Depression CNS introduction Flashcards

1
Q

CNS Diseases and Conditions

A
  • Neurodegenerative
    • Alzheimers
    • Parkinsons
  • Headaches
  • Epilepsy
  • Analgesics
  • Mood disorders
    • Depression
    • Anxiety
    • Insomnia
    • Schizophrenia
    • Mania
  • Substance abuse
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2
Q

Anatomical Organization

A
  • Cerebral cortex – outer layer – higher order part of the brain
  • Limbic system – below the cortex; activated in part by memory, feelings
  • Midbrain - movement
  • Brainstem – primitive function
  • Spinal Cord – pain – peripheral or neuropathic
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3
Q

Cerebral cortex

A
  • Cerebral cortex – outer layer – higher order part of the brain
    • Frontal lobe—planning
    • Motor
    • Speech
    • Somato-sensory
    • Association
    • Vision, Smell, Hearing
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4
Q

Limbic System

A
  • Limbic system – below the cortex; activated in part by memory, feelings
    • Hippocampus – memory
    • Amygdala – strong emotions such as fear and anxiety
      • Memory
      • Mood
      • Biological needs
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5
Q

Midbrain

A
  • Midbrain - movement
    • Substantia nigra
    • Basal ganglia
      • Movement
      • Motivation
      • Vision/hearing relay
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6
Q

Brainstem

A
  • Brainstem – primitive function
    • Reticular formation – sleep/arousal
    • Medulla – breathing/BP
    • Pons – breathing/BP
      • Sleep/arousal
      • Breathing
      • Blood pressure
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7
Q

Spinal Cord

A
  • Spinal Cord – pain – peripheral or neuropathic
    • Connects body to brain
    • Input of peripheral information
      • Pain, position, etc.
    • Output of central message
      • Movement, blood pressure, temperature
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8
Q

Which brain area would most likely be involved in mood disorders like anxiety?

A

Amygdala (limbic system)

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9
Q

Which brain area would most likely be involved in movement disorders like Parkinson’s disease?

A

Substantia nigra (midbrain)

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10
Q

Neurotransmission

A
  • Synthesis
  • Packaging
  • Release
  • Receptors
  • Reuptake
  • Degradation
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11
Q

List 4 specific ways that glutamate activity could be increased above normal:

A
  1. More glutamate is released – usually Ca++ dependent (increased Ca++ influx → more likely to produce an action potential)
  2. Increased number of glutamate receptors – upregulation of receptors or increased sensitivity at the receptors
  3. Decreased reuptake of glutamate – every time it is released, it is not removed from the synapse → increased effect
  4. Decreased degradation → increase synaptic concentration
  5. “Overstuff” vesicles for transport
  6. Increased production/synthesis of glutamate → increased vesicular content → more glutamate released with each action potential
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12
Q

How could you treat this excessive condition?

A
  1. Block excessive receptor activity
  2. Increase degradation
  3. It is difficult to decrease reuptake
  4. Interrupt synthesis or vesicular packaging
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13
Q

Amino Acid Neurotransmitters

A
  • Excitatory
    • Glutamate
  • Inhibitory
    • GABA
      • ***Balance is essential to proper brain functioning
      • They look very similar – glutamate is part of the production of GABA
      • Both very small and ubiquitous – they are everywhere in the brain → set the tone for the electrical activity in the brain – huge impact, not discrete
      • Too much excitation may lead to seizure activity
      • Stroke → cells damage and dump their glutamate → glutamate toxicity to cells around
      • Excessive GABA activity → sluggishness, lethargy, impaired brain function
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14
Q

Conditions Related to Glutamate and/or GABA

A
  • Epilepsy
  • Addiction
  • Stroke
  • Schizophrenia
  • Anxiety
  • Sleep disorders
  • Anesthesia
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15
Q

Glutamate Synthesis

A
  • Synthesis & Packaging
    • Know: glutamate is a very simple amino acid that is found throughout the brain
    • VGluT transporter packages glutamate
    • Glutamate and glutamine are NOT the same thing
    • Glutamate has 2 types of receptors
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16
Q

