1
Q
Mechanism of Neurotransmission
A
- Action potential causes rapid Ca2+ release at nerve terminal
- Rapid fusion of vesicles
- Diffusion of neurotransmitters across synaptic cleft
- Binding to postsynaptic receptor
- Change in membrane potential
- Depoarlization: more positive membrane potential deviation sufficient to initate AP
- Hyperpolarization: more negative membrane potential
- Graded response: depolarization not sufficient to initiate AP
2
Q
Defining
a
Neurotransmitter
A
- Present in neurons w/ enzymes involved in synthesis.
- Released from nerve terminal after depolarization in Ca2+ dependent process.
- Activates specific postsynaptic receptors causing depoarlization/hyperpolarization of postsynaptic membrane.
- Same effect with microiontophoresis as phsyiological.
- Blocked by specific antagonists.
- Action terminated by specific mechanism.
- Activates specific presynaptic autoreceptors which usually reduces release and regulates concentration in the synapse.
3
Q
Neurotransmitter Classes
A
- Small Molecules
- Acetylcholine (ACh)
- Amino acids
- Monoamines
- Peptides
- Endorphins
- Angiotensin
- Substance P
- Dissolved Gases
- Nitric oxide (NO)
- Carbon monoxide (CO)
- Neurosteroids
- Glucocorticoids
4
Q
Amino Acid
Neurotransmitters
A
- Glutamate (Glu) → major excitatory transmitter in cortex and spinal cord
- Gama-aminobutyric acid (GABA) → major inhibitory transmitter in cortex
- Glycine (Gly) → major inhibitory transmitter in spinal cord
5
Q
Monoamine
Neurotransmitters
A
- Catecholamines
- Epinephrine (EPI)
- Norepinephrine (NE)
- Dopamine (DA)
- Indolamines
- Serotonin (5-HT)
- Imidazoles
- Histamine (HIS)
6
Q
Ionotropic Receptors
(Fast)
A
- 5 subunits form receptor binding site and ion channel
- Maximized for speed
- Neurotransmitter binding alters receptor conformation
- permits fast exchange of ions across membrane
- alters membrane permeability
7
Q
Metabotropic Receptors
(Slow)
A
- 7 membrane spanning subunits
- Receptor binding activates second messenger systems through G proteins
- Gs stimulates adenylate cyclase
- Gi inhibits adenylate cyclase
- +/- of adenylate cyclase will active/inhibit protein kinase
- +/- of protein kinase will active/inhibit phosphoprotein phosphatase
- +/- of phosphoprotein phosphatase will phosphorylate/dephosphorylate various ion channels, enzymes, and proteins
- Protein phos/dephos can result in altered membrane permeability
- Can have long-term consequences such as regulation of gene expression
8
Q
Sensitization
A
Long Term Change
Decreased neurotransmitter levels result in increased receptor numbers leading to increased response.
9
Q
Desensitization
A
Long Term Change
Increased neurotransmitter levels result in reduced receptor numbers leading to reduced response.
10
Q
Plasticity
A
Long Term Change
Strengthening of synaptic connections that may allow for memory formation or recovery of function after injury.
11
Q
Termination of Action
A
- Degradation/Recycling by specific enzymes
- Acetylcholinesterase (AChE) for ACh
- Monoamine Oxidase (MAO) for monoamines
- Catechol-O-methyl transferase (COMT) for catecholamines
- Reuptake by high affinity membrane transporters
- glutamate, GABA, glycine, serotonin, dopamine, norepinephrine
- Diffusion (removal by extracellular peptidases)
- most neuropeptides
12
Q
Effects of Drugs
Presynaptic
A
- Block reuptake (e.g. antidepressants)
- Change precursor availability (e.g. L-DOPA for Parkinson’s)
- Inhibit neurotransmitter synthesis (e.g. alpha methyltyrosine)
- Inhibit storage of neurotransmitter (e.g. reserpine)
- Alter release of neurotransmitter (e.g. amphetamine)
- Provide presynaptic regulation through autoreceptors
- Provide presyntaptic regulation through heteroreceptors
13
Q
Effects of Drugs
Postsynaptic
A
- Agonists bind to receptor to produce a response.
- Antagonists bind to receptor and reduce or inhibit a response.
