Transcript Drug Sensitivity

Neurotransmitters
•Neuropeptides
•Amines
•Quaternary amines
•Acetylcholine (ACh)
•Monoamines
•Catelcholamines
•Epinephrine (EPI)
•Norepinephrine (NE)
•Dopamine (DA)
•Indoleamines
•Serotonin (5-HT)
•Melatonin
•Amino acids
•Gamma-aminobutyric acid (GABA)
•Glutamate (GLU)
•Glycine
•Histamine (HIST)
•Opioid peptides
•Enkephalins (ENK)
•Endorphins (END)
•Peptide Hormones
•Oxytocin (Oxy)
•Substance P
•Cholecystokinin (CCK)
•Vasopressin (ADH)
•Neuropeptide Y (NPY)
•Hypothalamic Releasing Hormones
•GnRH
•TRH
•CRH
Drugs can acts as Agonists
Normal receptor at rest,
channel is closed
Agonist binds and has same effect
as endogenous neurotransmitter,
channel opens
Neurotransmitter binds
receptor and opens channel
Drugs can act as Antagonists
Typical antagonist binds in place
of endogenous neurotransmitter,
prevents neurotransmitter action
Non-competitive binding antagonist doesn’t
interfere with neurotransmitter binding but
still prevents neurotransmitter action
Presynaptic Drug Actions
8. Blockade of NT
degradation
MAO inhibitors
Prozac
Chemical Weapons
Postsynaptic Drug Actions
Illegal Drug Use
in the U.S.
•Marijuana
•Cocaine
•Crack
•Amphetamines
•Heroin
•#1 most widely used illegal drug in US
•from cannabis sativa
•mild hallucinogen
•brain has cannabinoid receptors (CB1)
•cerebral cortex
•hippocampus
•basal ganglia
•cerebellum
•endogenous NTs are:
•Anandamide
•2-arachidonylglycerol (2-AG)
•oleamide
•THC is active ingredient
•causes
•memory loss
•impaired tracking ability
•lung damage
•anxiety or paranoia
•Amotivational syndrome
•Gateway drug?
Marijuana
Cocaine
•#2 most popular illegal drug in US
•from coca leave in South America
•CNS stimulant
•is addictive
•blocks reuptake of DA, NE, and 5HT
•creates
•stereotypic behaviors
•nail biting/teeth grinding
•pacing
•an irregular heartbeat
•arterial spasms
•seizures
•cardiac failure
•has a synergistic effect with alcohol
Opiates
•Opium, Heroin, and Morphine
•CNS depressant
•is very addictive
•human brain has opiate receptors
•limbic system
•hypothalamus
•locus coeruleus
•periaqueductal gray
•endogenous NT are
•endorphins
•enkephalins
•dynorphins
•causes
•analgesia/pain suppression
•down-regulation of receptors
•can lead to death by overdose
Hallucinogens
•LSD, Mushrooms
•acts as a 5-HT2 agonist
•causes
•vivid images in the absence of
input
•geometric forms
•meaningful images
•separation from the body
•similar effect as in
•oxygen loss
•sensory deprivation
•can lead to “Bad Trips”
•paranoia
•depression
•confusion
Ecstasy (MDMA)
MDMA : 3-4 methylenedioxymethamphetamine
•is related to
•Mescaline
•MDA
•methamphetamine.
•it prompts nerve cells to release a flood of serotonin.
•bring about the increased awareness of
•emotion
•intimacy
•self-confidence
•The ensuing chemical low tide could explain the
depression users describe when they are coming down.
•damages serotonin cells
•damages dopamine cells
Ecstasy (MDMA)
Earlier animal
studies had shown
that repeated ecstasy
use damages the
serotonin brain cells,
which help to
regulate mood and
behavior.
This image shows
that serotonin axons
are destroyed in a
squirrel monkey after
a single dose of
MDMA.
Control
Users
Ecstasy (MDMA)
BRAIN CHANGES appear
prominently in positron emission
tomography (PET) scans of Ecstasy
users as well as people who abstain.
Drug users (right), though, have far
less serotonin activity, as is indicated
by the dark areas, compared to the
controls (left). New studies show that
this difference may contribute to
permanent brain damage.
Serotonin Activity
Alcohol
•CNS Depressant
•is a great inhibitor
•causes
•slowing of brain activity that
controls reason
•slowing of reaction time
•depression of respiration
•increase in aggressiveness
•increase in risk of digestive
tract cancers
•increase in heart disease
•decrease in sex drive
•memory loss
•depression
•cirrhosis of the liver
•fetal alcohol syndrome
•brain cell death
Models of Addiction
Moral Model
Disease Model
Physical Dependence Model
Reward Model
Intra-Cranial Self-Stimulation
ICSS:
Electrodes are
placed in the
Medial Forebrain
Bundle (MFB)
Reward Pathway
Ventral Tegmental Area (VTA) to
Nucleus Accumbens via the
Medial Forebrain Bundle and then to
the Prefrontal Cortex
Drug Addiction
Initially the CREB protein dominates leading to Tolerance and the
feeling of discomfort with the absence of the drug
But the CREB protein falls after a few days if drug use discontinues
But Delta fosB stays elevated for weeks after the discontinued use
of the drug leading to Drug Sensitivity
Drug Tolerance
During drug use VTA cells are stimulated and
release Dopamine triggering the reward circuit
Dopamine binds the receptors of the Nucleus
Accumbens and increases cAMP and Ca2+
ion concentrations
cAMP and Ca2+ activate the CREB protein
CREB activates the Dynorphin gene to make
the Dynorphin protein
The Dynorphin protein is released back on
the VTA where it inhibits Dopamine release
depressing the reward circuit and causing the
user to need more drug for the same high
Drug
Sensitivity
Neurobiology of Drug Addiction
During drug use VTA cells are stimulated
and release Dopamine triggering the
reward circuit
Dopamine stimulates the formation of
Delta fosB
Nucleus
Accumbens
neuron
Delta fosB inactivates the Dynorphin
gene and activates the CDK5 gene
The CDK5 protein stimulates dendritic
spine growth in the Nucleus Accumbens
Increasing Drug
Sensitivity/Addiction
Drug Sensitivity/Addiction
Nucleus Accumbens neurons in non-human animals:
Non-Addictive Drugs
Cocaine
Greater density of Dendritic Spines
Contributes to Drug Sensitivity (increased risk of drug relapse)
Delta fosB may be the contributing factor of increased spine growth