Lectures 7 & 8 - Addiction I & II Flashcards
What is addiction?
In the DSM-V (Diagnostic & Statistical Manual of Mental Disorders) the criteria are:
- Tolerance, withdrawal
- Taking more than intended, failure to quit
- Time lost, social engagements lost, use despite knowledge of problem
In general, drug taking that negatively affects one’s life, is compulsive, and resistant to quit attempts
What does addiction result from?
Results from complex interactions between the drug, the user and the environment
What 5 drug factors influence addiction development?
- Pharmacological effects
- Rewarding effects
- Aversive side effects
- Potency
- Mode of delivery
What is tolerance?
Reduced behavioral or physiological response to the same dose
What is physical dependence?
Elicitation of a withdrawal syndrome when consumption is terminated
Symptoms of alcohol addiction?
The symptoms and severity are determined by the amount and duration of alcohol consumption and include:
- Sleep disruption
- SNS activation
- Tremors
- Seizures in severe cases
What 5 user factors influence addiction development?
- Age of onset
- Psychiatric comorbidity
- Genetics
- Family history
- Personality
What 3 environmental factors influence addiction development?
- Stress
- Availability
- Cultural norms
Between marijuana, alcohol, and tobacco, which is the most addictive?
Tobacco
Describe the typical human use pattern.
Initial experimentation => repeated intake, recreational use => compulsive drug seeking => attempted cessation, withdrawal and back to either 2 or 3
What group of people are more prone to developing addictions?
Adolescents
3 properties of alcohol?
- Anxiolytic
- Hypnotic
- Anesthetic
Incidence of people who die from alcohol related causes?
3 in 100
Number of people worldwide that are alcohol dependent?
76 M
5 brain parts associated with addiction and alcohol?
- Mesolimbic dopamine system
- Nucleus accumbens
- Amygdala
- Striatum
- Hippocampus
What is ethanol? How is it formed?
Ethanol is an amphipathic molecule and as such is readily soluble in aqueous and non-aqueous environments, can pass through biological membranes (in sec-min) and effects membrane fluidity dynamics
Fermentation between Hordeum vulgare/Humulus lupulus (hops and barley)and Saccharomyces cerevisiae (yeast): C6H12O6 (glucose from yeast anaerobically)→ 2 CH3CH2OH + 2 CO2
Alcohol addiction treatment?
Medications currently approved in the US to combat alcohol dependence include:
- Disulfiram (Antabuse): 1949
- Naltrexone (ReVia): 1994
- Acamprosate (Campral): 2004
- Long-Acting Naltrexone (Vivitrol): 2006
What is ethanol a target of in the body?
It is a target of many signaling molecules including most ligand-gated ion channels: NT gated ion channels for glutamate, GABA, acetylcholine, and serotonin are differentially affected by alcohol in a dose dependent fashion beginning with non-intoxicating levels
What chemical reactions can ethanol take part in? What to note?
- Hydrogen bonding at –OH group
- Very weak hydrophobic interactions (-CH3 end of molecule)
NOTE: limits alcohol to low affinity (~mM) interactions with biomolecules
8 effects of alcohol in vivo?
- Pregnancy: birth defects, Fetal Alcohol Syndrome
- Liver: damage, cirrhosis, fatty liver
- Diuretic (↓ vasopressin)
- Serum lipoproteins (↑ HDL)
- Cardiovascular effects
- Decreased muscle strength
- Internal body temperature falls
- Sexual function: initial increase in libido; long-term: gonadal atrophy
3 actionc of alcohol on the CNS?
- Inhibition of excitatory neurotransmission
- Enhancement of inhibitory neurotransmission
- Modulation of dopamine release
=> Disturbances in these balances produce dis-inhibition, ataxia and sedation, and depression of the CNS
When does alcohol tolerance develop?
After chronic use
When does alcohol physical dependence develop?
Upon alcohol withdrawal
How does alcohol cause death?
Respiratory arrest due to effects on brain respiratory center
At what alcohol level should you not drive?
