Unit 2 Class 1 - Catecholamines pt 1

issues with correlating neurological disorders with NTs

the reliance on classifying neurological disorders based on NT transmission solely leads to a limited perspective on the disorder

one to one links between diseases and NTs do not exist, it is an antique of the pharmacology industry trying to sell drugs

ex: serotonin being linked to depression

catecholamines

amines

• dopamine (DA)

• norepinephrine (NE)

• epinephrine (EPI)

dopamine synthesis

tyrosine -tyrosine hydroxylase → dopa -dopa decarboxylase → dopamine

norepinephrine synthesis

dopamine -DBH→ NE

rate limiting enzyme in dopamine and NE pathway

tyrosine hydroxylase

tyrosine hydroxylase regulation

1. high catecholamine levels in the terminal inhibits tyrosine hydroxylase (negative feedback)

2. neuron firing rate of action potentials: more firing will lead to more TH synthesis

3. second messenger associated proteins (PKA, PKG, PKC, CaMK) stimulates TH

how to activate and inhibit catecholamine synethesis through drugs

enhancing: administering precursors such as tyrosine or L DOPA (to treat Parkinson’s disease since dopamine in its final form cannot cross the blood brain barrier)

→ patients treated w L DOPA should be treated with carbidopa (blocks dopamine carboxylase) so dopamine is not synthesized outside of BBB)

inhibiting: AMPT blocks TH which blocks synthesis of catecholamines

dopamine deficient mouse significance

dopamine deficient mouse genetically knocked out the TH gene which led to inability to synthesize dopamine (but restored it in DBH expressing genes so the mouse could make NE)

significance: led to lack of eating, drinking, hypoactivity, and underweight, but could be restored with L DOPA administration

→ Dopamine = developmental success

vesicular monoamine transporter (VMAT)

carries catecholamines into vesicles (enzymes will break them down otherwise)

> VMAT 1 = adrenal medulla/kidney

> VMAT 2 = brain

VMATs can be blocked by the drug reserpine (old antipsychotic) to keep catecholamines out of vesicles

mechanism and effect of reserpine

if NE and DA is not protected in the cell they will be broken down by enzymes

This will lead to depressive like behavior that can be reversed with DOPA (DA precursor)

significance: catecholamine theory of depression

amphetamine mechanism

cellular effect: causes catecholamine release independent of cell firing

behavioral effect: increased locomotor activity and steryotyped behaviors (sniffing, head twitching) s a direct result of increased DA

how is catecholamine release inhibited

autoreceptors on cell bodies, dendrites, and terminals

→ for DA specifically, autoreceptors are G coupled protein receptors that lead to K+ channels opening (hyperpolarizes the cell and leads to shorter AP and inhibits VGCC to prevent excytosis)

autoreceptor subtypes for DA and NE

• DA autoreceptor = D2

• NE autoreceptor = a2

ex: mutant mice w no D2 receptors were more active and sensitive to cocaine than controls

drug interactions at catecholamine autoreceptors

autoreceptor stimulus = catecholamine inhibition

autoreceptor antagonists = enhanced release of catecholamine

clonadine (catapres)

anxiety caused by opiate withdrawal stimulates noradernergic pathway (anti reward pathway)

clonadine enhances a2 autoreceptors to inhibit NE

yohimibine

a2 antagonist that increases noradernergic cell firing and NE release

reuptake (catecholamines)

DA + NE move from synaptic cleft into nerve terminal via specific membrane transporter proteins DAT and NET for repackaging/breakdown

ex: mutant mice with no DAT do not respond to psychostimulants like cocaine

degredation of catecholamines (know the types of enzymes and metabolites)

occurs through enzymes MAO and COMT

• MAO-a: metabolizes NE

• MAO-b: metabolizes DA

• COMT: metabolizes NE and DA

DA metabolite: HVA

NE metabolite: MHPG (brain) or VMA (PNS)

→ these metabolites enter CSF and bloodstream and are excreted in urine

metabolic pathway

be able to draw this out for both DA and NE

which drugs inhibit the enzymes that metabolize catecholamines

• MAO inhibitors like phenelzine (Nardil) and tranycypromine (Parnate) are used to enhance catecholamine levels (antidepressants)

• COMT inhibitors like entacapone (Comtan) and tolcapone (Tasmar) enhance the effectiveness of L DOPA in treating Parkinson’s disease

where do the three ascending dopaminergic system pathways originate

brainstem

dopamine nigrostriatal tract

substantia nigra → striatum

these cells die along the progression in Parkinson’s Disease (leading to cell death in the striatum)

dopamine meso tracts (2)

1. mesocrotical dopamine pathway: VTA → prefrontal cortex and hippocampus

affects cognition, working memory, attention, implicated in schizophrenia and ADHD

2. mesolimbic pathway: VTA → NAc (and various structures in the limbic system)

reward processing, arousal, locomotion, implicated in addiction

different effects of DA neurons in the VTA

different DA neurons in the VTA can produce both reward and aversive behaviors differentiated by both their inputs and outputs

different DA receptor subtypes and where they are found

five in total D1, D2… D5, all metabatropic

> split into D1 like and D2 like

D1 like is D1 and D5: Gs or Gq protein (excitatory, stimulates adenylyl cyclase + cAMP production)

D2 like is D2, D3, D4: Gi/o protein (inhibitory, usually autoreceptors to inhibit adenylyl cyclase and cAMP by regulating calcium/potassium channels)

primarily found in NAc and dorsal striatum

D1-D2 heteromers

a complex of both types of dopamine receptors with its own Gq protein and two binding sites

agonists and antagonists can selectively target these receptors

DA affinity to subtypes (tonic and phasic bursts)

dopamine has higher affinity to D2 receptors than D1 receptors (10-100x higher)

• phasic (burst): DA firing engages D1 receptors (in addition to D2)

• tonic (slower): DA firing engages only D2 receptors

structures involved in basal ganglia

• striatum

• globus pallidus (GPexternal/GPinternal)

• subthalamic nucleus

• substantia nigra (split into SNR and SNC)

direct pathway of movement

important for initiation of movement, be able to draw

indirect pathway of movement

important for the inhibition of movement, be able to draw

why does dopamine regulate the movement pathways

both the direct and indirect pathways can send competitive signals, and the indirect pathway will usually win

→ dopamine guides both pathways in different ways but the effect is the same (movement is enhanced)

central noradernergic system

cell bodies in the brainstem (pons and medulla) → forebrain

implicated in arousal, cognition, consolidation of emotional memories

maintaining/transferring to wakefulness caused by NE neurons stimulated by orexin neurons

peripheral noradernergic system

sympathetic nervous system that causes fight or flight reaction

locus coeruleus

NE neurons made in pons and medulla

locus coeruleus is a dense collection of NE neurons in the pons that extend to nearly all areas of cerebellum, forebrain, spinal cord

adrenoreceptors

metabatropic, subtypes a and B

a1 receptors: Gq, enhances cAMP production through PLC3, IP3, and DAG

a2 receptors: Gi/o, inhibits cAMP production (autoreceptors)

B1 and B2: Gs protein, enhances cAMP production through stimulating adenylyl cyclase

NE and working memory

LC → PFC projections disrupts attention and working memory

• a2 agonists like guanfacine are a promising treatment for ADHD

what levels of NE optimizes working memory

intermediate

stress (lots of NE) or sedation (no NE) = less cognitive functioning

what does NE have higher affinity for

a2 than a1