Lecture 23-26 Flashcards
Neuroadaptation + 4 changes (5)
Repeated exposurure to a drug results in log-term changes in the brain that lead to a motivational transition
- cellular structure
- Neural circuitry
- Neurtransmiteer activity
- Gene expression
We observe within and between system neuroadaption:
Within: progressive downregulation of the reward circuit
Between: Graudual recruitment of the antireward system
Drug before addiction is through —–, repeated stimulation and addiction causes —— and recuits ——
- reinforce reward
- downregulation of reward circuit (antireward)
- anti-reward system is recruited
D2 receptor and drug addiction for cocaine (5):
People who abuse + low receptor causes + Lower D2 implies + biologic finding + detoxified addicts
- People who abuse cocaine often have a lower D2 receptor binding (lower dopaminergic transmission)
- People with low levels of dopamine receptors will have decreased natural stimuli and want want something more exciting to stimulate receptor (more likley to pyschoactive addiction)
- Lower D2 receptor density implies that a more powerful stimulus is required to elicit a normal response
- Lower dopamine D2 receptor availability has been observed in cocaine abusers, and non-addicted individuals with similar receptor levels may experience a heightened response to dopaminergic stimulation. These findings suggest that some individuals may have an inherent neurobiological predisposition to the rewarding effects of dopamine-enhancing drugs, potentially increasing their risk of addiction.
- Detoxified addictied individuals report a less intense high and show less DA levels in their brain in response to methylphenidate (repeated exposure to high dopamine levels may deplete presynaptic dopamine reserves or impair dopamine transporter function, reducing dopamine release upon stimulation).
DA increases in the striatum after methylphenidate (MPH) administration reveal:
a robust response in controls but not in cocaine abusers.
There is a —- in dopaminergic transmission and —- dopamine D2 receptor binding in dependent subjects
- decrease
- lower
Reduction in D2 receptor and decreased DA release causes —– sensitivity to natural reinforcers. This causes ———.
- decreased
- decreased motivational salience for environmental stimuli and greater risk for seeking drug stimulation
Drug induced reductions in striatal D2 receptors are associated with:
decreased activity in frontal cortex
Explain the effects of reduced striatal D2R stimulation in indirect pathway (6)
- VTA dopamine neurons project to striatum
- In striatum we have GABAnergic inhibitory receptor with D2 receptors
- Gaba neurons are inhibited and project to GPe
- This heightened activity increases the inhibitory output to the GPe, which in turn decreases inhibition of the STN.
- The resulting increased STN activity enhances excitatory input to the GPi/SNr, intensifying the inhibition of the thalamus.
- The overactive indirect pathway suppresses thalamic excitatory input to the motor cortex, resulting in reduced initiation of voluntary movements.
→ Increased inhibition of GPe → Hyperactive STN → Increased inhibition of the thalamus by GPi/SNr.
Thalamic Hypoactivity → Reduced excitatory output to the frontal cortex.
If D2 receptors are downregulated, VTA will project to striatum but they wont be able to inhibit the neurons to the same extent. In the end we have ——.
frontal cortex less activity
Hypofrontality
A state of reduced activity in the frontal regions of the brain, particularly in the prefrontal cortex/ low response to non-drug stimuli but regions have heightened activity for drugs.
Talk about the methamphetamine group experiment with control (2)
- More metabolitic activity with people addicted to drugs when presented visual drug cues
- Hoypoactivity in response to nondrug stimuli
As a result of chronic drug use, natural rewards become —- pleasurable abd release —- dopamine. Frontal cortex becomes inherently —- active and —– responsive to normal rewards but it is ———.
——— provides the motivation for complusilve drug use and is also believed to be responsible for relapse. Overtime stimuli that perdict drugs produe ——–. Such condtion or learned responses could elicity powerful craving sensutions in the frontal lobe which becomes —- to drug related stimuli.
- less
- less
- less
- less
- overactive in response to drugs or the stimuli that pedict drug use.
- Memory of positive effects of a drug
- a greater response in the reward pathway than the rewarding stimuli themselves
- sensitized
Delta FosB (4)
What + member + rapidly + gene
- a transcription factor (control regulation/expression of genes)
- Member of FOS gene family
- Rapidly induced in NAc and striatum after drug adminstration, repeated exposure to drug causes accumulation in NAc cells
- cFOS= Immediate early gene (rapidly and transiently expressed in response to cellular activation, often without the need for new protein synthesis)
Acute/chronic action of Fos family (2)
- Rapid induction of FOS family with cFos being first activated and return to baseline
- delta Fos B doesnt go to baseline it seem to accumulate and in chronic drug adminstration
Delta Fos B modulates gene expression by epigenetic mechanism, explain (2):
- Methylation : inhibition of gene expression as in promotor makes hard for TF to bind
- Histone acetylation: induction of gene expression (histone unwraps DNA to make more accessible)
Chronic cocaine on delta Fos B
Chronic cocaine = Fos B accumulation = Decreased methylationof Cdk5 = increased Cdk5 = structural changes (spine density) = heighten the brain’s responsiveness to cocaine and increase susceptibility to addiction through sensitization mechanisms
Chronic amphetamine on delta FosB
Chronic amphetamine = Fos B accumulation = methylation and repression of G9a (represses expression of FosB) = further induction of FosB = positive feedback
How do we treat addiction (5)?