0.08 mg/100 mL of blood ~ 20 mM
What is the neurological basis of the switch from controlled, volitional alcohol use to compulsive and uncontrolled addiction?
Remains obscure but 2 theories:
- Impairment of the dopaminergic reward system and the resulting increase in alcohol consumption in an attempt to regain activation of the system
- Prefrontal cortex is particularly sensitive to damage from alcohol abuse and influences decision making and emotion, processes clearly compromised in the alcoholic
Volumetric brain changes during chronic alcohol use?
- Larger ventricles
- Larger gaps between gyri and sulci
=> brain mass shrinks overtime
11 ion channel targets of acute ethanol actions in intoxication (25-100 mM)?
- Adenosine transporter
- Calcium-activated K+ channel (BK, Slowpoke)
- Dopamine transporter (DAT)
- GABAA receptor
- Glutamate receptors: NMDA and non-NMDA
- Nicotinic acetylcholine receptors
- Serotonin-3 receptor (5-HT3)
- Serotonin transport?
- TRPV1 receptor/channels (target of capsaicin)
- ATP gated purinergic receptors
- Numerous signaling proteins (G-proteins, PKC)?
Describe the subunit stoichiometry of the NMDA glutamate receptor and its functional implications.
NMDA receptors are tetramers of distinct subunits
Glycine binds as a co-agonist at NR1
NR2 subunits determine ligand affinity and ion channel properties and binds glutamate
Central importance of voltage-dependent Mg2+ block
2 functions of the NMDA receptors?
- Overactivation correlated with the progression of Huntington’s Disease
- Activation necessary for long-term potentiation (LTP) of CNS synapses
Effect of alcohol on NMDA receptors? What to note?
Inhibition by decreasing peak current amplitude (which increases with ethanol concentration)
NOTE: maximal inhibition occurs with 70% inhibition
What are 3 cys-loop ligand gated ion channels?
- Nicotinic ACh receptor
- Serotonin-3 receptor (5-HT3)
- GABAA receptor
Effect of alcohol on cys-loop ligand gated ion channels?
Potentiates ion flux
What to note about alcohol affecting membrane fluidity?
High dose to have a physiological effect
Treatment to reduce craving in early-onset alcoholics? How does it work? What is it usually used for?
Ondansetron: 5-HT3 antagonist (Zofran) used mainly as an antiemetic to treat nausea and vomiting frequently following chemotherapies
How does Disulfiram work to treat alcohol dependence?
It is an alcohol-sensitizing medication that produces an unpleasant reaction when alcohol is ingested so is used to deter alcoholics from drinking
It interferes with the breakdown of acetaldehyde, a toxic metabolite of alcohol
Ethanol + ADH => Acetaldehyde + ALDH => Acetate
How does Naltrexone work to treat alcohol dependence? Dosage? What to note?
Orally bioavailable antagonist of mu, delta, and kappa opioid receptors to reduce dopamine release associated with alcohol expectancies and consumption
FDA-approved oral dosage: 50 mg/day
NOTE: clear effect of naltrexone on risk of relapse to heavy drinking and borderline effect of naltrexone on abstinence rate
Why is it dangerous to ingest methanol? How to treat?
Converted to formaldehyde by ADH leading to tissue fixation in the retina => blindness (formaldehyde converted to formate by ALDH)
Treatment: ethanol to compete with methanol for ADH
How does Acamprosate work to treat alcohol dependence? Dosage? Note?
It has complex effects on glutamate-NMDA activity and is a GABA agonist (normal balance between these systems altered by chronic drinking) => it reduces deprivation-induced drinking
FDA-approved dosage is 2000 mg/day (divided in 3 doses)
What are 5 schedule I drugs?
- Heroin
- Lysergic acid dithylamide (LSD)
- Tetrahydrogestrinone (THG)
- MDMA: “Ecstacy”
- Cannabis
What can ecstasy be a treatment for?
PTSD
Definition of Schedule I drugs? What to note?
