Lect Notes 04
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Transcript of Lect Notes 04
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Lecture #3- Drugs and Development
Drugs
What is a drug?
Exogenous (foreign to body) substance that alters brain function
Repeated Administration
Addiction
Tolerance
Sensitization
How do drugs operate?
Interact with endogenous NT systems within the brain
Most psychoactive drugs act on receptors that are there for some other reason
Drugs differ from NTs in many ways:
Access to synaptic membrane
Composition
How bound to receptors
Drug Mechanisms
Agonist- Facilitate or mimic NT
Antagonist- Prevents NT action
Drug Effects
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1. Synthesis
2. Storage
3. Release (May Block Action Potentials)
4. Receptor Interaction
5. Inactivation
6. Re-uptake
7. Degradation
Sites of Drug Action
Many potential modes of action
Act on pre-synaptic sites
Act on post-synaptic sites
Neurotransmitter Systems
Acetylcholine
Cholinergic system in brain
Drug effects at neuromuscular junction
Black widow venom
Botulin toxin
Nicotine
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Curare
PhysostigmineSerotonin
Serotonergic system
Dopamine
Dopaminergic system
Nigrostriatal pathwaysSubstantia Nigra to Basal Ganglia
Mesolimbic pathways- The Reward Pathway
Ventral Tegmental Area to Nucleus Accumbens
Video
Increase in DA and drugs of addiction
Drugs of Abuse
Mouse Party
Cocaine & Amphetamine
Route of Administration
Behavioral effects
Changes in Brain Function
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Drug EffectsAt Synapse: Blocks dopamine re-uptake transporter
Self Administration and Dopamine Release in NA of rats
Marijuana (THC)
60 Cannabinoids
THC psychoactive agent
Behavioral effects
Low dose
Moderate to High dose
Receptor Location
Anandamide
Effects on the Brain
Drug EffectsAt Synapse: Blocks inhibition of dopamine release
Self Administration and Dopamine Release in NA of rats
Balance of excitation and inhibition
Study Questions
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Brain Development
Embryonic Development
Fertilization of the egg- single-celled zygote (Day 0)
Zygote divides, rapidly increasing number of cells (Day 1)
Ball of cell invaginates to form three layers (Day 7)
Three cell layers emerge:
Endoderm --> internal organs, gut lining
Mesoderm --> muscle, circulatory system, bones
Ectoderm --> epidermis, nervous system
Neurulation (Day 18)
Ectoderm induced to become neural tube by underlying notochord
Brain Development (Days 22-24)
Neural tube differentiates (i.e., cells begin to take on unique forms)
Anterior tube develops brain plate
Develops divisions
Posterior tube develops into spinal cord
Tube cavity develops into ventricles and central canal
Brain size increases massively prenatally (8th week, head half size of embryo)
Rapid proliferation of cells
Brain size also increases massively postnatally (from 350 g to 1000 g in one year)
Not due to large increase in number of neurons
Cells get larger
Glial cells proliferate
Rapid increase first 5 years
Peak b/w 18 & 30
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Gradual decline thereafter
Six Processes in Neural Development
1. Mitosis/Neurogenesis
Mitotic division of non-neuronal cells to produce neurons (occurs in neural tube)
2. Migration
Movement of cells to establish distinct populations
3. Differentiation and maturation
Transformation of neuron into distinct types
4. Synaptogenesis
Establishment of synaptic connections as axons and dendrites grow
5. Apoptosis (programmed cell death)
6. Synaptic remodeling
Loss/growth of synapses to refine connectivity
1. Neurogenesis
Starts with closure of neural tube
Birth-dating Neurons
All neurons & glia are derived from ventricular mitosis
Born in ventricular layer
Stem Cell: Memory for Division (~10,000 daughter cells)
Some neurons are born in adulthood
Olfactory receptor neurons
Hippocampus
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Newborn cells can integrate functionally into adults and restore function
Therapeutic applications
2. Migration
Cells migrate from ventricular zone to their final destination
Guided by glia or other neurons (Radial Glia = Guide Wires)
Neurons can also migrate along the surfaces of other neurons (e.g., axons)
For both: Cell adhesion molecules (CAMs) mediate migration
CAMs make cells stick to one another
Tangential migration (interneurons)
Abberant Migration
Dyslexia
3. Differentiation
Migrating cells immature, not differentiated (no neuronal phenotype)
Structurally
Functionally
When cells reach destination genes that make neuronal proteins are turned on
Cells differentiate into those appropriate for brain region
Determined by:
Genetic Blueprint
Cell will differentiate if taken out and raised in dish
Genes already been selected to be turned on
Environmental Signals
Induction by neighbors
Neighbors direct differentiation
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Induction Experiment
Motor neurons develop in ventral horn of spinal cord
How do they know to become motor neurons?
Transplant piece of notochord (n) to dorsal side (n')
Motor neurons develop on both sides
4. Synaptogenesis
Dendrites and axons grow out to make synaptic connections
Both possess growth cones, specialized structures that seek out target
Occurs throughout life of organism (plasticity, injury)
Particularly in terms of dendrites
How do they know which path to take?
CHEMOTROPIC GUIDANCE
Cells are finding the right concentration of a chemical
One set of studies examines regeneration of axons in frogs/newts/fish
Retina innervates the optic tectum (SC)
There is an orderly arrangement of the retina projections (flip flop)
Dorsal retina to ventral tectum; Ventral retina to dorsal tectum
If cut, regenerates within a few months
Cut and rotate eye 180
Connections were the same, but animal can't see correctly
Myelin
Begins before birth in M1 and S1
Continues into adolescence (frontal lobes)
Dendrites
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Usually begins after migration
Begins prenatally, but continues postnatally
5. Apoptosis (programmed cell death)
Up to 50% neurons born in 1st 7 months die
e.g., human spinal motor neurons
170,000 at 10 weeks gestation; 115,000 at 30 weeks gestation
Neurotrophic Growth Factors required for survival
Brain structure as much about sculpting as growthB
What regulates cell death?
Size of target regulates neuron number
Level of neurotrophic factors (e.g., NGF)
6. Synaptic Remodeling
Max # of Synapses at between 1 and 5 yrs of age
Surviving cells adjust synaptic connections throughout life of organism
Learning, growth, injury
Synaptic connectivity regulated by neuronal activity (use it or lose it)
Development Done?
By 5-6 years of age, 95% of structural development complete
The Aging Brain
The Teenage Brain
The Aged Brain
What matters in developmentNature versus Nurture?
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Intrinsic factors: Originating within organism (i.e., genes)
Mutations result in abnormalities
Extrinsic factors: Those provided by environment
Genetically identical organisms are not physically identical
Nervous systems, connectivity, size of neural structures, etc
PKU
Study Questions