Pharmacological treatments:
1. Agonist substitution therapy
2. Antagonist therapy
3. Targeting nondopaminergic system
Vaccination therapy
Deep brain stimulation
Agonist substitution therapy (4)
standard + what x2 + example
- Gold standard for opoid treatment
- Perscription of a substitute (similar mechanism) agent
- Perspection of a partial agonist to treat addiction
- Methadone : heroin treatment
Methadone (9):
Pros (5) + Cons (4)
Pros
- heroine treatment
- Full opoid agonist (Same receptor and pathway)
- Slower onset, longer half life (heroine shorter acting)
- Less of a rush (slow onset)
- Reduction of cravings/withdrawal (due to longer half life)
Cons
- Very addictive
- Fatal in overdose
- Expensive (hard to get into a clinic)
- Requires supervision
Buprenorphine (5)
what + efficacy + treats + half-life + risk
- Partial agonist for agonist substitution therapy
- Administering more wont have effect because they have reached their efficacy limit (ceiling effect)
- Used to treat fentanyl
- Long half-life, less severe withdrawal than methadone
- Risk of respiratory depression if combined with other sedative hypnotics
Antagonist therapy (3)
what + reduce + example
- Blocks the reinforcing effects of a drug by blocking receptor so opoids cannot bind
- Eventually reducing the compulsive behaviour
- Examples for opiate antagonist: Naloxone, Naltrexone, Nalmefene
Naloxone (3)
what + speed + causes
- Competitive opiod receptor antagonist
- Fast-acting
- Causes rapid removal of drugs bound to opiod receptors
Naltrexone (4）
What + treatment for + effects + speed
- Mu opoid receptor antagonist
- Treatments for opiod use disorder and alcohol use disorder
- Induces abstinence from opiods, reduced alchohol relapse, promotes abstinence from amphetamine (drugs inducing opiod release)
- Not fast acting
Nondopaminergic neurotransmitter system and addiction (2)
GABA (2) + GLUT (2)
- GABAergic system
- DA cells in VTA under GABA control. GABAB agonists (baclofen) reduce reinforcing effects of drugs of absuse
- Anticonvulsants (blocks the breakdown of GABA) increases GABA tone - Glutamatergic system
- Blockage of the AMPA receptor via topiramate reduces craving in alchohol-dependent people
- Bloackage of the NMDA receptor via ifenprodil reduces relapse in animal models of addiction
Vaccines therapy for addiction (4)
what happens (2) + version + example
- develope an anti-drug vaccine that produces an immune response when drug is taken. In response to the drug, body forms antibody
- Antibody binds to the drug preventing them from crossing the blood-brain barrier
- You need to give a modified version of the drug so the body can produce antibodies as they usually dont react to the drug itself (couple it to something)
- Nicotine = NicVAC, Cocaine = TA-CD
DBS therapy for addiction (2)
What + done where
- invasive lessions in brain that are reversible
- Most done in the nucleus accumebens (dopamine released) which is the prime site of addiction
Ethyl alcohol (Ethanol) (2）
used + effects
- used in beverages
- intoxicating effects
Good
Methyl alcohol (Methanol) (6)
known as + good/bad + metabolites + can cause (3)
- Wood alcohol
- Highly toxic
- Metabolites forms formaldehyde and formic acid which damages optic nerve
- Blindness
- Coma
- Death
Bad
Ethyl alcohol is produced by ——-
*Go in specific
- fermentation
- Yeast cells in air fall on fruits that have sugar. The type of sugar yeast fall on depend on the form of alcohol made
Most wine 14-15% before yeast die. Higher % you need —–
distillation
- boil, vapor pass through cooling tube and condense (40-50%)
Absorption of alcohol (5)
general rate + absorded where (2) + max blood concentration +rate is influence by
- Rapidly absorbed across all biological membranes
- 10% absorbed through the stomach (slower)
- 90% absorbed through upper GI tract (faster)
- Time from last drink to maximal blood concentration varies from 15-60 mins
- rate is influenced by volume + concentration of dose and prescence of food
Distribution of alcohol (5)
body tissue + metabolize (2) + BBB + Fetus
- Evenly distributed throughout body tissues and fluids
- 95% enzymatically metabolized
- 5% excreted from lungs
- Freely crosses the BBB
- Freely distributed to the fetus (same level as mom)
The breathalyzer criteria
Exhaled air vs venous blood
1:2300
2300ml of air contains the same amoun of alcohol as 1 ml of blood
Metabolism of alcohol pathway:
Alcohol doesnt oxidize quickly if you drink more
Metabolism of methyl alchohol pathway:
- Methyl alcohol
Alcohol dehydrogenase - Formaldehyde
Acetaldehyde dehydrogenase - Formic Acid
Oxidaction reaction - Optic nerve damage, mitochondrial dysfunction
10ml can cause blindness, 30ml can be fatal
What to do for people that are overdosed on methyl alcohol?
