L49. Pharmacology - Drugs targeting dopamine
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Questions and Answers

What is the primary mechanism by which cocaine increases dopamine levels in the brain?

  • Increasing the rate of dopamine neuron discharge through various synaptic inputs.
  • Blocking the reuptake of dopamine by directly inhibiting the dopamine transporter (DAT). (correct)
  • Displacing vesicular dopamine and raising free intraneuronal dopamine.
  • Stimulating dopamine synthesis within neurons.

Why can repeated drug use lead to substance use disorder?

  • Drugs enhance sensitivity to natural rewards, making them more appealing.
  • Drugs increase the activity of the prefrontal cortex, improving decision-making abilities.
  • Drugs overpower the brain’s response to natural rewards, leading to compulsive drug seeking despite negative consequences. (correct)
  • Drugs cause a permanent increase in dopamine production, leading to constant euphoria.

Which statement best describes the current prevalence of stimulant drug prescriptions within central nervous system (CNS) drugs?

  • Stimulant drugs make up nearly 1 in 10 CNS drug prescriptions, largely driven by amphetamine and methylphenidate. (correct)
  • Stimulant drugs represent less than 1% of the CNS drug market due to their limited therapeutic uses.
  • Stimulant drugs account for approximately 5% of all CNS drug prescriptions, primarily for anxiety disorders.
  • Stimulant drugs constitute about 25% of CNS prescriptions, mainly for the treatment of chronic pain.

How do amphetamines increase dopamine levels in the synapse?

<p>By accumulating in dopamine nerve terminals, displacing vesicular dopamine, and reversing the dopamine transporter (DAT). (D)</p> Signup and view all the answers

What is the current understanding of stimulants for cognitive enhancement in healthy individuals?

<p>Stimulants may enhance performance indirectly by increasing alertness, particularly when used in low doses. (B)</p> Signup and view all the answers

What is the primary mechanism by which dopamine (DA) exerts its neuromodulatory effects in the central nervous system?

<p>Activation of metabotropic (G protein-coupled) receptors, influencing intracellular signaling cascades. (D)</p> Signup and view all the answers

Which of the following best describes the therapeutic significance of dopamine (DA) and its receptors in CNS pharmacology?

<p>DA and its receptors are targeted in approximately 1 in 6 CNS drug prescriptions, addressing conditions like Parkinson's, schizophrenia, ADHD, and sleep disorders. (A)</p> Signup and view all the answers

In the context of Parkinson's disease treatment, which strategy directly addresses the underlying cause of the disorder?

<p>Using agents that restore dopamine transmission, either directly or indirectly, to compensate for neuronal loss. (B)</p> Signup and view all the answers

What is the key pharmacological feature that defines the therapeutic efficacy of antipsychotic medications?

<p>Blockade of dopamine D2 receptors to reduce positive symptoms of psychosis. (B)</p> Signup and view all the answers

How do amphetamines and methylphenidate augment dopamine transmission in the treatment of ADHD?

<p>By inhibiting dopamine reuptake and promoting dopamine release, thereby increasing dopamine levels in the synapse. (B)</p> Signup and view all the answers

What distinguishes first-generation antipsychotics from second-generation (atypical) antipsychotics?

<p>Second-generation antipsychotics exhibit a broader receptor binding profile, often including serotonin receptor antagonism in addition to D2 receptor blockade. (B)</p> Signup and view all the answers

What is the fundamental role of dopamine in reward mechanisms and substance use disorders?

<p>Dopamine neurotransmission is augmented by drugs of abuse, contributing to the reinforcing and addictive properties of these substances. (D)</p> Signup and view all the answers

Which statement best describes the challenge in developing highly specific drugs targeting dopamine (DA) systems?

<p>The extensive overlap in the distribution of DA pathways means that drugs affecting one pathway are likely to impact others, leading to side effects. (A)</p> Signup and view all the answers

What is the primary mechanism by which L-dopa alleviates Parkinson's disease symptoms?

<p>Converting into dopamine within the CNS, thereby replenishing dopamine levels in the basal ganglia. (D)</p> Signup and view all the answers

What role do COMT inhibitors play in the treatment of Parkinson's disease?

