Nigrostriatal tract

Cell bodies in substantia nigra project to striatum where they release DA (inhibits) --> GABAergic neurons

D2a: Gi coupled

In parkinson's the loss of DA leads to excessive ACh activity (extrapyramidal dysfunction)

SO: DA antagonists --> pseudo-parkinsonism

DA agonists --> dyskinesias

Mesolimbic-mesocortical tracts

cell bodies in midbrain project to cerebrocortical and limbic structures

D2c: receptors Gi coupled  

Function: regulation of affect, reinforcement, cognitive functions and sensory perception

SO: DA agonists (inc. DA function)--> inc reinforcement but at high doses psychoses

DA antagonists --> dec. cognitive function

Tuberoinfundibular

Cell bodies in hypothalamus project to anterior pituitary and release DA --> decreased prolactin

DA agonists --> used in hyperprolactinemic states (pergolide)

DA antagonists --> endocrine dysfunction including gynecomastia and amenorrhea/galactorrhea

Chemoreceptor trigger zone

Activation of DA receptors --> increased emesis (apomorphine)

DA antagonists --> antiemetic (prochlorperazine) 

Signs and Symptoms of Parkinson's

Bradykinesia

Muscle rigidity

Resting tremor

Pathology of Parkinson's

Degeneration of nigrostriatal DA tracts w/ imbalance b/n dec. DA and inc. ACh onto the GABAergic neuron in the striatum = hypokinetic dz

Levodopa

MOA: increases the synthesis of DA, here it is a precursor that is converted by AAAD

Given usu. w/ carbidopa (blocks the conversion of the levodopa to DA in the periphery so more is available in the brain) 

SE: dyskinesias

"on-off" effects

psychosis

hypotension

vomiting 

Tolcapone & Entacapone

MOA: inhibits COMT (which converts levodopa to 3-O-methyldopa in the periphery) so more is taken up across the BBB

Tocapone is hepatotoxic

Selegiline

MOA: MAOb-selective inhibitor so DA is not broken down into metabolites

SE: dyskinesias and psychosis

Bromocriptine

MOA: DA receptor agonist

Use: hyperprolactinemia and acromegaly

SE: dyskinesias and psychosis

Other DA agonists = pramipexole & ropinerole (parkinson's drugs)

Benztropine, Trihexyphenidyl, Diphenhydramine

MOA: muscarinic blockers, so decrease ACh function

Funtion: decrease tremor/rigidity but little effect on bradykinesia

SE: atropine-like

Amantadine

MOA: decrease ACh function

Function: antiviral that blocks muscarinic receptors

SE: atropine-like & livedo reticularis (purplish skin mottling)

Schizophrenia (pos/neg symptoms)

Pos = thought disorders, delusions, hallucinations, paranoia

Neg = amotivation, social w/drawl, flat affect, poor speech

Dopamine hypothesis

Sxs arise b/c of excessive DA activity in mesolimbic system

DA agonists: cause psychosis

DA antagonists: antipsychotic actions

Some now include the Serotonin hypothesis (5HT)

Pimozide

DOC: for Tourette's syndrome

DA receptor antagonist helps w/ involuntary motor mvmt/vocal tics

SE's from DA blockade

1. Dyskinesias (etrapyramidal symptoms)

Acute: pseudoparkinsonism, dytonia, akathisia

Tx: antimuscarinic drugs

Chronic: Tardive dyskinesia (writhing/lip smacking)

Tx: d/c drug

2. Dysphoria

3. Edocrine dysfunction

Temp regulation (tx w/ dantrolene/bromocriptine)

Inc. prolactin (galactorrhea, amenorrhea, gynecomastia)

Inc. weight gain   

Typical antipsychotics

Chlorpromazine, Thioridazine

Typical antipsychotics (too much DA)

 MOA: primarily

M block (tachycardia/dec seizure threshold)

Sedation

Alpha1 block: hypotension

Thioridazine = worry about cardiotoxicity (torsades)

Fluphenazine & Haloperidol

MOA: typical antipsychotic that blocks DA

Has alot of EPS (pseudoparkinsonims)

Haloperidol = cause of neuroleptic malignant syndrome (temp. regulation) and tardive dyskinesia

Atypical antipsychotics

Clozapine, Olanzapine, Risperidone, Aripiprazole

block 5HT too!

Clozapine SE's 

Agranulocytosis (weekly CBCs)

Weight gain

Increased salivation ("wet pillow")

Seizures