Glutamate Receptors

A
  • Receptors
    • Ionotropic – gated to an ion channel – very fast receptor
      • AMPA
      • NMDA
      • Kainate
    • Metabotropic – more complex makeup – second messenger, g-protein coupled receptor – slower receptor, more steps and cascades must occur
      • Found both pre and post-synaptically
        • Presynaptic receptors are usually autoreceptors – feedback mechanism when there is excess glutamate
      • mGluR
  • Reuptake
    • Astrocytes
  • Recycled!
    • Glutamate back to glutamine
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17
Q

GABA synthesis

A
  • GABA
    • Synthesis & Packaging
      • Glutamic acid decarboxylase (GAD) converts glutamate to GABA
      • You will only have GAD if the neuron is making GABA
      • Packaged into vesicles via VGAT
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18
Q

GABAA receptors

A
  • GABAA receptors
    • Ionotropic – hyperpolarize the cell (open ion channel and Cl- flows in – makes the cell more negative)
    • Cl- transported into post-synaptic cell
    • Benzodiazepines, alcohol, barbiturates, inhalants
    • Causes sedation
    • Allosteric agonist – increase the effects that are seen with GABA
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19
Q

GABAB receptors

A
  • GABAB receptors
    • G-protein coupled receptors (metabotropic)
      • Gi coupled – inhibitory
    • Can be pre- or post-synaptic
      • Presynaptic on other (Glu, DA, NE, 5-HT) neurons to decrease release from those neurons (inhibits release of the neurotransmitter from that terminal)
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20
Q

Monoamine Neurotransmitters

A
  • Dopamine (catecholamine)
  • Norepinephrine (catecholamine)
  • Serotonin (5-HT) – NOT a catecholamine
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21
Q

Catecholamine Synthesis

A
  • Dopamine AND Norepinephrine
    • Synthesis
      • Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the production of dopamine
      • AADC is also referred to as dopa-decarboxylase
      • Dopaminergic neurons generally don’t have DBH
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22
Q

Catecholamine Degredation

A
  • Dopamine and Norepinephrine
    • Degradation
      • Monoamine Oxidase (MAO)
        • Intracellular (mitochondria)
        • Extracellular (in synapse)
      • Catechol-O-methyl transferase (COMT)
        • Extracellular only (in synapse)
        • Only catecholamines
        • Dopamine and NE can be degraded by MAO and COMT
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23
Q

Dopamine

A
  • Cell bodies in only two places
    • ~500,000 neurons are DA+ out of 100 billion in brain
    • Ventral Tegmental Area—motivation, reward, and attention – areas involved in addiction
      • Axons project very far away
    • Substantia nigra—motor learning and execution
      • Cell bodies die in Parkinson’s disease
24
Q