<p>They prevent the peripheral metabolism of administered L-dopa, increasing its bioavailability to the brain. (C)</p> Signup and view all the answers

Why is carbidopa often administered alongside L-dopa in the treatment of Parkinson's disease?

<p>To inhibit the peripheral conversion of L-dopa to dopamine, reducing side effects and increasing L-dopa availability to the brain. (D)</p> Signup and view all the answers

D2R/D3R agonists are used in the treatment of Parkinson's disease. What is their mechanism of action?

<p>They directly stimulate dopamine receptors, mimicking the effects of dopamine. (D)</p> Signup and view all the answers

In the context of dopamine pathways, what is the functional role of the projections from the midbrain to the limbic areas?

<p>Regulation of motivation, goal-directed thinking, affect, and reward. (A)</p> Signup and view all the answers

What is the significance of dopamine receptors located in the area postrema?

<p>They mediate emesis (vomiting) due to the area postrema's location outside the blood-brain barrier. (C)</p> Signup and view all the answers

How do MAO inhibitors, such as selegiline, provide symptomatic treatment for Parkinson's disease?

<p>By preventing the breakdown of dopamine in the CNS, thus increasing its availability. (A)</p> Signup and view all the answers

Profound loss of dopamine cells innervating the basal ganglia underlies the symptoms of Parkinson's disease. What is the primary function of the basal ganglia?

<p>Modulation of learning and execution of purposeful movement. (B)</p> Signup and view all the answers

Why are dopamine receptor agonists often preferred over L-DOPA as a first-line treatment for Parkinson's disease?

<p>They bypass the need for enzymatic conversion, leading to more predictable and consistent dopamine receptor activation. (D)</p> Signup and view all the answers

A patient with Parkinson's disease experiences nausea and vomiting after starting dopamine-based drug therapy. What is the most likely mechanism contributing to these side effects?

<p>Stimulation of dopamine receptors in the area postrema outside the blood-brain barrier. (A)</p> Signup and view all the answers

How do amphetamines, which release dopamine, relate to the symptoms of schizophrenia?

<p>Amphetamines can exacerbate or elicit some schizophrenic symptoms, even in previously non-psychotic individuals. (B)</p> Signup and view all the answers

What is the primary mechanism of action shared by all effective antipsychotic drugs?

<p>Dopamine D2 receptor antagonism. (B)</p> Signup and view all the answers

Large clinical studies have demonstrated what about newer, atypical antipsychotic drugs (e.g. quetiapine, aripiprazole, risperidone) compared to older, typical antipsychotics (e.g. haloperidol)?

<p>No significant difference in therapeutic efficacy was observed, despite the newer drugs dominating the market. (B)</p> Signup and view all the answers

What distinguishes clozapine from other atypical antipsychotics?

<p>Clozapine has unique therapeutic efficacy in treatment-resistant cases but also high toxicity. (B)</p> Signup and view all the answers

Why might dopamine receptor antagonists remain an important treatment for schizophrenia, even though abnormalities of dopamine signaling are unlikely to be the primary cause of psychosis?

<p>Because they effectively manage the acute psychotic symptoms, regardless of the primary cause. (A)</p> Signup and view all the answers

A patient with bipolar disorder is prescribed an atypical antipsychotic as an adjunctive treatment. What is the rationale for this?

<p>To stabilize mood and manage psychotic symptoms that may be present in bipolar disorder. (B)</p> Signup and view all the answers

Which of the following is the most accurate description of how dopamine-based drug therapy for Parkinson's disease can lead to off-target adverse effects?

<p>The drugs non-selectively activate dopamine receptors throughout the brain, affecting systems beyond the basal ganglia. (D)</p> Signup and view all the answers

A researcher is studying the effects of a novel drug on schizophrenia. What pharmacological property would be most indicative of the drug's potential antipsychotic efficacy?

<p>High affinity for dopamine D2 receptors. (B)</p> Signup and view all the answers

Why does blocking DA signaling in higher brain areas sometimes induce movement disorders?

<p>Because concurrent blockade of DA receptors in the basal ganglia, a region critical for motor control, can disrupt normal movement. (B)</p> Signup and view all the answers

Which of the following best explains the delayed therapeutic effects of D2R blockade?

