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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