Dopamine Synthesis

A

· Rate limiting enzyme is TH

25
Dopamine Packaging
* Packaging * Vesicular monoamine transporter (VMAT) – will package any monoamine
26
Dopamine Synaptic Transporter/Reuptake
* Synaptic Transporter/Reuptake * 1° removal from synapse * Dopamine transporter
27
Dopamine Degredation
* MAO (intracellular and synaptic) * COMT (synaptic only)
28
Dopamine Receptors
* Receptors (metabatropic) * D1 Family (D1, D5) * Coupled to Gs (stimulatory) – only found postsynaptic * D2 Family (D2, D3, D4) * Coupled to Gi/Go (inhibitory) * Presynaptic autoreceptors * Postsynaptic
29
Dopamine Circuitry and Diseases
* Circuitry * VTA project to limbic (nucleus accumbens, amygdala, hippocampus) and cortex * Substantia nigra project to dorsal striatum * Diseases/Conditions * Parkinson’s * Substance Abuse * Mood disorders Interrupt synthesis, vesicular packaging, receptors, degradation, and reuptake
30
Norepinephrine
* Cell bodies in only two places * Locus ceruleus (LC) – midbrain/brainstem * Brainstem * Projections to: cerebral cortex, thalamus, amygdala * Functions: sleep/wake, attention (ADHD), negative memories (fear, anxiety, PTSD)
31
Norepinephrine Synthesis
From DA (dopamine b hydroxylase)
32
Norepinephrine Degredation
* MAO * COMT
33
Norepinephrine Vesicular Packaging
VMAT
34
Norepinephrine Synaptic transporters
* 1° removal from synapse * Norepinephrine transporter (NET) → packaged into vesicles or broken down by MAO
35
Norepinephrine Degredation
* MAO (intracellular and synaptic) * COMT (synaptic only)
36
Norepinephrine Receptors
Receptors (metabotropic) * a1 * Coupled to Gq * a2 * Coupled to Gi * Presynaptic autoreceptors * Postsynaptic * ß * Coupled to Gs
37
Norepinephrine circuitry and diseases
* Circuitry * Cell bodies in locus ceruleus, brainstem * Projections to cortex, amygdala, thalamus * Diseases/Conditions * Cognition * ADHD * Depression * PTSD
38
Serotonin
* Cell bodies primarily in raphe nuclei in the brainstem/midbrain * Several hundred thousand neurons are 5-HT+ * Project to limbic forebrain, cortex, striatum and DA neurons (can cause a piggy-back effect) * Enormous implication on mood - attention, sleep/arousal, emotion and mood, appetite, nausea
39
Serotonin Synthesis and Degredation
* Synthesis * From tryptophan (tryptophan hydroxylase - TPH) – can get from diet * Degradation * MAO (intracellular and synaptic)
40
Serotonin Transporters
* Transporters * Vesicular * Vesicular monoamine transporter (VMAT) * Synaptic—1° removal from synapse * Serotonin transporter (SERT)
41
Serotonin Receptors
Receptors * 13 different receptors identified (12 metabotropic, 1 ionotropic) * 5HT1D and 1A—autoreceptors * 1A coupled to Gi (inhibitory) * 5HT 1D can be presynaptic * Migraine (agonists) * 5HT2A * Coupled to Gq (stimulatory) * Antipsychotics (antagonists) * 5HT3 –ionotropic * Anti-nausea (antagonists)
42
Serotonin Circuitry and Diseases
* Circuitry * Cell bodies in cerebellum, brainstem * Projections to cortex, limbic, midbrain * Diseases/Conditions * Depression * Antipsychotics * Migraines * Obesity/Weight Loss
43
Acetylcholine
* Cell bodies in forebrain and brainstem * Interneurons in striatum * Project to limbic forebrain, cortex, striatum * Cognition (cortex), movement (striatum), reward (limbic)
44
Acetylcholine Synthesis and Degredation
* Synthesis * From choline and acetyl CoA * Degradation * AChE (intracellular and synaptic) * Broken down by any cholinesterase
45
Acetylcholine Transporters
* Transporters * Vesicular * Vesicular acetylcholine transporter * Synaptic—Choline only (NOT ACh) * Choline transporter – recycles choline into presynaptic terminal
46
Acetylcholine Receptors
* Receptors * Muscarinic * Can be presynaptic * G-protein coupled receptors * Nicotinic * Ionotropic
47
Acetylcholine Diseases
* Diseases/Conditions * Alzheimers * Parkinsons * Antidepressants
48
Global blockade of glutamate may cause other effects: Is there a therapeutic approach that would conserve some glutamate activity but block excessive stimulation?
Yes, give a partial agonist (will block some activity, but reach a ceiling and not block all activity)
49
Q: Vesicular monoamine transporter moves monoamines:
A: into vesicles in the presynaptic neuron
50
Q: Monamine oxidase would degrade all of the following neurotransmitters EXCEPT:
A: Glutamate
51
Q: COMT would degrade all of the following neurotransmitters EXCEPT:
A: GABA and serotonin
52
Q: The neurotransmitter most associated with movement disorders and addiction is:
A: Dopamine
53
Q: The neurotransmitter most associated with epilepsy and brain damage after a stroke is:
A: glutamate
54
Q: Which neurotransmitter is primarily removed from the synapse by degradation?
A: Acetylcholine
55
Q: Which of the following is an ionotropic receptor?
A: 5-HT 3
56
Q: ____ cell bodies are located in the raphe nuclei
A: Serotonin