APP Module (GTown) - Addiction, Alcoholism, and Drugs of Abuse (Hrs 1 and 2) Flashcards
All drugs of abuse interfere in some way with what?
ventral striatum
What is tolerance?
Decreased response to a repeated dose of substance over time; or the need to increase a dose to obtain a similar effect
What are some withdrawal symptoms of alcohol?
- tremor
- seizure
- DTs
What are the three factors which influence addiction?
- drug
- user (genetics)
- environment
Per statistics, which substance seems to be the “most” addictive?
nicotine
What is the typical human use pattern?
1) initial experimentation or use
2) repeated use
3) compulsive drug-seeking
4) abstinence
What properties does alcohol have?
anxiolytic, hypnotic, and anesthetic properties
How do you make beer?
1) Harvest some hops and barley.
2) Get some brewer’s yeast.
3) Get a container with some water and add the yeast with the barley and hops and then wait.
What is the affinity of ethanol for interactions?
millimolar range
What is the affinity of dopamine for its receptor?
nanomolar range
What do the differing affinities of dopamine and ethanol mean?
Lower affinities mean you mean much less of the substance to produce a response
What might be considered an intoxicating dose of ethanol?
Those above ~15mM (A moderately intoxicating blood alcohol level of 0.08% (80 mg/dl) is equivalent to an ethanol concentration of 17 mM.)
What are some molecular characteristics of ethanol?
amphipathicity and ability to readily cross lipid membranes
What are the main CNS effects of alcohol?
- inhibition of excitatory neurotransmission and enhancement of inhibitory neurotransmission
- DA release modulation
- disinhibition, ataxia, and sedation
- chronic use leads to tolerance, dependence, etc.
How does alcohol mediate its effect on plasma membranes?
Alcohol intercalates itself between lipid molecules in the plasma bilayer and affects both the membrane fluidity as well as protein function
What are the main brain regions affected by alcohol?
- mesolimbic DA system
- amygdala
- striatum
- hippocampus
- cortex/cerebellum
What changes do you see in the brain of a chronic alcohol user?
↓ brain mass
↑ ventricle size
larger gaps between gyri and sulci
What effect does alcohol have on the firing at a NMDA synapse?
Markedly attenuates the inward current usually seen with glutamate dosing
What are the main channels which alcohol affects?
1) NMDA and kainate
2) GABA-A
3) nACh
4) 5-HT3
What are the features of an NMDA receptor?
1) tetramer
2) binds glutamater and glycine as a co-agonist
3) voltage-dependent Mg2+ block
4) NR1 and NR2 subunits
What type of receptors does alcohol seem to affect?
“cys-loop” family which includes nAChRs, 5-HT3, GABA-A
How does alcohol affect GABA-A receptors?
potentiates flux of potassium ions
Where are 5-HT3 receptors primarily expressed?
emetic centers of the brain
What is Zofran?
Ondansetron is an anti-emetic which antagonizes 5-HT3 receptors
Why is Zofran being used for alcohol abuse?
Seems to reduce cravings in early-onset alcoholics
What are the six major receptor effects that alcohol has?
1) decrease in NMDAR activity
2) decrease in kainate receptor activity
3) decrease in voltage-sensitive calcium channels
4) increase in GABA-A activity
5) increase in 5-HT3 activity
6) increase in nAChR activity
What do you see in fMRI images of intoxicated patients while performing a task?
Global depression of brain activity
What are the four current pharmacological treatments for alcohol dependence?
1) disulfiram
2) naltrexone
3) acamprosate
4) long-acting naltrexone
What is disulfiram and how does it work?
Disulfiram blocks the action of acetaldehyde dehydrogenase leading to an accumulation of acetaldehyde in the body which has a lot of unpleasant effects
What is the treatment for acute methanol poisoning and how does it work?
Ethanol. Using ethanol actively competes for the alcohol dehydrogenase enzyme which in turn produces acetaldehyde instead of the far more toxic formaldehyde from methanol
What is naltrexone and how does it work to treat alcohol abuse?
Naltrexone is an opioid receptor antagonist which decreases DA release associated with alcohol expectancy and consumption
What is acamprosate and how does it work to treat alcohol abuse?
Acamprosate has complex effects on the glutamate-NMDA system and is also a GABA agonist. It seems to increase abstinence rates by working in opposition to the effects of alcohol
What are some examples of Schedule I drugs?
- heroin
- LSD
- marijuana
- MDMA
- THG (an anabolic steroid)
What are three requirements for a schedule I drug?
1) high potential for abuse
2) no currently accepted medical use
3) a lack of accepted safety for its use under medical supervision
Can you prescribe Schedule I drugs as a physician?
