Dopamine

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Questions and Answers

Which function is NOT influenced by dopamine in the central nervous system?

Motor control

Attention control

Emotion regulation

Thermoregulation (correct)

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

Bind dopamine to postsynaptic receptors

Transport dopamine back into the synaptic cleft

Transport dopamine into the storage vesicles (correct)

Release dopamine into the extracellular space

Which of the following best describes the mechanism of dopamine release from storage vesicles?

Diffusion through the vesicular membrane

Ca2+ dependent fusion with the vesicle membrane (correct)

DAT mediated release into the synaptic cleft

G protein activation of autoreceptors

Which statement correctly describes dopamine transport and degradation?

Dopamine transporter reuptake is critical for inactivation. Signup and view all the answers

Which type of dopamine receptor subtype is primarily concentrated in the central nervous system?

MAO-B Signup and view all the answers

In which condition is dopamine specifically considered a therapeutic target?

Parkinson's disease Signup and view all the answers

Which pharmacological agent is most likely to inhibit dopamine degradation?

Monoamine oxidase inhibitor Signup and view all the answers

What is the primary effect of amantadine in patients with Parkinson's disease?

Block excitatory NMDA receptors Signup and view all the answers

Which neurotransmitter dysregulation is primarily associated with the positive symptoms of schizophrenia?

Dopamine Signup and view all the answers

What is the role of centrally acting antimuscarinic agents in treating Parkinson's disease?

Manage tremors Signup and view all the answers

Which hypothesis suggests that schizophrenia results from underactivity of NMDA receptors?

NMDA hypofunction hypothesis Signup and view all the answers

Which of the following is considered a negative symptom of schizophrenia?

Social withdrawal Signup and view all the answers

What is the primary function of D1 class dopamine receptors?

Increases cAMP levels Signup and view all the answers

Which dopamine receptor class is primarily involved in the management of schizophrenia?

D2 Signup and view all the answers

What is the role of the mesolimbic pathway in the brain?

Plays a crucial role in pleasure and reward Signup and view all the answers

Which dopaminergic pathway is directly associated with Parkinson's disease due to degeneration?

Nigrostriatal pathway Signup and view all the answers

Which pathway inhibits prolactin secretion?

Tuberoinfundibular pathway Signup and view all the answers

What is the main function of pre-synaptic D2 dopamine receptors?

Decrease dopamine synthesis and release Signup and view all the answers

Which area of the brain acts as a blood chemoreceptor due to the presence of D2 class receptors?

Postrema Signup and view all the answers

Which dopaminergic pathway is highly involved in cognition and decision-making?

Mesocortical pathway Signup and view all the answers

What is the effect of stimulating dopamine receptors in the area postrema?

Activates vomiting centers Signup and view all the answers

What is the primary area affected by the loss of dopaminergic neurons in Parkinson's disease?

Substantia nigra pars compacta Signup and view all the answers

What percentage of dopaminergic neurons are typically destroyed by the time Parkinson's disease symptoms first manifest?

70% Signup and view all the answers

Which adverse effect is most commonly associated with levodopa therapy in Parkinson's patients?

Dyskinesias Signup and view all the answers

How does levodopa primarily affect motor symptoms in Parkinson's disease?

It most significantly improves bradykinesia. Signup and view all the answers

What is a characteristic feature of 'off' periods during levodopa therapy?

Increased rigidity and freezing Signup and view all the answers

Which pharmacologic agents are primarily used to restore dopaminergic activity in Parkinson's disease?

Levodopa and dopamine agonists Signup and view all the answers

What is the oral bioavailability percentage of levodopa due to first-pass metabolism?

5% Signup and view all the answers

What is the goal of using antimuscarinic drugs in Parkinson's disease treatment?

To restore the balance of cholinergic and dopaminergic influences Signup and view all the answers

What is one of the motor features of Parkinson's disease that predisposes patients to falls?