- The drug or other substance has a high potential for abuse
- The drug or other substance has no currently accepted medical use in treatment in the United States
- There is a lack of accepted safety for use of the drug or other substance under medical supervision
NOTE: no prescriptions may be written for Schedule I substances, and such substances are subject to production quotas by the DEA
What is the opposite of tolerance?
Sensitization
What drug causes sensitization?
Cocaine
How does nicotine affect our body? 4 effects.
- Complex effects on CNS and PNS: improve attention, facilitate memorization, anxiolytic and anti-nociceptive properties
- Both stimulant and relaxant
- Activates the NAc reward system
- Can stimulate and subsequently desensitize receptors
Nicotine affinity for its receptors?
nM range
2 types of nicotinic receptors? What is each permeable to?
- Homo-oligomeric α7: five α7 subunits => Ca++ permeable
2. Heteromeric α4β2: two α4 and three β2 subunits => Ca++ and Na+ permeable
Where are both types of nicotinic receptors found? What does this mean?
On dopamine neurons => hypothesis that dopamine efflux reinforces tobacco use
How does nicotine regulate neuronal nicotinic receptors? How?
Chronic nicotine administration increases the density of α4β2 nAChRs in human and rodent brains, primary cultures, and cells heterologously expressing nAChRs
In vivo, up-regulation is not dependent on mRNA transcription but on enhanced receptor assembly and decreased receptor degradation
How does the upregulation of nicotinic receptors by nicotine impact health and disease?
- Up-regulation of nAChRs in brain likely contributes to nicotine addiction
- nAChR expression in brain is decreased with aging, dementia, and in Alzheimer’s patients so up-regulation may play a role in enhancing cognitive and attention
Pharmacological interventions for nicotine addiction? Bottom line?
- Nicotine replacement therapy: NICOTROL inhaler, nasal spray (prescription needed)
- Nicorette gum, transdermal patch (OTC)
- Varenicline: partial agonist at α4β2 type nAChR and full agonist at α7 receptors
- Antidepressant: bupropion improves abstinence rates of smokers
- Rimonabant: CB1 receptor antagonist (progressing through FDA approval process)
- Nicotine metabolism inhibitors to decrease # of cigarettes (e.g. CYP2A6 in liver)
- Others: vaccines, dopamine receptor targets, etc
BOTTOM LINE: LONG-TERM ABSTINENCE THERAPIES ARE LESS THAN OPTIMAL
Relationship between smoking and drinking?
Under normal conditions, neurons from the pedunculopontine tegmental nucleus (PPT) that release ACh extend to the ventral tegmental area (VTA) => released ACh stimulate nicotinic receptors on neurons that in turn release the neurotransmitter dopamine (DA) in several brain regions, including the nucleus accumbens (NAC)
- When nicotine enters the brain from the circulation, it acts on the nicotinic receptors on the dopamine-containing neurons in the VTA, resulting in increased dopamine release in the NAC
- Alcohol also causes dopamine release in the VTA and NAC through an unknown, but likely indirect, mechanism
=> combined effects of alcohol and nicotine can enhance dopamine release in the NAC
What may be important in the therapeutic index for some individuals addicted to nicotine?
The pharmacokinetic profiling of nicotine ingestion
What is the mechanism of action of cocaine?
Inhibits dopamine reuptake transporter
Other than sensitization, what does cocaine administration cause?
Plasticity and conditioning
What are some neurochemical changes associated with cocaine administration?
Increase in AMPA:NMDA ratio in the nucleus accubens + changes in shape and size of dendritic spines in chronic cocaine, abstinence, and a
challenge => similar to changes seen in LTP in the hippocampus
Is the adolescent brain more prone to daily cocaine intake? Explain.
YUP
The reward circuitry in our brain involves the limbic system and its interconnections to the prefrontal cortex. Since this is the last brain region to mature, it makes sense that
adolescents would have less control over their reward-seeking behavior than adults
Describe the local anesthetic properties of cocaine.
It crosses the lipid bilayer, becomes charged within the intracellular pH and then binds and blocks Na+ channels => blocks AP firing
In what 2 brain areas does cocaine elevate dopamine levels?
