Dopamine

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Dopamine

• Structure and Function
• John Hill and Natalia Toporikova

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What is Dopamine?

• Dopamine (DA) is a monoamine neurotransmitter
  that upon binding to a dopamine receptor
  (G-protein coupled) releases a variety of
  downstream signals.

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Dopamine synthesis
Precursor of dopamine is amino acid tyrosine
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Where is Dopamine formed?

• Dopamine is mainly synthesized in areas of the
  central and peripheral nervous systems, such as
  in the hypothalamus, the arcuate nucleus, and the
  caudad

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How does dopamine work?

• Dopamine is released into synaptic cleft.
• Dopamine binds with receptor.
• Once done, dopamine is taken back into the cell,
  so not too much is present in the cleft.
• The control mechanism for this signaling is found
  in the endorphin (pink).
• Endorphin can either enhance of inhibit the
  action of dopamine.

Note this is similar to what we learned about
acetylcholine release.
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What are the Functions of Dopamine?

• Dopamine plays a significant role in the
  cardiovascular, renal, hormonal, and central
  nervous systems. It is thought to control
  processes as diverse as movement to drug
  addiction.
• Dopamine dendrites extend into various regions
  of the brain, controlling different functions
  through the stimulation of a and ß adrenergic and
  dopaminergic receptors (D1 and D2)

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Functions of Dopamine in the Body

• Function depends on type of receptor.
• Involved in pleasure (cocaine blocks its
  reuptake)
• Involved in motor control of muscles in body.
• Assists in normal brain function (thoughts)
• Induces emotions.

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Dopamine-related diseases

• Dopamine deficiency in the striatum or substantia
  nigra results in Parkinsons-like symptoms. In
  this case, movement becomes slow and rigid,
  accompanied by muscle tremor.
• An excessive amount of dopamine is affiliated
  with schizophrenia, characterized by altered
  behavior, and delusions.
• A deficiency of dopamine (DA) is a leading
  candidate for the etiology of certain symptoms of
  depression.

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Research involving dopamine

• May have a role in obesity
• May play a role in drug addiction
• May have a role in alcoholism
• May use dopamine derivatives to treat disease

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Drugs can stimulate dopamine receptors

• Some drugs are known as dopamine agonists.
• These drugs bind to dopamine receptors in place
  of dopamine and directly stimulate those
  receptors.
• They can stimulate dopamine receptors even in
  someone without dopamine neurons.

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Drugs can fail to stimulate dopamine receptors

• Antagonists are drugs that bind but don't
  stimulate dopamine receptors.
• Antagonists can prevent or reverse the actions of
  dopamine.
• They prevent dopamine from attaching to
  receptors.

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Drugs can act directly or indirectly on dopamine
receptors

• Drugs such as cocaine and amphetamine produce
  their effects by changing the flow of
  neurotransmitters.
• These drugs are defined as indirect acting
  because they depend on the activity of neurons.

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Drugs can act directly or indirectly on dopamine
receptors

• In contrast, some drugs bypass neurotransmitters
  altogether and act directly on receptors.
• Such drugs are direct acting.
• Direct agonists stimulate dopamine receptors even
  when dopamine neurons are missing.

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Two ways to affect dopamine levels

• Some drugs increase dopamine by preventing
  dopamine reuptake, leaving more dopamine in the
  synapse (i.e., cocaine, methylphenidate)
• While another drug helps to release more dopamine
  (amphetamine).

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How cells adapt to previous drug exposure

• Long-term treatment with dopamine antagonists
  increases the number of dopamine receptors.
• The receptors themselves become more sensitive to
  dopamine.
• This process is called sensitization.

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How cells adapt to previous drug exposure

• Overstimulation decreases the number of
  receptors, and the remaining receptors become
  less sensitive to dopamine.
• This process is called desensitization.

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Disease and drugs can produce faulty sensitization

• Sensitization or desensitization normally occurs
  with drug exposure. However, addiction can
  tamper with the reuptake system.
• This disrupts the normal levels of
  neurotransmitters in the brain and can lead to
  faulty desensitization or sensitization.

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Reward pathway

• Dopamine neuron connected with part of the brain
  that is activated by natural rewards and by
  artificial rewards such as addictive drugs.
• This part of the brain is called the reward
  system.

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How reward pathway works

• This pathway is activated by a rewarding
  stimulus.
• The dopamine system compares the brain
  expectations of reward with what is actually
  happening at the moment.
• If the reward is higher than predicted, dopamine
  is sent to many parts of the brain, giving the
  green light to action to get more reward.

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Cocaine addiction

• Cocaine binds to the uptake pumps and prevents
  them from removing dopamine from the synapse.
• More dopamine in the synapse, and more dopamine
  receptors are activated.

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Cocaine addiction

• The increased activation of dopamine receptors
  causes increased production of cAMP inside the
  post-synaptic cell. This lead to abnormal firing
  patterns.
• With continued use of cocaine, the body relies on
  this drug to maintain rewarding feelings.

A PET Scan (glucose uptake)
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Nicotine addiction

• Nicotinic acetylcholine receptors respond to
  nicotine as it enters the body after smoking a
  cigarette.
• That burst of activity in the neurons causes
  dopamine release that contributes to the
  sensation of pleasure.
• Over time some nicotinic receptors desensitize,
  even though nicotine is still present.

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Nicotine addiction mechanism.

• The first cigarette of the day gives smokers
  their first exposure to nicotine in 8-10 hours,
  so the neurons experience an extreme burst of
  activity.
• The dopamine system gives the signal to get more
  reward (cigarette).
• Later in the day there will be a mixture of the
  receptors being desensitized and activated, so
  that a smoker will not get the same large burst
  of activity and pleasure that the first cigarette
  provides.

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Food addiction

• Obese people have about 20 fewer receptors for
  the chemical dopamine in the area of the brain
  that regulates reward.
• Desensitization may trigger overeating in an
  effort to stimulate the reward pathway.

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Conclusion

• Dopamine plays a major role in addiction.
• The activation and deactivation of dopamine
  receptors can lead to activation of the brain
  center responsible for pleasure.
• Dopamine is a key element in the reward system -
  the expectation of reward can change behavior.