Impaired postural balance Signup and view all the answers

What indicates the progression in the need for dosages of levodopa as the treatment continues?

Increased requirement for higher doses to achieve symptom relief Signup and view all the answers

What is the primary advantage of using carbidopa in combination with levodopa?

Reduces the daily requirement of levodopa by about 75%. Signup and view all the answers

Which of the following is a drawback of dopamine receptor agonists compared to levodopa?

Dopamine receptor agonists have more frequent dosing requirements. Signup and view all the answers

What is a major adverse effect associated with the use of ergot derivatives as dopamine receptor agonists?

Fibrosis of cardiac valves. Signup and view all the answers

Which statement is true regarding selective inhibitors of MAO-B such as selegiline?

They enhance the effectiveness of levodopa therapy. Signup and view all the answers

What is the primary action of COMT inhibitors like entacapone?

They decrease the peripheral metabolism of levodopa. Signup and view all the answers

What common cognitive side effect is associated with dopamine receptor agonists?

Hallucinations and excessive sedation. Signup and view all the answers

Which consequence is NOT associated with the use of carbidopa with levodopa?

Increased cardiovascular effects of levodopa. Signup and view all the answers

What makes pramipexole significant compared to older dopamine receptor agonists?

It has a stronger affinity for D3 receptors. Signup and view all the answers

What is the impact of continuous levodopa therapy over time?

Responsiveness fluctuates and decreases. Signup and view all the answers

How does the metabolism of selegiline impact patients?

It metabolizes into amphetamine, potentially leading to insomnia. Signup and view all the answers

Study Notes

Pharmacology of Dopaminergic Neurotransmission

Dopamine is a catecholamine neurotransmitter in the central nervous system (CNS)
It affects motivation, arousal, attention, motor control, emotion, mood, prolactin secretion inhibition, emesis, and sleep regulation
Dopamine is a therapeutic target for Parkinson's disease and schizophrenia
Dopamine is a precursor for norepinephrine and epinephrine

Dopamine Synthesis

Tyrosine is the precursor to dopamine
Tyrosine hydroxylase converts tyrosine to L-DOPA
L-DOPA is converted to dopamine by DOPA decarboxylase

Dopamine Storage and Release

Vesicular monoamine transporter (VMAT) transports dopamine into vesicles against concentration gradient
Nerve cell stimulation causes DA storage vesicles to fuse with the plasma membrane and release dopamine into the synaptic cleft
Dopamine binds to both postsynaptic and presynaptic DA autoreceptors in the synaptic cleft

Dopamine Reuptake and Inactivation

Dopamine transporter (DAT) transports most of the released dopamine back into the presynaptic cell
MAO or COMT degrade dopamine
MAO exists as two isoforms: MAO-A and MAO-B
MAO-B is more concentrated in the CNS

Dopamine Receptor Subtypes

Dopamine receptors are G protein-coupled proteins
Dopamine receptors are classified by their effect on cAMP formation
D1-like receptors (D1 and D5) increase cAMP
D2-like receptors (D2, D3, and D4) decrease cAMP

Dopamine Receptors

Are G-protein coupled
Activation of D1 class receptors increases cAMP
Activation of D2 class receptors inhibits cAMP generation
D1 and D5 receptors increase cAMP
D2, D3, and D4 receptors inhibit cAMP

Dopaminergic Pathways in the CNS

Nigrostriatal pathway: Contains about 80% of the brain's dopamine, involved in purposeful movement; degeneration leads to Parkinson's disease
Mesolimbic pathway: VTA > nucleus accumbens; plays a role in pleasure and positive reinforcement (reward)
Mesocortical pathway: VTA > prefrontal cortex; involved in cognition, working memory, and decision-making; dysfunction possibly linked to schizophrenia
Tuberoinfundibular pathway: Hypothalamus > pituitary glands; inhibits prolactin secretion

