the addicted brain Flashcards
list three classes of addictive drugs
what do they ave in common?
1) psychostimulants
– e.g. cocaine, amphetamines, MDMA
– block monoamine transporters (DA, NA)
2) opioids
– e.g. opium, morphine, heroin
– opioid receptor agonists
3) cannabinoids
– e.g. cannabis
– cannabinoid receptor agonist
COMMONALITY: activate dopamine receptor to place more dopamine in synaptic cleft of appropriate neurons
what are 8 signs of substance dependence?
1) tolerance
2) withdrawal
3) use increases over time despite intent
4) unsuccessful efforts and persistent desire to stop
5) much time spent trying to obtain drug and recovering from use
6) activities reduced/given up because of substance use
7) continued use despite known or experienced harm
8) three or more symptoms in the past year
what are three key features of addiction?
compulsion: excessive or uncontrolled use
withdrawal: cluster of symptoms when drug is withheld after a period of continuous use
relapse: drug-taking resumes after long abstinence
what is the mesocorticolimbic pathway and how is it involved in drug addiction?
REWARD, EUPHORIA, SALIENCE
• dopamine afferents originate in the VTA
• project to nucleus accumbens
• from nucleus accumbens, project to amygdala, pre-frontal cortex and cingulate
• prefrontal cortex especially associated with drug seeking
• noradrenaline also used as neurotransmitter
PERSECERATION, HABITS
• nucleus accumbens receives glutamatergic innervation from hippocampus, PFC and amygdala
• nucleus accumbens has glutamatergic projects to pallidum and thalamus
how is addiction positively / negatively reinforced
addiction is maintained by the positive aspects of drug use (euphoria, memory of pleasure)
addiction maintained by negative aspects of abstinence (physical and psychological effects of withdrawal)
how does long-term addiction change the response to a drug?
how are these changes mediated by cellular and molecular events?
addict adapts to the drug
• effect of drug decreases = counter-adaption
• enhanced effect of drug = sensitisation
behavioural changes mediated by molecular/cellular changes
MOLECUAR
• changes in level / type of neurotransmitter receptors
• change in neurotransmitter release
– TF site called cAMP response element binding (CREB). CREB response upon activation of dopamine receptor. may mediate sensitisation
– c-Fos and Acute Fras peak in acute phase of drug use. ∆FosB increases into chronic drug use
– NMDAR NR2B controls excitotoxicity response. changed expression in alcohol withdrawal. mediates tolerance
CELLULAR
• change in neurocircuitry (learning + memory)
• alcohol → widespread pruning of dendrites, demyelination, selective cell loss in cortex
• cocaine → increase branching of dendrites in NAc and PFC
• opioids → decrease number of dendrites in NAc and dopamine neurons
what neural pathways mediate withdrawal symptoms?
dysphoria, malaise, negative emotions are induced by CRH + noradrenaline + dynorphin inputs from amygdala to stria terminalis
decreased reward sense associated with glutamatergic input from stria terminalis to ventral striatum
how does counter-adaption occur in alcohol abuse
alcohol inhbitis NMDA glutamate receptors → disrupts glutamate-mediated transmission
as a result, receptors increase their level and response → tolerance to alcohol
no alcohol = sensitivity to glutamate + disproportionate response = withdrawal symptoms
this can lead to dependence and addiction
what is sensitisation and how does is contribute to addiction?
hypersensitivity to drug or drug cues (not necessarily a “like” or positive feeling)
contributes to craving and relapse behaviour ∴ very important component of addiction
what are the benefits of using animal models opposed to humans?
humans:
• ethical issues around forced addiction and withdrawals
• can’t use brain tissue for study
animals:
• can induce addiction and withdrawal
• can use genetic manipulation
• can’t answer questions about how they feel :(
how does forced dependence differ from conditioned dependence in animal models (during drug)?
forced:
– lace food/water with drug or drug in air
– useful for general effects of drug
– not useful for addiction → no voluntary component
condition:
– choice between drug and none
– self administration
– drug can be linked with stimulus
what is the fixed vs progressive ratio approach in animal models (during drug)?
fixed ratio:
• fixed number of responses to obtain drug
• e.g. one lever press = drug
progressive ratio:
• number of responses to obtain drug increases over time
• animal must work to obtain drug
• continue to increase number until animal gives up (break point)
what is the choice paradigm in animal models (during drug)?
give animal the choice of drug vs “incentive stimuli” (IS)
concurrent:
• measure number of times drug is chosen over IS
discrete:
• trial ends after one choice
• measure number of trials in which drug is chosen
what is the extinction paradigm in animal models (after drug)?
replace drug with saline in self-administering apparatus = forced abstinence
duration of extinction = time until last attempt of self-administration / no. of attempts per time
measures the duration of craving
what is conditioned reinforcement and what does it measure?
associate “neutral reinforcer” with drug → place if often used
measure the duration of memory of association
indicated the role of non-drug cues in addiction
