2. Overview of
Neurotransmission
Key Concepts:
Action Potentials
Life-cycle of the
Neurotransmitter
Synapses and Receptor
Types
G-Proteins and
Regulation of Ion
Channels
3. Electric current through cell
membrane resulting in
intracellular action at a
synapse
Absolute threshold
All or none behavior
Excitatory (EPSPs)
increases electrical
potential
Inhibitory (IPSPs)
decreases electrical
potential
Saltatory conduction, as
Schwann cells wrap cell
membranes
Current hits presynaptic
terminal and opens voltage-
gated Ca++ channels
Leads to neurotransmitter
release
Action Potentials
4. Neurotransmitter Lifecycle
Location of synthesis
Soma (peptides)
Presynaptic
terminals (small-
molecule
transmitters)
Storage until release
signal (electrical
current)
Released with Ca++
increase through
exocytosis
Involves many
intracellular
proteins
Re-uptake after
release
Degradation after
release
5. Synapses and Receptor Types
Receptor types:
Ligand-gated
(ionotropic)
G-protein-coupled
(metabotropic)
A subunit activates
effector enzyme
2nd
messenger
effects ion channel
Additionally,
intracellular
receptors
Marijuana’s effects
on amanamide
receptors
Can effect gene
expression
Enzyme coupled
(tyrosine
hydroxylase)
6. Downstream Effects
Neurotransmitters interacting
with these receptors can:
Elicit short- or long-term
modulatory processes
Impact learning and memory
Impact an important process
called synaptogenesis
Create connections
between neurons in memory
structures reiterated by the
same stimuli
Involved in triggers for
relapse
Ingrained in memory with
connections and pathways
New pathways that form
are difficult to destroy
quickly.
7. G-Proteins and Secondary
Receptors
Cascades and amplification of signal
G-proteins activated by ligand binding (neurotransmitter)
Activates effector protein (such as adenylyl cyclase)
Creates many other effectors (such as cAMP)
Which then release the catalytic subunit on a kinase (such as PKA)
Kinase phosphorylates many second effectors
Many targets of which regulate channels
Other targets of which impact gene regulation (epigenetic changes)
8. The Limbic System
Structures
Ventral Tegmental Area
Nucleus Accumbens
Lateral Nuclei of Hypothalamus
Reticular Activating System
(regulation and affective stimuli),
Cingular Gyrus (top of brainstem
affecting emotions, too)
Main Neurotransmitters
Dopamine
Associated with pleasure
100,000 molecules per neuron in a
dopaminergic system
Dopamine in cocaine abuse
Main transmitter involved
Agonist amantadine decreases
craving
GABA
Inhibition
Mediates reinforcement in
hippocampus and amygdala when
paired with stress
Reinforcement
Initially build to
associate behavior with
feeding and sex
Controls emotional
memory, as well as other
behavioral responses
Highjacked by drugs of
abuse
Much like a biological
simulation of Pavlov’s
conditioning
9. Affects of Neurotransmitters
Gene Regulation
G-proteins effect CREB genes, which modulate cAMP
production via adenylyl cyclase
cAMP systems implicated in many systemic affects of addiction
Additionally, amphetamines and cocaine induce c-fos gene
Also acts on CREB gene regulation
Creates regulation loop involving CREB, cAMP, and transmitters
Channel Regulation
Long-term synaptic depression
Makes it more difficult to activate the neuron’s electrical
potential
Long term depression and glutamate
Hits NMDA receptor
Then acts on PLC, which clips PIP2 to IP3 and DAG
DAG, with the addition of Ca++ from intracellular store release
and from Ca++ channels opening, acts on PKC
IP3 acts on endoplasmic reticulum stores of Ca++, which then
binds to calmodulin, which activates CaM-KII
PKC and CaM-KII act on channel effectors that produce long-term
depression
10. Types of Neurotransmitters
Acetylcholine
Acts on the
parasympathetic
system
Anti-excitatory
Substances affecting
acetylcholine
receptors
Nicotine
nAChR ionotropic
receptors
Increases
parasympathetic
activity
Faster response,
effect from the
neuron
Excitatory effect
(EPSPs)
11. Types of Neurotransmitters
Catecholamines
Synthesized from amino
acid tyrosine
Dopamine from dopa
conversion via tyrosine
hydroxylase
Metabolized into
norepinephrine and then
into epinephrine
Pathway modulated by
mAChR receptors via PKA
interactions with CaM-KII
Degraded by COMT and
MAO enzymes
Functions
Reward pathways
Mimicked by many drugs of
abuse (cocaine,
amphetamines)
12. Drugs and Catecholamines
Norepinephrine
Circuits acted upon by
amphetamine and cocaine
Modulates learning and
memory circuits, including