<p>The initial blockade triggers a cascade of downstream cellular and circuit changes that are necessary for clinical responses. (A)</p> Signup and view all the answers

How do amphetamines primarily increase dopamine neurotransmission?

<p>By entering dopamine terminals via DAT, releasing vesicular dopamine stores, inhibiting MAO, and reversing DAT transport. (A)</p> Signup and view all the answers

How does methylphenidate differ from amphetamines in its mechanism of action on dopamine neurotransmission?

<p>Methylphenidate increases synaptic dopamine primarily by blocking DAT-mediated dopamine reuptake. (D)</p> Signup and view all the answers

What is the role of VMAT2 in the mechanism of action of amphetamines?

<p>VMAT2 transports amphetamines into vesicles, causing the release of vesicular dopamine stores into the dopamine terminal. (A)</p> Signup and view all the answers

What is the mechanism by which amphetamine increases extracellular dopamine levels via the dopamine transporter (DAT)?

<p>Amphetamine induces DAT to reverse its function, transporting dopamine out of the neuron. (B)</p> Signup and view all the answers

Why are amphetamines sometimes used to treat sleep disorders despite their stimulant properties?

<p>Amphetamines can improve focus and reduce daytime sleepiness in certain sleep disorders like narcolepsy. (D)</p> Signup and view all the answers

How does the inhibition of MAO by amphetamines contribute to increased dopamine levels?

<p>MAO inhibition prevents the breakdown of dopamine within the neuron, leading to an increased pool of available dopamine for release. (B)</p> Signup and view all the answers

A researcher is investigating a novel compound that enhances dopamine neurotransmission. Which of the following mechanisms would most closely mimic the action of amphetamine?

<p>A compound that is transported into dopamine terminals by DAT and causes the release of dopamine from vesicles. (B)</p> Signup and view all the answers

What accounts for the use, both prescribed and illicit, of DA-potentiating drugs such as amphetamines?

<p>Their effectiveness in treating a wide range of symptoms, including increased alertness, decreased fatigue, and appetite suppression. (C)</p> Signup and view all the answers

Flashcards

Dopamine (DA)

A neurotransmitter and neuromodulator targeted by drugs used to treat Parkinson's, schizophrenia, ADHD, and sleep disorders.

Parkinson's Disease Drugs

Drugs that restore DA transmission, either directly or indirectly.

Antipsychotics

Medications that reduce dopamine activity, primarily by blocking D2 receptors.

Amphetamines

Drugs that enhance DA transmission, often used for ADHD treatment.

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D2 Receptor Blockade

The most critical feature of antipsychotics is their ability to block D2 receptors.

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Ionotropic Receptors

Glutamate and GABA receptors where neurotransmitters act.

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Metabotropic Receptors

Receptors modulated by neurotransmitters like DA.

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Local DA circuits

Localized DA neurons in circuits within the retina and olfactory bulb.

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DA receptors in the area postrema

DA receptors outside the BBB that trigger vomiting.

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Hypothalamic DA projections

DA projections within the hypothalamus that control hormones.

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Midbrain DA pathways

DA cells in the midbrain projecting to the cortex, limbic areas, and basal ganglia.

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DA in Parkinson's Disease

Loss of DA neurons in the basal ganglia that causes motor control issues.

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Parkinson's Treatment Strategy

Boost CNS DA levels to alleviate Parkinson's symptoms.

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L-dopa

A precursor to DA that can cross the BBB and increase DA levels in the brain.

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Carbidopa

Inhibits peripheral conversion of L-dopa to DA, increasing L-dopa availability in the brain.

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COMT inhibitors

Prevents peripheral metabolism of dopa, used as an adjunct therapy.

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Modafinil

A stimulant drug used for narcolepsy and shift work sleep disorder, possibly working by augmenting dopamine.

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Rewarding drugs

Drugs that the brain interprets as intrinsically positive, leading to repeated behavior.

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Reinforcing drugs

Drugs that increase the likelihood of repeating behaviors that lead to drug access.

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Substance Use Disorder

Compulsive drug seeking and consumption despite negative consequences.