- Give them alot of ethanol (drunk) as they compete for active site of the same metabolic enzyme and less methanol can bind and be metabolized
Alcohol kinectics
- Zero order kinectics: ethanol is cleared at a constant rate regardless of concentration
Alcohol metabolsim in woman and men (3)
- Woman have 50% less gastric ADH (alcohol dehydrogenase) making them have higher blood alcohol concentration and easier to get drunk
- Men have a greater ratio of muscle to fat (which has lower blood supply). More blood volume in males = lower blood alcohol
- Woman with higher fat content than men resulting in concentrated alcohol in plasma, raising apparent blood alcohol level.
Genetic variability in metabolsim of alcohol (2):
- There are different forms of the enzyme acetaldehyde dehydrogenase enzyme. In 10% of asian population have inactive form. If they drink small amount of alcohol they have high amount of acetaldehyde as it is not metabolized. This causes bad side effects like flushng nausea, headache so they tend to stay abstinence.
- About 40% of asian population is heterozygous for the inactive gene so there still are some side effects
Disulfiram (antabuse)
- Inhibits acetaldehyde dehydrogenase by strong irreversible binding. This blocks the conversion from acetaldehyde to acetic acid.
- Treatment for alcoholism as the excess acetaldehyde produce bad side effect
Because alcohol is such a simple molecule, it readily crosses cell membranes, including the blood–brain barrier, and can be detected in the brain within minutes after consumption. Alcohol has both specific and non- specific actions. Nonspecific actions depend on ———. As you might expect, the protein molecules that are embedded in that membrane are likely to function differently when their “environment” changes so dramatically and becomes less rigid. In contrast, at low to moderate doses, alcohol seems to interact with specific sites on particular proteins, and these specific actions are probably responsible for most of the acute effects of ethanol at intoxicating doses.
- ## its ability to move into membranes, changing the fluid character of the lipids that make up membrane
Alcohol and GABA (3)
GABA /synthesis + what the two does + anxiety
- GABA is the main inhibitory neurotransmitter in the CNS and synthesized from glutamate in one step by GAD (Glutamic acid decarboxylase)
- Alcohol binds to GABA A receptors, opens channels, Cl- enters the cell and the membrane hyperpolarizes causing inhibition
- Reduction in anxiety but chronic alcohol cause anxiety??
Alcohol and Glutamate (4)
Glutamate + what the relationship is + reduces + specificity
- Glutamate is the main excitatory neurotransmitter in the CNS and an essential amino acid
- All glutamate receptors are inhibited by acute alcohol exposure, but some are only affected by high concentrations. Of the several subtypes of glutamate receptor, alcohol has its greatest effect on the NMDA (N-methyl-d-aspartate) receptor, which is a ligand-gated channel that allows positively charged ions (Ca2+ and Na+) to enter and cause localized depolarization
- Reduces LTP, learning and memory
- Specific to certain brain regions (differnt types of dysfunction depending on region affected)
Metabolic tolerance of Alcohol (3)
What + accounts for + results
- Chronic alcohol use significantly increases the P450 liver microsomal enzymes that metabolize the drug.
- This accounts for up to 25% of the tolerance to alcohol
- More rapid metabolism means that blood levels of the drug will be reduced, producing diminished effects.
The blue line represents blood levels before a 7-day period of drinking; the red line shows blood levels in the same person after 7 days of drinking. Tolerance after repeated alcohol consumption is shown by the more rapid decrease in blood alcohol.
Pharmacodynamic (tissue/functional) tolerance
- Neurons also adapt to the continued presence of alcohol by making compensatory changes in cell function. The tolerant person may appear less intoxicated but still subject to reduced cognition, memory ability etc.
Behavioural tolerance of alcohol
- In animal experiments, alcohol initially reduces body temperature, but when the drug is administered repeatedly in the same environment, a compensatory increase in body temperature occurs, and this reduces the initial hypothermia (low body temperature). If these animals are given saline instead of alcohol in this environment, they show only the compensatory mechanism and their body temperature rises (hyperthermia). The importance of environment is further demonstrated by evidence that in a novel environment, tolerance is significantly less, because no conditioned hyperthermia is present
Alcohol initially causes hypothermia (lower body temperature) when administered to animals.
