Lec 43 Addiction Flashcards
What is intoxication?
substance-specific acute syndromes associated with impaired function
What is tolerance?
reduced effect of a drug given at a constant dose [need escalating dose to get same effect]
What is sensitization?
reverse of tolerance –> increasing drug effect at constant dose
What is dependence?
altered psychological state induced by repeated exposure to a drug
–> shows withdrawal symptoms when drug is discontinued
What is addiction?
- compulsive seeking and taking of drug despite adverse consequences
What is craving?
intense urges to take a drug
What is relapse?
return to drug abuse after period of abstinence
What are the CAGE screening questions for alcohol?
- thought about cutting down
- annoyed when others criticized
- felt guilty
- eye opener
What are the AUDIT-C screening questions?
- how often do you have a drink containing alcohol
- how may standard drinks containg alcohol do you have on a typical day
- how often do you have six or more drinks on one occasion
What is reward?
positive emotional effects
What is reinforcement?
stimulus that causes reponse to be maintained and increased
positive –> increase behavior to get positive reward
negative –> increase behavior to end punishment
What is the most important brain reward circuit
the mesolimbic dopamine system
DA neurons in VTA of midbrain –> nucleus accumbens [in ventral striatum of limbic forebrain]
What is activity of VTA dopamine neurons from reward, from expectation of reward, from absence of expected reward, vs from unexpected reward?
reward: activates VTA
expectation of reward: activates VTA
absence of expected reward: inhibits VTA neurons
unexpected reward: activates neurons even more than any of the others
What is effect of drugs of abuse on mesolimbic dopamine path?
- they activate VTA-nuc accumbens
- with repeated exposure, cause changes in circuit that dampen its sensitivty –> natural rewards no longer able to activate VTA neurons, only the drug of absue powerful enough to produce effect
—-> thus pt only feels normal when drug is on board
What is role of hippocampus in drug addiction?
- involved in drug-related memories
What is role of amygdala in drug addiction?
- normally: establishes association between environmental cues and negative emotional experience = fear conditioning
- with drugs: establishes association between environmental cues and positive emotional experience of drug use
What is the role of frontal cortical regions in drug addiction?
- each area functionally connected to VTA- nucleus accumbens circuit
- their function = attention, working memory, planning, impulsivity
What is hypofrontality?
- addiction is associated with hypofunction of frontal cortical regions –> increased impulsivity and compulsivity
Which 3 drugs mimic neurotransmitters by activating receptors?
- morphine
- nicotine
- marijuana
What 2 drugs block the dopamine pump?
- cocaine
- amphetamine
What 3 drugs activate or inhibit channels?
- alcohol
- PCP
- ketamine
What is action of opiates?
- opioid receptor agonists [primarily mu]
- mimic enkephalins/endorphins/dynorphins
- inhibit inhibitory GABA neurons in VTA –> more activation of VTA DA neurons
effects: analgesia, euphoria, sedation, constipation, respiratory depression
- physical dependence and tolerance to analgesic effect can be independent from
receptor signaling = Gi
What is action of cocaine?
- blocks monamine reuptake inhibitor –> increased effect of DA [and 5HT, NE] transmission
- inhibition of DA reuptake at nucleus accumbens nerve terminals = more reward action
effects: euphoria, increased arousal/self-cofidence, decreased fatigue/appetite
repeated chronic use –> tolerance of positive effects, sensitization of adverse effects
receptor signalling = Gi and Gs
What can be used to treat opiate overdose?
- opioid receptor antagonists = naloxone, naltrexone
What is action of amphetamines [amphetamine/ methamphetamine/ ritalin[methylphenidate]]?
- bind to DAT [dopamine transporter] –> pumps more DA [and 5HT, NE] into the synapse –> increased effect of DA transmission
- increase DA in nucleus accumbens
effects: euphoria, increased arousal/self-confidence, decreased fatigue/appetite
repeated chronic use –> tolerance of positive effects, sensitization of adverse effects
receptor signalling = Gi and Gs
What is action of nicotine?
- agonist at nicotinic ACh ligand-gated channel receptors
- directly activates VTA DA neurons or acts via glutamate nerve terminals [that normally activate DA neurons]
effects: mild euphoria, increased alertness, muscle relaxation, analgesia, nause
What is action of PCP?
- non-competitive antagonist of NMDA ligand-gated glutamate receptor
- inhibits glutamate inputs to nucleus accumbens –> same net functional effect as activation of DA/opioid receptors
effect: psychotic state similar to schizophrenia
What is action of alcohol?
- acts only at very high conc = low affinity for binding sites in the brain
- diffuse action, not well characterized
- acts first on GABA-A receptors –> then NMDA –> then voltage-gated channels
- activate GABA-A = anxiolytic/sedative
- inhibit NMDA-R: dissociative, psychotic effects
- inhibit voltage-gate ion channels: coma, death
What brain adaptations underly addiction
- neuroplastic changes
- hypofrontality
- altered gene expression
What neuroplastic changes occur with drug use?
- changes in reward (VTA-NAc) and learning (hippocampus, amygdala, PFC) circuits
- synaptic + electro adaptations persist for years, trigger sensitization, tolerance, craving, relapse, reduced response to natural reward
What is the mech of cAMP path alteration in presence of chronic opiate exposure?
- opiate initially inhibits cAMP synthesis by stimulating Gi
- with repeat exposure –> cell undergoes homeostatic response to upregulate CREB [camp response element binding protein] –> increased synthesis adenylyl cyclase and PKA
- -> increase capacity of cAMP path –> opposes opiate inhibition = tolerance
when drug discontinued –> cAMP continues to be upregulated and now unopposed = abnormal activity in cell after absence of drug = dependence/withdrawal
Is addiction genetic?
50% of risk is genetic –> no specific genes identified
What is methadone?
mu opioid receptor agonist = prodrug of morphine with long half life, allows for no withdrawal and less of a high
What is analogous to methadone but for nicotine addiction treatment?
nicotine patch or chewing gum
What is burprenorphine?
partial opioid agonist
thus causes enough agonist to satisfy drug craving but taking more buprenorphine will not cause high
What is varenicline?
- new treatment for nicotine addiction
- partial agonist at nicotinic cholineragic receptors [target of nicotine]
- like buprenorphine but for nicotine
What is naltrexone?
opioid receptor blocker
prevents ability of opiates to produce their effects
can also be used for alcohol and nicotine addiction
What are CB1 antagonists [eg rimonabant]?
- used for cannabinoid addiction
What is acamprosate?
- used for alcohol addiction
- reduces glutamatergic function