emotionally-charged memories
Dopamine acts especially in the
VTA-NA systems
Translates motive states into
overt motor responses
Powerful reinforcement
mechanism
Cocaine and amphetamine as
main drugs of abuse impacting
dopamine
13. Specific Drug Mechanisms
Dopamine re-uptake transporters inhibited (blocked)
by both amphetamines and cocaine
Cocaine
Works on monamine up-take system (inhibits)
Increases mood
MAO inhibitors reverse depression similarly, accounting
for the high of cocaine
Amphetamines
Stimulates more release of dopamine
NE transporter effected similarly
Except that amphetamine works from within the cell on
this receptor (“cell-permeant” drug, as opposed to
cocaine as “cell-impermeant”)
Alcohol
Effects specifically:
VTA
Substantia nigra (“shakes” with withdrawal)
14. Types of Neurotransmitters
Amino Acids
Glutamate
Main excitatory neurotransmitter
Glutamate synthesized from glial glycine release
Converted back to glycine with uptake into glial
cells after transmission
Also can be turned into GABA (inhibitory analogue)
Works through metabotropic receptors
Substances effecting glutamate
Suspected general role in addiction
Possible antagonist of NMDA receptors in
hippocampus when reacts with GABA
Causes long-term potentiation
15. Types of Neurotransmitters
Y-aminobutryric Acid (GABA)
Structure
Ionotropic binding sites
Synthesized from recycled
glutamate via glutamate
decarboxylase
Function
Main inhibitory transmitter
(hyperpolarizing impact through
Cl- influx)
Effects every brain system
(connected with epilepsy)
Connection to glutamate
(depolarizing effect)
Substances effecting GABA regulation
Gamma subunit implicated in
alcohol’s effects on GABA
systems (benzodiazepines and
barbiturates, as well)
These act on GABA-alpha
ionotropic receptors
Produces various inhibitory
responses in body
16. Types of Neurotransmitters
Serotonin
Structure
Indolamine
Function
Regulate sleep-wake
patterns
Mood regulation
Role in Psychiatric
Disorders
Imbalances lead to many
psychiatric mood
disorders.
Bipolar I and II
Depression
Psychodelics and serotonin
responsible for psychedelic
effects
17. Types of Neurotransmitters
Neuropeptides
Function
Endogenous opioid peptides
Role in pain regulation
Long-term depression
in mechanosensory
pathways
Role in reward systems
Substances effecting opioid
receptors
Mainly opiates
Examples include heroin,
morphine, oxycodone, and
fentanyl
Work on mu-1 receptors in
the nucleus accumbens,
triggering dopamine
pathways
18. Neuropeptides In-Depth
Neuropeptide chains effecting pain regulation, especially
(enkephlins and dynorphins)
Periaquiductal gray of midbrain
Controls pain with dynorphins for long-term depression of pain
pathways
Also affect reward systems by the pleasure response
Works on VTA-NA system, especially with mu receptors
Morphine, heroin act as agonists
Heroin changed to morphine in brain
Heroin has 2 additional acetyl groups on the 3 and 7 carbons,
as well as an additional methoxy group)
Act on G-protein receptors (mu and delta)
Increases PK+ and PCa++
In turn inhibits adenylyl cyclase and cAMP
Tolerance develops rapidly
Rregular use over a few months, can tolerate 40-50 times dose L50
Mu and delta receptors reduce consumption of alcohol and opioids
when blocked (effects of Naltrexone
Naloxone is a pure antagonist used in overdoses to block opiate
binding
19. Neurobiological Mechanisms Agonists
Opiates acting directly on opioid receptors
Antagonists
Block drug from binding (use of naloxone in heroin overdoses)
Re-uptake blockers
Amphetamines blocking dopamine re-uptake
Sensitivization/desensitivization and neuronal adaptation
Role in tolerance/reverse tolerance
Cells adapt by increasing/decreasing receptor density at synapse
Dendrites growing or shrinking in response
Remove substance responsible for changes and cells have to re-adjust
to less/more neurotransmitters (law of opposites and withdrawal
symptoms)
20. Neurobiological Model of
Addiction Causes
Genetic predisposition
MZ/DZ twin studies and family studies
Trauma plus genetics implicated in veteran
studies and survivors of child abuse
Genes implicated in addiction
Channel abnormalities
NMDA glutamate receptor
Metabolic abnormalities
Alcohol dehydrogenase
21. Causes of Addiction in the
Neurobiological Model
The Substrate Itself
Actions on Neurotransmission
Channels and Metabolism
TIQs
Local and Global Effects of
Neurotransmission Disturbance
Pathways and Neuronal Adaptation
Stimulants and Re-uptake
22. Diagnosis
DSM-IV Criterion
Substance abuse vs.
