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Chapter 5: Catecholamines (Dopamine, Norepinephrine, Epinephrine), EPI and…

- - - - L-Tyrosine acted on by enzyme Tyrosine hydroxylase
        
        Gives us L-DOPA which is acted on by enzyme AADC
        
        dopamine
    - - L-Tyrosine acted on by enzyme Tyrosine hydroxylase
        
        Gives us L-DOPA which is acted on enzyme AADC
        
        Gives us DA which is acted on by enzyme dopamine beta-hydroxylase
        
        norepinephrine
    - - baseline levels of L-tyrosine SATURATES TH enzyme
        
        an increase in L-tyrosine WOULD NOT increase dopamine because baseline levels already saturate enzyme
        
        AADC has higher capacity than TH
  - - - vesicular monoamine transporter (VMAT)
        
        VMAT2 - brain
        
        VMAT1 - adrenal medulla
    - - Some drugs of abuse case DA and NE release INDEPENDENT OF CELL FIRING (don't need action potential to arrive at nerve terminal)
        
        calcium-independent mechanism
        
        drug causes reversal of DA transporter
        
        add on presynaptic terminal, cause reversal of vesicular transporter in synaptic vesicle
        
        DA flows out of DA transporter and into the synapse
    - - Autoreceptors (negative feedback): regulate excess NT in synaptic cleft
        
        somatodendritic autoreceptors (VTA and SNc): SLOW RATE OF NEURON FIRING
        
        enhances opening of K+ channels, hyperpolarization makes AP less likely
        
        terminal autoreceptors: on presynaptic nerve terminal INHIBITS FURTHER TRANSMITTER RELEASE
        
        enhance opening of K+ channel, inhibit Ca++ entry through v-gated Ca++ channels (Ca++ dependent release won't work)
        
        DECREASE expression of TH, INCREASE expression of DAT
        
        Autoreceptor agonists: REDUCE NT release
        
        Autoreceptor antagonists: INCREASE NT release
      - NE autoreceptors (GPCRs a2 subtype)
        
        somatodendritic: enhance opening of K+ channgels
        
        terminal: inhibit VGCCs
        
        Inhibit adenylyl cyclase --> decrease in cAMP and intracellular Ca++ concentration
        
        Pharmacology of NE autoreceptors
        
        clonidine (treats high blood pressure, opioid withdrawal, anxiety) STIMULATES NE AUTORECEPTORS, reduces NT release
        
        Yohimbine ANTAGONIZES NE AUTORECEPTORS, increase NE release, exacerbates opioid withdrawal
  - - - specific membrane transporters: DAT and NET
        
        molecules are then either
        
        REPACKAGED into vesicles (via VMAT)
        
        BROKEN DOWN (via MAO or COMT)
        
        COMT: can degrade free floating NTs
        
        COMT inhibitors can INCREASE L-DOPA
        
        COMT is MORE IMPORTANT in PFC than DAT for DA inactivation
        
        genetic variations in COMT activity might affect PFC activity during executive and working memory tasks
        
        MAO
        
        MAO-A (NE)
        
        MAO-B (DA)
        
        Metabolites are formed from the breakdown of enzymes, excreted in urine (indirect measure of catecholamine)
        
        DA: homovanillic acid (HVA)
        
        NE
        
        BRAIN: 3-methoxy-4-hydroxyphenylglycol (MHPG)
        
        PNS: vanillymandelic acid (VMA)
    - - tricyclic antidepressants (TCAs) inhibit reuptake of BOTH NE and 5-HT
      - Cocaine inhibits reuptake of ALL MONOAMINE NTs: DA, NE, 5-HT
- - - - Nigrostriatal tract: axons in SUBSTANTIA NIGRA extend to STRIATUM
        
        voluntary movement
        
        Parkinson's: MASSIVE LOSS of DA neurons in the SUBSTANTIA NIGRA
      - A10 cell group: ventral tegmental area (VTA) give rise to MESOLIMBIC DA pathway and MESOCORTICAL DA pathway
        
        Mesolimbic (VTA --> nucleus accumbens (NA))
        
        motivated behaviors
        
        positive shizophrenia symptoms
        
        Mesocortical (VTA --> PFC)
        
        working memory
        
        negative and cognitive schizophrenia symptoms
  - - - D1 and D5: D1-like
        
        STIMULATE AC via Gs
      - D2, D3, D4: D2-like
        
        INHIBIT AC via Gi
        
        enhance K+ channel opening
        
        D2 are autoreceptors AND postsynaptic receptors
    - - side effect of most antipsychotics
      - Repeated administration of D2 receptor antagonists: if treatment is STOPPED and agonist is given, rat's response is GREATER than naive control subjects (BEHAVIORAL SUPERSENSITIVITY)
    - - similar to effects of psychomotor stimulants
    - - DAT KO mice: extremely HYPERACTIVE (no reuptake of DA)
      - D1 KO mice: deficits in COGNITIVE TASKS
      - D2 KO mice: impaired spontaneous movement, coordination, posture control
  - - - high doses of amphetamine can produce psychotic reaction in healthy individuals
      - psychotic behavior is driven by excess postsynaptic D2 receptor activation
      - antipsychotic drugs: D2 receptor antagonists
        
        significant motor side effects: extrapyramidal symptoms (EPS)
        
        dystonia (continuous spasms, muscle contractions)
        
        akathisia (motor restlessness)
        
        parkinsonism (rigidity, bradykinesia, tremor)
        
        tardive dyskinesia (PERMANENT) - irregular, jerky movements
    - - HVA (DA metabolite) levels DO NOT DIFFER between patients and controls
      - HVA levels DO NOT CORRELATE with symptom type or severity
      - Better hypothesis: DA imbalance hypothesis
        
        symptoms are bc of REDUCED DA FUNCTION in MESOCORTICAL SYSTEM (negative symptoms and impaired thinking) along with EXCESS DA in MESOLIMBIC SYSTEM (positive symptoms)
- - - - ascending fibers go to many forebrain structures (cortex, thalamus, hypothalamus, limbic system) and to the cerebellum and spinal cord
  - - - a2: REDUCE synthesis of cAMP and INCREASE K+ channel opening (like D2 receptors)
        
        a2-receptors function as autoreceptors in LC and nerve terminals
      - a1: operate via 2nd messenger system (Gq), leads to increase in Ca++ in postsynaptic cell and PKC activation
    - - STIMULATE AC and ENHANCE synthesis of cAMP
  - - - activation of postsynaptic a2 receptors in PFC enhances working memory
        
        optimal working memory at intermediate levels of PFC noradrenergic activity (a2 mostly activated, a2 mostly inactive)
      - stress stimulates NE release in the PFC
        
        leads to activation of a1 receptors --> negative effect on cognitive functions mediated by PFC
    - - One-trial passive avoidance learning: foot shock induces fear (emotional learning)
        
        injection of EPI immediately after training trial caused a SIGNIFICANT INCREASE in latencies to cross (increased consolidation)