Neuroscience: Dopamine Function and Synthesis
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Neuroscience: Dopamine Function and Synthesis

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What is the role of vesicular monoamine transporter (VMAT) in dopaminergic neurotransmission?

  • Releasing dopamine into the bloodstream
  • Breaking down dopamine into inactive metabolites
  • Transporting dopamine into vesicles (correct)
  • Binding dopamine to autoreceptors

    • Which of the following functions does dopamine NOT influence in the central nervous system?

  • Memory retention (correct)
  • Mood regulation
  • Emesis
  • Motor control

    • Which enzyme is responsible for the degradation of dopamine in the presynaptic cell?

  • Monoamine oxidase (MAO) (correct)
  • DA transporter (DAT)
  • AChE
  • COMT

    • Which type of dopamine receptor is more concentrated in the central nervous system?

    <p>D2 receptors</p> Signup and view all the answers

    In the context of dopaminergic neurotransmission, how does dopamine primarily bind to its receptors?

    <p>By binding to postsynaptic and presynaptic receptors in the synaptic cleft</p> Signup and view all the answers

    Which of the following is NOT a therapeutic target for dopamine in the central nervous system?

    <p>Epilepsy</p> Signup and view all the answers

    The reuptake of dopamine into the presynaptic cell primarily occurs through which mechanism?

    <p>Dopamine transporter (DAT)</p> Signup and view all the answers

    Which of the following statements about monoamine oxidase (MAO) isoforms is correct?

    <p>MAO-B is concentrated in the central nervous system.</p> Signup and view all the answers

    What is the primary mechanism through which amantadine is believed to reduce dyskinesias in Parkinson's disease?

    <p>Blocking excitatory NMDA receptors</p> Signup and view all the answers

    Which neurotransmitters are primarily implicated in the pathogenesis of schizophrenia?

    <p>Dopamine and glutamate</p> Signup and view all the answers

    What clinical manifestation do centrally acting antimuscarinic agents primarily target in Parkinson's disease?

    <p>Tremor</p> Signup and view all the answers

    According to dopamine hypotheses, which aspect of schizophrenia is the result of mesolimbic hyperactivity?

    <p>Positive symptoms</p> Signup and view all the answers

    What effect does the use of dopamine receptor antagonists have on schizophrenia symptoms?

    <p>They relieve a number of symptoms</p> Signup and view all the answers

    What is the primary effect of activating D1 class dopamine receptors?

    <p>Increases cAMP levels</p> Signup and view all the answers

    Which dopaminergic pathway is most affected in Parkinson's disease?

    <p>Nigrostriatal pathway</p> Signup and view all the answers

    Which class of dopamine receptors primarily regulates dopamine synthesis and release?

    <p>D2 receptors</p> Signup and view all the answers

    The Mesolimbic pathway is primarily associated with which function?

    <p>Pleasure and positive reinforcement</p> Signup and view all the answers

    Which dopamine receptors are predominantly found post-synaptically in regulating pleasure?

    <p>D3 type</p> Signup and view all the answers

    What is the role of the tuberoinfundibular pathway?

    <p>Inhibiting prolactin secretion</p> Signup and view all the answers

    Which dopamine class is primarily involved in the development of schizophrenia?

    <p>D2 receptors</p> Signup and view all the answers

    What is a key characteristic of the D2 class dopamine receptors?

    <p>Included in presynaptic regulation of DA</p> Signup and view all the answers

    Which area is known to activate the vomiting centers when stimulated by dopamine receptors?

    <p>Postrema</p> Signup and view all the answers

    Which pathway is crucial for cognition and working memory?

    <p>Mesocortical pathway</p> Signup and view all the answers

    What is the primary site of neuronal loss in Parkinson’s disease?

    <p>Substantia nigra pars compacta</p> Signup and view all the answers

    What percentage of dopaminergic neurons are typically destroyed by the time Parkinson’s disease symptoms appear?

    <p>70%</p> Signup and view all the answers

    Which of the following is NOT a core motor feature of Parkinson’s disease?

    <p>Impaired voice clarity</p> Signup and view all the answers

    Levodopa is primarily used in the treatment of Parkinson’s disease for its ability to:

    <p>Restore dopaminergic activity</p> Signup and view all the answers

    What adverse effect is most commonly associated with the long-term use of levodopa?

    <p>Dyskinesias</p> Signup and view all the answers

    In patients undergoing levodopa therapy, what are 'off' periods characterized by?

    <p>Increased rigidity and freezing</p> Signup and view all the answers

    What is the oral bioavailability of levodopa, considering its first-pass effect?

    <p>5%</p> Signup and view all the answers

    Which therapeutic approach is complemented with antimuscarinic drugs in Parkinson’s disease treatment?

    <p>Restoration of cholinergic and dopaminergic balance</p> Signup and view all the answers

    Symptoms of Parkinson's disease typically worsen over time, necessitating what change in levodopa treatment?

    <p>Increase in dosage</p> Signup and view all the answers

    Which motor feature of Parkinson’s disease is most sensitive to improvement with levodopa therapy?

