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The Neurobiology
of Addiction
By Colleen M. Farrelly
Overview of
Neurotransmission
 Key Concepts:
 Action Potentials
 Life-cycle of the
Neurotransmitter
 Synapses and Receptor
Types
 G-Proteins and
Regulation of Ion
Channels
 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
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
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)
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.
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)
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
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
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)
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)
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
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)
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
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
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
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
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
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)
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
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
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
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
 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
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
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.
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

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The Neurobiology of Addiction

  • 1. The Neurobiology of Addiction By Colleen M. Farrelly
  • 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

Editor's Notes

  1. 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
  2. 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.
  3. 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
  4. 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
  5. 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
  6. 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)
  7. 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