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Brain areas for DA release

Forebrain nucleus accumbens and caudate-putamen

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DA Receptor Agonists

Drugs that directly activate DA receptors, bypassing DA biosynthesis.

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Off-Target DA Effects

Cognitive changes, mood shifts, and nausea can occur as adverse effects.

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Schizophrenia

A psychotic disorder characterized by delusions, hallucinations, thought disorders, apathy, and emotional blunting.

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DA-Releasing Drugs & Schizophrenia

Drugs that release dopamine can worsen or trigger schizophrenic symptoms.

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Amphetamines & Schizophrenia

They can exacerbates or elicit some schizophrenic symptoms.

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D2 Receptor Antagonists (Antipsychotics)

Effective antipsychotics that block D2 receptors or act as weak partial agonists.

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Atypical Antipsychotics

Atypical antipsychotics interact with other monoamine receptors (e.g., serotonin) in addition to D2 receptors.

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Clozapine

An atypical antipsychotic with unique efficacy in treatment-resistant cases but also high toxicity.

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DA Antagonists & Schizophrenia Treatment

DA receptor antagonists that remain a key treatment in Schizophrenia.

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Atypical Antipsychotics (other uses)

Used as adjunctive treatments for bipolar disorder and other mood disorders.

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DA Receptor Blockade Side Effects

Blocking DA receptors in the basal ganglia can cause movement disorders.

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Delayed Antipsychotic Effects

Full therapeutic effects of D2R blockers take weeks/months, suggesting downstream changes.

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ADHD Treatment

Increases DA neurotransmission, used to treat ADHD, despite unclear DA role; inattentiveness, impulsivity and hyperactivity.

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How Amphetamines Enter Neurons

They gain access to DA terminals via DAT transport.

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Amphetamine Action on Vesicles

They enter vesicles via VMAT2, cause DA release into the terminal.

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Amphetamine & MAO Inhibition

Amphetamines inhibit MAO, increasing free DA.

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Amphetamine & DAT Reverse Transport

DAT reverse transport increases extracellular DA.

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Methylphenidate Mechanism

It increases synaptic DA by blocking DAT-mediated DA reuptake.

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Effects of DA-Potentiating Drugs

They increase alertness, decrease fatigue, and suppress appetite.

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Structural Similarities

Structural similarities exist between amphetamines (and to a lesser extent, methylphenidate) and DA

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Study Notes

  • The lecture discusses drugs targeting dopamine and its receptors for Parkinson's, psychosis, ADHD, and sleep disorders.
  • Dopamine (DA) and/or its receptors are therapeutic targets for CNS disorders and stimulant abuse.
  • The lecture reviews the DA life cycle, receptor interaction, physiological regulation, and therapeutic mechanisms.

Life Cycle of DA

  • Dopamine is a catecholamine neurotransmitter
  • DA is the final neurotransmitter product in central DA neurons.
  • It can be converted to norepinephrine (NE) or epinephrine in other cell types.
  • Tyrosine hydroxylase is the first and rate-limiting enzyme in DA biosynthesis.
  • Aromatic amino acid decarboxylase is more ubiquitous and performs the final biosynthetic step.
  • Once made, DA accumulates within storage vesicles via the vesicular monoamine transporter 2 (VMAT2).
  • VMAT2 uses a proton gradient to transport protons out and DA into the vesicle.
  • Depolarization causes vesicles to release DA into the extracellular space.
  • Dopamine effects are terminated by DA-sodium co-transport (DAT), metabolism (MAO and COMT), and diffusion.
  • Recaptured DA can be reaccumulated by VMAT2.
  • NE is derived from DA, and serotonin (5HT) is from another amino acid, showing relatedness in biosynthesis.
  • Drugs affecting DA neurons can affect NE or 5HT neurons.
  • DA, NE, and 5HT projection neurons originate in the midbrain or brainstem and innervate forebrain areas.

DA Receptors

  • DA interacts with five receptors: D1, D2, D3, D4, and D5.
  • D1 receptors (D1R, D1 and D5) are 'excitatory' and increase second messenger production.
  • D2 receptors (D2R, D2, D3, and D4) are 'inhibitory' and decrease cell excitability.
  • D1R and D2R predominate in the brain.
  • Other DA receptors have unique distributions in the CNS implying functional roles.