Nope
Who determines whether drugs are controlled and in which schedule they are put?
DEA, FDA, and congress
What is the difference between desensitization and tolerance?
Sensitization is the increase in response to a repeated administration of drug. Tolerance is the decrease in a response to a repeated administration of a drug.
What are some pharmacological effects of nicotine?
- facilitates memory
- anxiolytic
- anti-nociceptive properties
- improves attention
- both stimulant and relaxant
What is the affinity of nicotine for the nicotinic receptor?
nanomolar range
What are the two main subtypes of nicotinic receptor in the brain?
α7 homomeric receptor
α4β2 homomeric receptor
What type of receptor is a nAChR?
pentameric ionotropic receptor
What is the ion channel that the α4β2 receptor is associated with?
non-selective cation channel permeable to sodium and calcium
Where are the nAChRs found in the brain?
dopaminergic neurons which reinforces the rewarding effect of nicotine
What is activation of the nicotinic receptor characterized by in the presence of nicotine
rapid desensitization
Why is cytisine not addictive like nicotine?
- no effect on increased receptor expression
- no desensitization at the receptor
What is found regarding nicotinic receptors in post-mortem brain tissue
In chronic smokers, the nicotinic receptor has been upregulated
What is special about the upregulation of receptors which nicotine causes?
It is not dependent on mRNA transcription which means nicotine is actively stabilizing and facilitating receptor expression directly
What factors decrease nicotinic receptor expression in the brain?
- aging
- dementia and Alzheimer’s
How does varenicline work?
full agonist at the α7 receptor. partial agonist at the α4β2 receptor
What are examples of some other pharmacological therapies for nicotine addiction?
- bupropion
- rimonabant (CB1R antagonist)
How does the CB1R antagonist rimonabant exert its effect?
It’s thought that chronic nicotine use leads to increased expression of CB1Rs in the mesolimbic system and antagonizing this lessens nicotine’s rewarding effects
What does alcohol do in conjunction with nicotine?
Alcohol potentiates the DA release of nicotine when used together
How does cocaine work?
Inhibits DAT leading to increased concentrations of dopamine in the synapse for longer times
What is a pharmacological effect seen with cocaine administration?
Sensitization. Increased response to repeated doses of cocaine and even generalization to associated and similar stimuli
What effect does cocaine have on the neurons in the NAc?
Increased AMPA receptor expression. Change in shape and size of dendritic spines
Who self-administers more cocaine on a daily basis if given the chance? Adolescents or adults
Adolescents!
How does cocaine exert its local anesthetic effect?
inhibition of sodium channels
What are the four receptor subtypes of opioid receptor?
mu, delta, kappa, and nociceptin
What is the delta receptor in the brain involved with?
- pain relief
- antidepressant effects
- physical dependence
What is the kappa receptor in the brain and spinal cord associated with?
- sedation
- spinal analgesia
- pupil constriction
What is the mu receptor in the brain and spinal cord associated with?
- physical dependence
- respiratory depression
- euphoria
- pupil constriction
- supraspinal analgesia
What is the nociceptin receptor in the brain and spinal cord associated with?
- appetite
- depression and anxiety
- development of tolerance to mu agonists
What are some effects of the opiate system?
pain relief
euphoria
strong tolerance and withdrawal effects
What is a mu agonist?
morphine
What separates heroin from methadone?
Heroin has larger peaks and valleys during administration while methadone is longer-lasting leading to a more level concentration in the body
What are some endogenous opiates?
- endorphins
- dynorphin
- enkephalins
What types of molecules are the endogenous opiates?
neuropeptides
How do the opioid receptors signal?
As GPCRs through the Gi signaling pathway
What are the CNS endorphin pathways like?
similar to brain reward pathways
What are some maintenance medications for opiate abuse?
- naltrexone
- methadone
What is the active component of cannabis?
THC
How many cannabinoid receptor types are there?
Two: CB1 and CB2
What are some endogenous cannabinoids?
2-AG and anandamide
Where is the CB1 receptor located?
Pretty much through the body and CNS/PNS
Where is the CB2 receptor located?
immune system
What type of receptors are the CB1 receptors?
GPCRs which signal through Gi and inactivate pre-synaptic calcium release
What is the effect of CB1 receptor agonists?
Inhibition of motor performance
Why do CB1R agonists affect motor movement?
Because they are highly expressed in the GP and striatum
What is unique about the CB1 receptor?
It engages in retrograde signaling
What is the effect of CB1 receptors in the hypothalamus linked to?
appetite regulation