    <p>Bradykinesia</p> Signup and view all the answers

    What is the primary effect of carbidopa when administered with levodopa?

    <p>It reduces the gastrointestinal and cardiovascular effects of levodopa.</p> Signup and view all the answers

    Which statement about dopamine receptor agonists is correct?

    <p>They have longer half-lives than levodopa.</p> Signup and view all the answers

    What are common adverse effects associated with dopamine receptor agonists?

    <p>Nausea, peripheral edema, and cognitive disturbances.</p> Signup and view all the answers

    What is a major consequence of using selegiline in treating Parkinson's disease?

    <p>It is metabolized into amphetamine.</p> Signup and view all the answers

    How do catechol-O-methyltransferase (COMT) inhibitors like entacapone affect levodopa therapy?

    <p>They decrease peripheral metabolism of levodopa.</p> Signup and view all the answers

    Which of the following is an advantage of dopamine receptor agonists over levodopa?

    <p>They do not require transport mechanisms to enter the brain.</p> Signup and view all the answers

    Which statement correctly describes the pharmacokinetics of levodopa when combined with carbidopa?

    <p>The half-life of levodopa decreases.</p> Signup and view all the answers

    What distinguishes pramipexole from other dopamine receptor agonists?

    <p>It has a lower incidence of cardiac fibrosis.</p> Signup and view all the answers

    What is a significant challenge associated with long-term levodopa therapy?

    <p>Fluctuation in responsiveness and eventual decrease in effectiveness.</p> Signup and view all the answers

    Which of the following reflects the primary mechanism of action of MAO inhibitors like selegiline?

    <p>They prevent the breakdown of neurotransmitters.</p> Signup and view all the answers

    Study Notes

    Dopamine

    • Dopamine belongs to the catecholamine family of neurotransmitters.
    • It affects motivation, arousal, attention, motor control, emotion, mood, inhibition of prolactin secretion, emesis, and sleep regulation.
    • It is a therapeutic target for central nervous system disorders like Parkinson’s disease and schizophrenia.
    • Dopamine is a precursor for the other catecholamine neurotransmitters norepinephrine and epinephrine.

    Synthesis of Dopamine

    • Tyrosine is converted to DOPA by tyrosine hydroxylase (TH) - the rate limiting step.
    • DOPA is converted to Dopamine by DOPA decarboxylase (AADC).

    Dopamine Storage and Release

    • The vesicular monoamine transporter (VMAT) transports DA into the vesicle against its concentration gradient.
    • Upon nerve cell stimulation, vesicles fuse with the plasma membrane in a Ca2+ dependent manner, releasing DA into the synaptic cleft.
    • In the cleft, DA can bind to both postsynaptic DA receptors and presynaptic DA autoreceptors

    Dopamine Reuptake and Inactivation

    • Most of the DA released into the synaptic cleft is transported back into the presynaptic cell by dopamine transporter (DAT).
    • It is then taken into the vesicle for further release or degraded by MAO or COMT.
    • MAO exists in two isoforms: MAO-A (in both CNS and periphery) and MAO-B (concentrated in the CNS).

    Dopamine Receptor Subtypes

    • Dopamine receptors are members of the G protein-coupled family of receptor proteins.
    • Dopamine receptors were initially classified by their effect on the formation of cyclic AMP (cAMP).
    • Activation of D1 class receptors leads to increased cAMP. This class contains D1 and D5 receptors.
    • Activation of D2 class receptors inhibits cAMP generation. This class contains D2, D3, and D4 receptors.

    Dopamine Receptors

    • D1 & D2 are involved in motor control.
    • D2 plays a role in schizophrenia.
    • Pre-synaptic DA receptors are mostly D2 type and regulate DA by decreasing its synthesis and release.

    Dopaminergic pathways in the CNS

    • There are four main dopaminergic pathways:
      • Nigrostriatal pathway:
        • Contains about 80% of the brain’s DA.
        • Substantia nigra > corpus striatum.
        • Involved in the stimulation of purposeful movement.
        • Degeneration results in the abnormalities of movement characteristic of Parkinson’s disease.
      • Mesolimbic pathway:
        • Ventral tegmental area (VTA) > the nucleus accumbens (nAc)
        • Plays an important role in pleasure and positive reinforcement (reward).
      • Mesocortical Dopamine Pathways:
        • From the VTA to the prefrontal cortex
        • Highly involved in cognition, working memory, and decision-making.
        • Disorder of these pathways may be involved in the development of schizophrenia
      • Tuberoinfundibular pathway:
        • Hypothalamus> pituitary glands
        • Inhibits prolactin secretion.

    Dopaminergic pathways in the CNS cont.

    • The postrema is located on the floor of the fourth ventricle.
    • It contains a high density of dopamine receptors (mostly of the D2 class).
    • It functions as blood chemoreceptors.
    • Stimulation of DA receptors in this area activates the vomiting centers of the brain and causes emesis.
    • Drugs that block dopamine D2 receptors are used to treat nausea and vomiting.

