucinations and delusions

• Anticholinergic
• Cholinergic input at the striatum activates the indirect pathway -- these drugs reduce the indirect pathway

Side Effects:

• constipation
• dryness of mouth
• urinary retention
• blurred vision
• exacerbate forms of glaucoma

• Anticholinergic
• Cholinergic input at the striatum activates the indirect pathway -- these drugs reduce the indirect pathway

Side Effects:

• constipation
• dryness of mouth
• urinary retention
• blurred vision
• exacerbate forms of glaucoma

• Anticholinergic
• Cholinergic input at the striatum activates the indirect pathway -- these drugs reduce the indirect pathway

Side Effects:

• constipation
• dryness of mouth
• urinary retention
• blurred vision
• exacerbate forms of glaucoma

• Loss of cholinergic neurons originating in the basal forebrain
• Presence of Beta-Amyloid plaques and neurofibrillary tangles
• Inflammation (cytokines, glial cells) associated with plaques

1. Abnormal protease digestion of amyloid precursor protein (APP) causes the production of beta-amyloid protein
2. Beta-amyloid aggregates (plaques) and neurofibrillary tangles (comprised of polymerized tau proteins) begin to form -- these lesions are associated with neuron death especially those of the cholinergic type
3. Neuron loss contributes to shrinkage of areas of the cortex and hippocampus causing dementia

AChE Inhibitor

Side Effects:

Cholinergic side effects (nausea, vomiting, diarrhea)

hepatic toxicity (limits usage)

AChE Inhibitor

Longer t1/2 compared to tacrine

More selective for CNS AChE

Side Effects:

Cholinergic side effects (nausea, vomiting, diarrhea)

AChE Inhibitor

More selective for CNS AChE

Side Effects:

Cholinergic side effects (nausea, vomiting, diarrhea)

AChE Inhibitor

More selective for CNS AChE

Side Effects:

Cholinergic side effects (nausea, vomiting, diarrhea)

NMDA receptor antagonism

Thought to reduce excitotoxicity through blocking glutamate activity --> Ca2+ channels that are thought to be related to the neurotoxic effects of excessive NMDA receptor activation are closed

Injection/vaccination of mice with beta-amyloid protein attenuates plaque formation and preserves cognitive function

Trials in humans halted