- Striatum
2. Nucleus accumbens
What does opiate use lead to?
Opioids often produce a state of euphoria and there is a strong trend to develop:
- Tolerance
- Withdrawal symptoms when given over extended periods of time
What do opioids bind?
GPCRs expressed in pain pathways throughout the brain and spinal cord (Gi: decreases the concentration of cAMP by inhibiting the action of adenylyl cyclase)
Most prominent opioids?
Morphine from P. somniferum (poppy plant)
What are the 4 major subgroups of opiate receptors? Describe each.
- Delta: involved in pain relief, antidepressant effects and physical dependence
- Kappa: linked with sedation, spinal analgesia and pupil constriction
- Mu: physical dependence, respiratory depression, euphoria, pupil constriction and supraspinal analgesia
- Nociceptin: involved with appetite, depression, anxiety and the development of tolerance to mu agonists
Example of endogenous opioid?
Substance P
What are endorphins?
Endogenous compounds that bind opioid receptors: enkephalin, dynorphin, β-endorphin
Highest affinity to morphine?
Mu receptors
Differences in responses to heroin and methadone? Implication?
Heroin has higher highs and lower lows than methadone does => makes methadone, a potent μ-agonist as well, a popular pharmacological replacement therapy for heroin users
Other than opioid receptors, what other receptor is a GPCR using Gi?
D2 and CB1 receptors
2 drugs to treat opioid addiction?
- Methadone (schedule II)
2. Naltrexone (prescription)
Describe the clinical management of opioid addiction.
- Management almost by necessity is individualized
- Treatment may take months or years of rehab
- Probably with periods of relapse and remission
Names of 2 endogenous cannabinoids? What to note?
- Anandamine
- 2-arachidonoylglycerol (2-
AG)
NOTE: very lipophilic and discovering more and more of these
What was cannabis originally described as? What is its active compound?
Originally described as an analgesic and the active compound, delta9-tetrahydrocannabinol (THC) has been found to have a very high affinity to another group of GPCRs
Role of endocannabinoids?
Influence synaptic physiology throughout the CNS and seem to be crucial in many forms of learning and are currently hypothesized to act in a retrograde fashion
8 centrally attributive effects of cannabis?
- Hallucinations
- Dissociation
- Euphoria
- Enhanced appetite
- Impaired cognition and memory
- Muscle relaxation
- Impaired motor function
- Analgesia
5 potential medicinal use of cannabinoids?
- Movement disorders
- Migraine
- Irritable Bowel Syndrome
- Alzheimer’s disease
- Tourette’s syndrome
2 cannabinoid receptors? Describe each.
- CB1: widely expressed in the brain (e.g. basal ganglia), but also peripherally throughout the body; CB1 activation is largely responsible for the acute cognitive and intoxicating effects of cannabis
- CB2: located almost entirely in the immune system and are responsible for the antiinflammatory properties of cannabis
Why do cannabinoids affect memory?
CB1Rs are prominent in the hippocampus
Effect of CB1 receptor agonists? What is this called?
Inhibit motor performance due to the high density of CB1 in the globus pallidus and striatum (aka basal ganglia)
= catalepsy
Effect of nicotine on endocannabinoids?
Chronic nicotine increases eCB levels in the mesolimbic dopamine system
Effect of cannabinoids on the synapse? What is this called?
Post-synaptic neuron releases eCBs to the pre-synaptic terminal (where the CB1 receptor is located) => decreased release of other NTs (through blocking Ca2+ influx), such as acetylcholine, serotonin, norepinephrine, dopamine, and even peptides
= presynaptic inhibition via retrograde signaling
Effect of cannabinoids on the hypothalamus?
Decreased release of peptides in the hypothalamus is thought to be a contributor to appetite regulation in cannabinoids
Other than cannabinoids, what other NT performs presynaptic inhibition?
When glutamate is released in the synapse, it will bind autoreceptors (mGluRs) on the pre-synaptic surface which inhibit its own release
What do cannabinoids have to do with LTP?
Endocannabinoids likely contribute to the formation of LTP