substance dependence
(withdrawal)
Metabolite tests
Vital functions
Chemical assessment
Other medical problems
closely associated with
addiction
Cirrhosis
HIV/hepatitis/others related
to injecting practices
Brain damage and nutritional
deficiencies
Comorbid psychiatric
disorders
23. Detoxification as a First Step
in Treatment
Detoxification
Drugs administered
Overdose
Naloxone and opiate
overdoses
Rehabilitation detoxification
Benzodiazepines and
alcohol withdrawal
Treatment options after
detoxification
Psycho-behavioral treatment
Cognitive-behavioral
therapy
12-step groups
Pharmacological treatment
24. Maintenance
Methadone Programs
Long-term treatment
Aversion therapy
Disulfiram and Alcoholism
Treatment of co-morbid disorders
Antidepressants
Antipsychotics
Anti-Craving Drugs
Naltrexone
Alcoholism, narcotic addiction
Bupropion
Anti-smoking drug
Relapse risk for comorbid cocaine addiction)
Pharmacological Treatment
of Addiction
25. Merits of the
Neurobiological Approach
Understanding the risks and mechanisms
behind behavior
Withdrawal avoidance
Importance of abstaining from potentially
addicting drugs
Allows for treatment under Health Care Plans
Developing drugs to reverse overdoses
Shifts the blame
Not completely the addict’s fault
Less guilt over the addiction
More likely to seek treatment
26. Problems of the
Neurobiological Approach
Not everyone with a biological
predisposition becomes addicted to
drugs.
The phenomena of relapsing
Physiology returns to normal at most a 1-2
years after cessation.
Emotional memory should also return to
normal after cessation.
Shifts emphasis from responsibility to
determinism
Allows for an excuse to relapse or to not
seek treatment.
27. Sources
Crabbe, John C., Jr., Harris, R.
Adron, The Genetic Basis of
Alcohol and Drug Actions. Plenum
Press, New York, New York: 1991
Feldman, Robert S., Meyer,
Jerrald S., Quenzer, Linda F.
Principles of
Neuropsychopharmacology.
Sinauer Associates, Inc.,
Sunderland, MA: 1997
http://www.biopsychiatry.com/in
dex.html
http://www.psychologytoday.com
/articles/pto-19980201-
000010.html
http://www.drugdevelopment-
technology.com/projects/bifepru
nox/bifeprunox3.html
Niewink, RJM, Jaspers, RMA, et
al. Drugs of Abuse and Addiction:
Neurobehavioral Toxicology. CRC
Press, Boca Raton, FL: 1999
Perrine, Daniel M. The Chemistry
of Mind-Altering Drugs. American
Chemical Society, Washington
D.C.: 1996
Purves, Dale, Augustine, George
J., et al. Neuroscience. Sinauer
Associates, Inc., Sunderland, MA:
2004
Thompson, Richard F. The Brain.
W. H. Freeman and Company,
New York, New York: 1995
Zernig, Gerald, Saria, Alois, et al.