- Receptor adaptation ⇒ repeated doses of drugs lead to long-term changes in receptor number and affinity resulting in sensitization or desensitization
14
Q
Effects of Drugs
Degradation Enzyme Inhibition
A
Inhibition of degrading enzymes increases amount of neurotransmitter in the synapse.
MAO inhibitors: selegilene
AChE Inhibitors: neostigmine or donepezil
15
Q
Cholinergic System
A
Major nuclei for neurotransmitter synthesis:
- Septal nuclei project via fornix to hippocampus
- Nucleus Basalis of Meynert
- projects to neocortex
- degenerates in Alzheimer’s disease
- Striatum
- contains cholinergic interneurons
- degenerates in Hungtington’s disease
- Neocortex contains cholinergic interneurons
- Dorsal tegmental area of pontine reticular formation
- projects to thalamus
- involved in maintaining states of consciousness
16
Q
Dopaminergic System
A
Major nuclei for neurotransmitter synthesis:
- Substantia nigra pars compacta
- projects to striatum via nigrostriatal pathway
- degenerates in Parkinson’s disease
- Ventral tegmental area of reticular formation
- projects to many cortical and subcortical lumbic nuclei
- Schizophrenia associated with increased DA production
- Arcuate nucleus of hypothalamus
- projects to infundibular portal system
- regulates prolactin release
17
Q
Noradrenergic System
A
Major nuclei for neurotransmitter synthesis:
- Locus coeruleus
- projects diffusely to entire CNS
- involved in attention and states of arousal
- Lateral tegmental area of reticular formation
- involved in descending control of pain
18
Q
Serotonergic System
A
Major nuclei for neurotransmitter synthesis:
- Raphe nuclei
- located all along the midline of the brainstem
- projects diffusely to entire CNS
- reduced 5-HT associated with depression and insomnia
- increased 5-HT associated with mania
- involved in descending control of pain
- Pineal gland
- converts 5-HT to melatonin
- regulates cicadian rhythms
19
Q
Alzheimer’s Disease
A
- Caused by loss of cholineric neurons
- Short term treatment:
- Increase Ach at synapse
- Donepezil
- Inhibits acetylcholinesterase (AChE)
- Also used with myasthenia gravis
20
Q
Parkinson’s Disease
A
- Neurodegenerative disease
- Progressive loss of dopaminergic neurons in the substantia nigra pars compacta
- See low levels of dopamine
- Short term treatment
- Precuror loading with L-DOPA
- Dopamine cannot cross BBB
- L-DOPA can cross BBB
- Carbidopa
- false substrate for peripheral aromatic amino acid decarboxylase (AAAD)
- AAAD acts on Carbidopa allowing L-DOPA to diffuse through BBB more efficiently
- Central AAAD uses L-DOPA to make DA
- Precuror loading with L-DOPA
21
Q
Anxiety
A
- Involves inability to inhibit conflicting behaviors
- Suspected that GABA-ergic neurons of limbic system imvolved with compensatory behavior
- Stimulation of GABA-A receptors ⇒ Cl- mediated hyperpolarization of membrane potential
- GABA-A receptor has benzodiazepine site
- Binding incudes conformation in receptor
- Potentiates GABA-induced inhibition
- GABA-A receptor has benzodiazepine site
- Treatment
- Lorazepam (Ativan)
- Binds benzo site of GABA-A receptor
- Increases inhibitory action
- Old drugs:
- Diazepam (Valium)
- Chlordiazepoxide (Libirum)
- generally less tolerance when used for anxiety
- more tolerance when used for anticonvulsive, sleep, and muscle relaxation
- Lorazepam (Ativan)
22
Q
Depression
Original Treatments
A
- Theory that depression results mainly from serotonin imbalance
- Then effects balance of other monoamines
- Drugs that affect the monoaminergic system
- Iproniazid
- Monoamine oxidase inhibitor
- Blocks MAO allowing monoamine levels to increase in synapse
- NE, 5-HT, DA
- Tricyclic antidepressants (TCAs)
- Block reuptake of monoamines
- Increases levels of monoamines at synape
- Many act on NE and 5-HT reuptake
- Different affinities and effects
- Not always effective
- Many side effects