Central DA Pathways

  • DA cells and receptors exist in discrete cells within local circuits within the retina and olfactory bulb.
  • DA receptors also reside in the area postrema outside the BBB, mediating emesis.
  • Short DA projections exist in the hypothalamus and regulate hormones, like prolactin and growth hormone.
  • Crucially, DA cells originate in the midbrain (substantia nigra and ventral tegmental area) and innervate the cortex (cognition), limbic areas (motivation, affect, reward), and basal ganglia (learning and movement).
  • Targeting one DA pathway with drugs leads to predictable adverse effects due to effects on other DA systems.

DA Drugs in Parkinson's Disease

  • Parkinson's is characterized by a loss of DA cells in the basal ganglia, a brain region involved in motor control.
  • Treatments aim to boost CNS DA levels:
    • L-dopa: Converted to DA in the CNS, typically used with carbidopa.
    • Carbidopa: A peripheral inhibitor of conversion to DA.
    • COMT inhibitors (e.g., Entacapone): Prevent peripheral metabolism of administered dopa.
    • MAO inhibitors (e.g., Selegiline): Prevent the breakdown of DA that's residual within the CNS.
    • D2R/D3R agonists (e.g., ropinirole, pramipexole): Directly activate DA receptors and bypass DA biosynthesis.
  • Replacement of basal ganglia DA can cause off-target effects like cognitive changes, mood changes, nausea, and emesis.

DA Drugs in Schizophrenia

  • Schizophrenia includes delusions, hallucinations, thought disorders, apathy, and emotional blunting.
  • DA-releasing drugs, like amphetamines, exacerbate schizophrenic symptoms.
  • Antipsychotics are D2R antagonists, and aripiprazole which is a weak partial D2R agonist is effective.
  • Newer 'atypical' antipsychotics (e.g., quetiapine, aripiprazole, risperidone) interact with other monoamine receptors (e.g., 5HT2A) in addition to D2R.
  • Clozapine, the 'original' atypical antipsychotic has unique efficacy in treatment-resistant cases.
  • DA receptor antagonists remain important in schizophrenia treatment even though DA signaling abnormalities may not be a primary cause of it.
  • Blocking DA signaling can cause movement disturbances.
  • D2R blockade occurs rapidly, but full therapeutic effects take weeks to months.

DA Drugs in ADHD and Sleep Disorders

  • Drugs that increase DA neurotransmission help with symptoms or disorders even without much data showing a direct DA role in underlying pathophysiology.
  • Attention deficit hyperactivity disorder is marked by inattentiveness, impulsivity, and hyperactivity.
  • Amphetamines enter DA terminals via DAT transport.
  • Intracellular amphetamines cause a release of vesicular DA into the DA terminal, and inhibit MAO.
  • Reverse transport by DAT also increases extracellular DA.
  • Methylphenidate increases synaptic DA by blocking DAT-mediated DA reuptake.
  • DA-potentiating drugs increase alertness, decrease fatigue, and suppress appetite.
  • Modafinil, a newer stimulant, works through a DA-augmenting mechanism.
  • DA-augmenting drugs account for a significant portion of CNS drug prescriptions.

Dopamine in Reward and Substance Use Disorder

  • Drugs of abuse are rewarding and reinforcing, leading to repeated behavior.
  • Animals and humans self-administer drugs over natural reinforcers.
  • Repeated drug use causes substance use disorder despite diminished rewarding properties.
  • Drugs of abuse augment DA release, particularly in the nucleus accumbens and caudate putamen.
  • Cocaine blocks DAT similarly to methylphenidate.
  • Amphetamines accumulate in DA nerve terminals, displace vesicular DA, and cause DA release via DAT reversal.
  • Other drugs like nicotine, ethanol, marijuana, and heroin increase DA neuron discharge.
  • Rewarding properties relate to the rate of rise and decline within the CNS
  • DA neurons respond to acute exposure, anticipation of reward, and differences between anticipated and received reward.
  • DA cells respond to cues associated with past drug exposure.
  • Drug addiction is a form of learning and memory, with molecular changes underlying relapse.

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