    PARKINSON’S DISEASE

    • There is a selective loss of dopaminergic neurons in the substantia nigra pars compacta.
    • The extent of loss is profound, with at least 70% of the neurons destroyed at the time symptoms first appear.
    • Often, 95% of the neurons are missing at autopsy.
    • The destruction of these neurons results in the core motor features of the disease:
      • Bradykinesia, or slowness of movement
      • Rigidity, resistance to passive movement of the limbs
      • Impaired postural balance predisposes to falling
      • A characteristic tremor when the limbs are at rest.

    Pharmacologic Agents Used in Parkinsonism

    • Restoration of dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder.
    • Complementary approach: Restoration of the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs.

    Levodopa

    • Pharmacokinetics:
      • Oral bioavailability: 5% (the first-pass effect is very large; 95% is metabolized in the gut wall and in the liver).
      • Additional amounts of levodopa are converted into dopamine. Only 1-3% enter the brain.
    • Adverse effects:
      • The most profound adverse effect of levodopa is its propensity to cause dyskinesias, or uncontrollable rhythmic movements of the head, trunk, and limbs.
    • Therapeutic uses:
      • Levodopa ameliorates all signs of parkinsonism.
      • Bradykinesia is the most sensitive to improvement.
      • The drug does not cure the disease and responsiveness fluctuates and decreases with time.

    Carbidopa

    • It is a DOPA decarboxylase inhibitor that does not cross the blood-brain barrier.
    • When given with levodopa, the peripheral metabolism of levodopa is reduced with the following consequences:
      • The half-life of levodopa is increased.
      • More levodopa is available for entering the brain.
      • The gastrointestinal and cardiovascular effects of levodopa are substantially reduced.
      • CNS adverse effects are increased.
    • Levodopa is usually given in combination with carbidopa.

    Dopamine Receptor Agonists

    • Examples include:
      • Ergot derivatives such as bromocriptine (D2 agonist) and pergolide (agonist for both D1 and D2).
      • Newer agents include pramipexole (agonist for D3>D2).

    Advantage of DA agonist over levodopa

    • Nonpeptide molecules do not compete with levodopa or other neutral amino acids for transport across the BBB.
    • They do not require enzymatic conversion by AADC, and they remain effective late in Parkinson’s disease.
    • They have longer half-lives than levodopa, which allows for less frequent dosing and a more uniform response to the medications.

    Dopamine Receptor Agonists

    • Adverse effects:
      • Nausea, peripheral edema, and hypotension.
      • Cognitive effects: excessive sedation, vivid dreams, and hallucinations, particularly in elderly patients.

    MAO Inhibitors

    • Selegiline and Rasagiline:
      • Selective inhibitors of MAO-B (at low dose).
      • Selegiline metabolized into amphetamine.
      • Improve motor function in Parkinson’s disease.
      • They can augment the effectiveness of levodopa therapy.

    COMT Inhibitors

    • Entacapone:
      • Selective COMT inhibitors.
      • Decrease the peripheral metabolism of levodopa, making more levodopa available to the CNS.
      • Reduce the “off” periods associated with decreasing plasma levodopa levels.

    Other Antiparkinsonian Drugs

    • Amantadine:
      • An antiviral drug with antiparkinsonian effect.
      • Used to treat levodopa-induced dyskinesias that develop late in the disease.
      • It may reduce dyskinesia by blocking excitatory NMDA receptors.

    Centrally Acting Antimuscarinic Agents

    • Benztropine:
      • Muscarinic receptor antagonists that reduce cholinergic tone in the CNS.
      • They reduce tremor more than bradykinesia and are therefore more effective in treating patients for whom tremor is the major clinical manifestation.

    SCHIZOPHRENIA

    • It is a psychotic illness.
    • Has two major clinical features:
      • Positive symptoms: Hallucination, delusion, racing thoughts.
      • Negative symptoms: Emotional blunting, social withdrawal, lack of motivation, lack of emotion.

    SCHIZOPHRENIA (cont..)

    • Cognitive impairment – disorganized thoughts, difficulty concentrating/following instructions/completing tasks.
    • Possibly depression.

    Neurochemical Basis of Schizophrenia

    • The main neurotransmitters involved in the pathogenesis of schizophrenia are dopamine and glutamate.
    • Two hypotheses:
      • The dopamine dysregulation hypothesis
      • The NMDA hypofunction (glutamate underactivity) hypothesis

    Neurochemical Basis of Schizophrenia

    • Schizophrenia is caused by increased and dysregulated levels of DA neurotransmission in the brain.
    • Evidence:
      • Treatment with DA receptor antagonists, specifically D2 antagonists, relieves a number of the symptoms of schizophrenia.
      • Patients taking drugs that increase DA levels or that activate dopamine receptors in the CNS, including amphetamines, cocaine, and apomorphine, develop a schizophrenia-like state that subsides when the dose of the drug is lowered.
      • Hallucinations are a known adverse effect of levodopa therapy for Parkinson’s disease.
      • Decreased DA levels, with clinical improvement in some schizophrenic symptoms.

    The Dopamine Hypothesis

    • Mesolimbic hyperactivity is responsible for the positive symptoms of schizophrenia.
    • The mesocortical dopamine pathway is responsible for the negative symptoms of schizophrenia.

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