- Iproniazid
23
Q
Depression
Second Generation Treatment
A
- Selective serotonin reuptake inhibitors (SSRI)
- specifically targets serotonin reuptake system
- Ex. Fluoxetine (Prozac)
- fewer side effects
- Also have a lesser affinity for NE and DA transports
- May take 2-3 weeks before clinical effects
- Most likely cause long term sensitization or desensitization changes in post-synaptic receptors
- Involves mechanisms that restore synapses to normal function
24
Q
Schizophrenia
A
- Attributed to an imbalance in dopaminergic system
- LIkely involves overstimulation of the dopamine receptor
- Positive symptoms ⇒ hallucinations
- Negative signs ⇒ withdrawal, lack of affect
- Often starts in teenage years
- Proportion of positive/negative symptoms change with disease progression
- Treatments:
- haloperidol (Haldol)
- Receptor antagonist of dopamine receptor
- Prevents overstimulation
- Modulate postive signs better than negative ones
- Clinical improvements associated with mesocorticolimbic system
- Side effects associated with:
- nigrostriatal system ⇒ tardive dyskinesia
- tuberoinfundibular system ⇒ hyperprolactinemia
- haloperidol (Haldol)
25
Pleasure Pathway
* Pathway always activated during pleasurable events
* Part of _limbic pathway_ called **Medial Forebrain Bundle**
* **Dopaminergic neurons** involved in drug abuse and addition
* Located in V**entral tegmental area (VTA)**
* VTA neurons _project to limbic area_ called **nucleus accumbens**
* **Modulates prefrontal cortex activity**
* Cocaine overactivates pathway in unregulated fashion
* Sets up a **behavioral state**
* User expects same degree of overactivation each time
* Chronic cocaine users experience same autonomic effects of taking the drug if put in an environment of previous exposure
* Adds to addictive cycle
26
Drugs of Abuse
Direct Effectors
* Cocaine \> Amphetamine and methamphetamine
* Directly affects the dopamine system ⇒ most potential for abuse
* **Blocks the dopamine reuptake transporter**
* Cocain most addictive
* High affinity and fast onset drug
* Single dose of cocaine can permanently alter function of the dopamine receptor system
* Long term changes include:
* Sensitization
* Plasticity
* Neurotoxic effects
* Fast onset and amount of drug that reaches the brain that determines pleasurable effects vs addictive/dangerous effects
27
Drugs of Abuse
Indirect Effectors
* **Heroin, nicotine, and ethanol** indirectly effects pleasure pathway
* **Blocks interneurons** that normally inhibit VTA cycle
* "Less addictive"
* **Heroin ⇒ opiod receptors** (usually bind endorphins)
* Treat with **Methadone**
* Drug substitute for heroin
* Prevents heroin or morphine from interacting with opiod receptors
* Can cause mild euphoria and drowsiness
* Continued use can restor sexual, immune, and adrenal function
* Cessation can result in methadone withdrawal
* **Nicotine ⇒ acetylcholine receptors**
* Treatment:
* **Nicotine patches**
* Concentration progressively reduced
* **Buproprion (Wellbutrin)**
* produce dopamine release in mucleus accumbens & modulate limbic circuitry
* **Ehtanol ⇒ GABA receptors**
* Treat with **disulfiram (Antabuse)**
* Blocks acetaldehyde dehydrogenase
* Causes build up of acetaldehyde
* Produces immediate and severe negative reaction to alcohol intake
IMS: Neuroanatomy
flashcards
Decks in class (23)
# Cards
-
Craniofacial Complex37
-
Nervous System Development33
-
Blood Brain Barrier21
-
Neurotransmitters27
-
Intro to Nervous System29
-
Action Potentials and Channelopathies18
-
Neuronal Degeneration and Regeneration19
-
Neuronal Interactions24
-
Nerves, Spinal cord, and Pathways124
-
Spinal Cord Lesions16
-
Pain35
-
Hypothalamus63
-
CNS Pathways & ANS35
-
Limbic System70
-
Cerebral Cortex107
-
Cerebellum50
-
Basal Ganglia30
-
Motor Systems18
-
Brainstem13
-
Cranial Nerves15
-
Thalamus23
-
Aging and Alzheimers15
-
CVA, TBI, and Coma17