The body adapts over repeated exposures in the same environment by developing a compensatory mechanism, such as increasing body temperature to counteract the drug’s effects. The environment where alcohol is repeatedly administered becomes associated with the drug’s effects.
This leads to a conditioned hyperthermic response when the animal is later exposed to the same environment, even if alcohol is replaced with a saline injection.
Acute tolerance of alcohol (2)
Occurs when + what
- occurs within a single exposure to alcohol.
- Several of the subjective and behavioral drug effects are greater while the blood level of are rising and are less while the blood level is falling even if the BAC is the same at both times
In a trial using a human participant given three doses of alcohol (a,b,c), signs of intoxication (such as incoordination in the balance beam test) appeared during the rising phase of blood alcohol lev- els at about 0.20%. However, as blood alcohol was declin- ing, the person became “sober” at a higher concentration (about 0.265%), showing that acute tolerance had occurred. In this case sober does not mean unimpaired in skills other than the balance beam test.
The signs of withdrawal are characteristically a “rebound” phenomenon and represent a hyperexcitable state of the nervous system after the prolonged depressant effects of alcohol. Tretament includes (2):
- GABA agonists
- NDMA antagonists
Black out
starting at a blood alcohol of around 0.25, concious but no memory of event
Acute effect of alcohol (5)
Primary effect + low dose + high dose + sleep + blood vessels
- Primary effect: graded reversible depression of behaviour, mental functioning and cognition
- low doses: respiratory stimulation
- High does: respiratory depression
- Induces sleep (supression of REM)
- Dilates blood vessels in the skin: flase feeling of warmth but body heat is actually lost
The number of NMDA receptors in both the cerebral cortex and hippocampus is —– in human alcohol abusers, as well as in animal models of chronic alcohol exposure. In addition, in dependent rats, glutamate release, normally —– by alcohol, is dramatically increased at about 10 hours after withdrawal of alcohol. The time course of CNS hyperexcitability and the seizures that are typical of the alcohol abstinence syndrome matches the pattern of increased glutamate release during withdrawal.
- elevated
- inhibited
Alcohol and opiods (4)
Relationship between the two + u receptor (2) +glutamate
- Acute alcohol increases opioid release and increases gene expression of opioid peptides. Chronic alcohol reduces gene expression and lowers levels of peptides.
- Alcohol consumption stimulates the release of endogenous opioids (like beta-endorphins). These bind to μ-opioid receptors.
- μ-opioid receptor act as inhibitory metabotropic receptors on GABA neurons, by inhibiting GABAergic neurons, μ-opioid receptors indirectly increase the activity of dopaminergic neurons in the VTA.
- reduce glutamate input
Alcohol acutely —– glutamate neurotransmission by ——– and reducing glutamate release.
- inhibits
- reducing the effects of glutamate at the NMDA receptor
Chronic ethanol leads to down-regulation of —— receptors, making the organism more sensitive to seizure-inducing agents. Chronic ethanol up-regulates —– in humans and animal models and increases glutamate release, providing an explanation for the hyperexcitability and seizures seen at abrupt withdrawal.
- GABAA
- NMDA receptors
Alcohol use disorder is a multimodal phenomenon (4)
Age of onset of drinking behaviour is a signifigant perdictor for AUD. Heavy drinking during adolescence —- the likelihood of —– later in life. By age 24, those that drank heavily in adolescence show increased level of substance abuse disorders, levels of depression :(, and levels of antisocial/borderline personality disorders.
- increases
- alcohol dependency
Binge Drinking
- consuming fice or more alcoholic drinks in a row
Disulfiram (Antabuse) (2)
What it does + effects
- The drug disulfiram (Antabuse) inhibits aldehyde dehydrogenase, the enzyme that converts acetaldehyde to acetic acid in the normal metabolism of alcohol.
- An individual who drinks as little as a quarter of an ounce of alcohol within a week of taking disulfiram experiences a sharp rise in blood acetaldehyde accompanied by facial flushing, tachycardia, pounding in the chest, drop in blood pressure, nausea, vomiting, and other symptoms.
- This method is clearly aimed at making ingestion of alcohol unpleasant. Patients must be cautious about unknowingly consuming alcohol in beverages, foods, over-the-counter medications like cough syrup, or mouthwash.
What is the goal of pharmacotherapy (4)?
- Reverse acute pharmacologic effects of alcohol (no treatment currently exist)
- Treat/prevent withdrawal symptoms
- Maintain abstinence
- Treat co-existing psychiatric disorders (depression/anxiety)