Parkinson's Disease

Selective loss of dopaminergic neurons in the substantia nigra pars compacta
Core motor features: bradykinesia, rigidity, impaired postural balance, resting tremor
Degeneration of neurons leading to abnormalities of movement characteristic of Parkinson's disease

Pharmacologic Agents Used in Parkinsonism

Restoration of dopaminergic activity: Levodopa, dopamine agonists
Complementary approach: Restoration of cholinergic and dopaminergic balance; influence on basal ganglia with antimuscarinic drugs

Levodopa

Immediate metabolic precursor of dopamine
Oral bioavailability: low (5%) due to extensive first-pass metabolism in the gut and liver
Enters brain (1-3%)
Adverse effects: dyskinesias (uncontrollable rhythmic movements of the head, trunk, and limbs) that appear in 50% of patients
Fluctuations: "on" periods (normal or excess involuntary movement) and "off" periods (freezing and increased rigidity)
Not a cure, responsiveness declines with time
Usually given in combination with carbidopa

Carbidopa

Inhibits DOPA decarboxylase in the periphery to minimize levodopa metabolism in the periphery and increase levodopa entering the brain
Reduces peripheral metabolism of levodopa, increasing levodopa available for the brain
Reduces gastrointestinal and cardiovascular side effects from levodopa
Adverse effects are increased in the CNS

Dopamine Receptor Agonists

Bromocriptine and pergolide (Ergot derivatives, D2 agonist): cardiac fibrosis and other adverse effects
Pramipexole and ropinirole ( newer agents): agonist for D3 and D2
Advantages over levodopa: Don't compete with levodopa and other neutral amino-acids for transport across the blood-brain barrier, they don't require enzymatic conversion, remain effective late in Parkinson's
Adverse effects of dopamine receptor agonists: Nausea, peripheral edema, hypotension, excessive sedation, vivid dreams, hallucinations.

Monoamine Oxidase (MAO) Inhibitors

Selegiline and Rasagiline: Selective MAO-B inhibitors (at low doses)
Selegiline metabolizes into amphetamine
Improve motor function in Parkinson's disease and can augment the effectiveness of levodopa therapy

Catechol-O-Methyltransferase (COMT) Inhibitors

Entacapone: Selective COMT inhibitor
Decreases peripheral metabolism and increases levodopa available to the CNS
Reduces "off" periods

Other Antiparkinsonian Drugs

Amantadine: antiviral drug with anti-Parkinsonian effect, used to treat levodopa-induced dyskinesias, may reduce dyskinesia by blocking excitatory NMDA receptors
Centrally acting antimuscarinic agents (e.g., benztropine): reduce cholinergic tone, reduce tremor more than bradykinesia; effective in treating patients where tremor is primary symptom

Schizophrenia

Psychotic illness
Clinical features: positive symptoms (hallucinations, delusions, racing thoughts), negative symptoms (emotional blunting, social withdrawal, lack of motivation, lack of emotion), cognitive impairment (disorganized thoughts, difficulty concentrating/following instructions)
Possible symptoms: depression
Neurochemical basis: involvement of dopamine and glutamate
- Dopamine dysregulation hypothesis: mesolimbic hyperactivity
- NMDA hypofunction hypothesis: reciprocal synaptic connections between neurons

Schizophrenia Treatment

First-generation antipsychotics: potent D2 antagonists, affect other receptors (5HT2, alpha, histamine, muscarinic); helpful in alleviating positive symptoms; adverse effects: strong extrapyramidal effects (rigidity, bradykinesia, dystonia, tremor, akathisia), tardive dyskinesia (TD), neuroleptic malignant syndrome (NMS)
Second-generation antipsychotics (atypical): D2/5HT2a antagonists, also affect other receptors, effective in positive and negative symptoms, milder extrapyramidal adverse effects, some do not use D2 as initial receptor; some have significant risk of agranulocytosis (e.g., clozapine), and seizures

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