Handbook of Alcoholism. CRC
Press, Boca Raton, FL: 2000
Hinweis der Redaktion
Neuropeptide chains effecting pain regulation, especially (enkephlins and dynorphins)
--periaquiductal gray of midbrain controls pain with dynorphins for long-term depression of pain pathways
-- also affect reward systems by the pleasure response
--works on VTA-NA system, especially with mu receptors
Morphine, heroin act as agonists
--in fact, heroin changed to morphine in brain
--heroin has 2 additional acetyl groups on the 3 and 7 carbons, as well as an additional methoxy group)
Act on G-protein receptors (mu and delta)
--increases PK+ and PCa++
--in turn inhibits adenylyl cyclase and cAMP
Tolerance develops rapidly
--regular use over a few months, can tolerate 40-50 times dose L50
Mu and delta receptors reduce consumption of alcohol and opioids when blocked (effects of Naltrexone)
Naloxone is a pure antagonist used in OD
Need to Cross Blood-Brain Barrier
--lipid or aqueous soluble properties
Agonist/Antagonist display
Re-uptake and Cocaine Addiction
--dopamine and norepinephrin mechanisms
--cocaine blocks re-uptake of these NTs
--more NE and DA hit receptors, eliciting a pleasure response (ADAPTS)
--dysphoria when cocaine withheld
Sensitivization in stimulants
--reverse tolerance found in stimulants
--augmented response that increases with increased dosage
--hence, the mimicking of schizophrenia with extremely high cocaine and amphetamine consumption
Desensitivization in Depressants
--Tolerance consequence of:
--decrease in effective concentration of the agonist
--reduction in number of receptors
--change in response elicited because of the activation of a homeostatic mechanism
--pharmacodynamic tolerance also appears in depressants
--which is a general cellular tolerance to the substances
Re-uptake and Cocaine Addiction
--dopamine and norepinephrin mechanisms
--cocaine blocks re-uptake of these NTs
--more NE and DA hit receptors, eliciting a pleasure response (ADAPTS)
--dysphoria when cocaine withheld
Heroin addiction
acts on dynorpin/endorphin metabotropic receptors.
--activates Gi protein, inhibiting adenylyl cyclase, which decreases cAMP concentration.
--decrease of cAMP and downstream effectors counteracted by increasing adenylyl cyclase concentration.
--balance regained in time (TOLERANCE)
--remove heroin, adenylyl cyclase freed—WITHDRAWAL SYMPTOMS appear
--can eventually return to normal
Withdrawal effects opposite of drug effects and operates on the same time-frame.
--Example: heroin slows stomach contractions, is fast acting.
--Withdrawal has stomach contractions, is fast-acting.
Predisposition
--2.5 times higher chance of alcoholism in Children of Alcoholics than other children
Channel Abnormalities
--second messengers (G-proteins) affected by receptor differences, such as in NMDA receptors and the D4 receptors
--can also interfere with IPSP and EPSP interference in membrane potentials as a consequence
Metabolic Enzyme Differences
-- rate-limiting steps differ
--ex. Alcohol Dehydrogenase gene ADH and ALDH (aldehyde hydrogenase)
--active ALDH gene increases likelihood of alcoholism
--ALDH2-1 as opposed to ALDH2-2
--ADH2 &ADH3 have near loci on chromosomes 11 and 4
--in addition, differences in MAO concentrations in platelet counts
--plus differences in B-endorphin response with alcohol consumption
How Drugs Effect Synapses
--increase/decrease synthesis of NTs
--increase/decrease transport of NTs
--modify storage vesicles
--modify release of NTs
--increase/decrease rate of degradation of NTs
--block re-uptake
--mimic NT (agonist)
--block receptor (antagonist)
--affect up-/down-regulation of receptors
TIQs—
--dopamine + acetaldehyde (from alcohol breakdown)
--possible opioid-like response
DSM-IV Criteria
--tolerance or withdrawal necessary with dependence (physical, rather than only psychological)
Physical tests for Alcoholism
--malnutrition
--red blood cell counts
--liver enzyme analysis (glutamate dehydrogenase, AST/ALT levels)
--carbohydrate-deficient transferrin (CDT) levels
OD
--naloxone acts as antagonist on opioid receptors, reverses effects of heroin/morphine…
AWS Signs
--tremor, hyperhidrosis, tachycardia, insomnia, anxiety, clouding of consciousness, seizure (opposite of intoxication)
--detoxification with benzodiazepines
--usually with diazepam (valium)
Methadone
--less psychological effects than heroin
--longer duration to stave withdrawal
--lots of controversy
Aversion Therapy
--Alcohol metabolism
-- disulfiram blocks aldehyde dehydrogenase (build of acetaldehyde, which causes unpleasant feelings—flushing, vomiting)
--Ro 15-45B blocks behavorial and neurochemical effects of alcohol
Co-Morbid disorders can exacerbate substance use (self-medication)
Anti-Craving Drugs
--Naltrexone in craving prevention in alcoholism (modification of NTs and receptors)
--works on opioid system as well, GABAa system, Glutamate system
--Amantadine for glutamate and dopamine modification in cocaine addicts
--Ibogaine trials in Israel and Netherlands as an anti-craving drug
--unfortunately Schedule I substance in USA
--danger of Bupropion