Genetics; Routes of Administration Flashcards
twin studies
monozygotic twins have more similar rates of addiction than heterozygotic twins
adoption studies
more likely to display birth family than adopted family habits
genetic predispositions
randomized control trial
double-blind, randomized, and controlled clinical studies
more informed
reward deficiency hypothesis
nature then nurtured
self-medicating a chronic deficiency in subjective hedonic tone that is genetic by using additive drugs
neurobiological causes of reward deficiency hypothesis
- deficiency of D2 receptors in the reward circuit = less effective signaling
- an aberration (impaired functioning) in D3 receptors in the reward circuit
- deficiency in presynaptic dopamine levels in the nucleus accumbens = terminals don’t release enough; affect pathway
mice preferences for addictive drugs
bred mice sort themselves into high or low seeking behavioural categories by repeated exposure to addictive drugs - Lewis vs Fischer rats
addictable mice
display a pathological atrophy of the neurofillamentary transport system for the dopamine synthesizing enzyme tyrosine hydroxylase in dopaminergic VTA neurons
= deficiency in dopamine synthesis
deficiency in dopamine synthesis in addictable mice
concomitant aberrations in post-receptor signal transduction mechanisms compared to drug-avoidant animals
molecular event contributes to psychological effect
striatal dopamine D2 receptor expression level - Ritalin
predicts subjective experience with methylphenidate
healthy male subjects with naturally high dopamine synthesis report dipleasurable experience with Ritalin
subjects with deficits in striatal D2 levels report a pleasurable experience
PET scan
PET scan
measuring radioactivity - measure activity in the brain
label D2 receptors - show striatal D2 receptor level expression
animal attributes predict vulnerability to addiction
high:
reactivity to stress
novelty induced locomotor activity
novelty-seeking
trait impulsivity
epigenetics
chemical modifications that determine gene transcription are inherited
human attributes predict vulnerability to addiction
sensation- and novelty-seeking
trait impulsivity
anti-social conduct disorder
past traumatic experiences or mood-related conditions
Striatal D2 levels in monkeys
high levels in socially dominant monkeys
low levels in submissive monkeys
differences amplified in socially-housed monkeys
submissive - lower D2 receptor levels and higher vulnerability to cocaine self-administration
impulsivity and dopamine biology pre-dispose self-administration in rats
reduced D2/D3 receptor expression in NAc of drug-naive high-impulsive rats
high impulsive rats display greater cocaine self-administration
reactivity and impulsivity predict a shift to compulsive drug-taking
high reactivity to novelty predicts a tendency to self-administer addictive drugs
high impulsivity rats display higher compulsive cocaine self-administration
biopsychosocial model of addiction
nature sets a dopamine level that is nurtured by social interactions
- drug exposure
- dopamine (and D2 receptor) functionality
- behavioural traits
- social factors (dominance)
all contribute to model of addiction
polygenecity
multiple genes are involved in addiction
predispositions
tendency/vulnerability to suffer from a particular condition
link between a gene and addiction
genes + proteins → pharmacodynamics → physiology → behaviours
SNPs
single nucleotide polymorphisms
base pair differences within coding and non-coding regions between alleles of genes in the population
transgenerational epigenetic effect
methylation affects rate of transcription and gene expression → traits passed on to offspring
studying genes
genome-wide association studies
dopamine networks → dopamine transporters, receptors in VTA + NAc
neuronal adhesion - important for plasticity
DNA/RNA processing
transcriptional regulation
cell structure
addiction is viewed as a learning disease
addictive drugs hijack the learning/reward circuit
association between dopamine + reward → learning
genetics x environment
play a 50-50 role to produce behavioural phenotypes of addiction
routes of administration
inhalation (smoking)
injection (IV, IM)
insufflation (snorting)
oral (chewing tobacco, sublingual - not swallowing)
transdermal patch
ingestion
Faster absorption routes
faster delivery to the brain → higher peak - more dopamine; correlated with stronger high; drug does not remain in the brain for very long
slower absorption routes
peak not as high, less intense high, prolonged duration in the brain - sustained release
bioavailability
amount of administered drug reaching systemic circulation
inhalation
drugs cross into blood by diffusion = smaller hydrophobic drugs are absorbed the fastest
7-10 second onset
2-4 hour duration
5-99% bioavailability
shortest circulatory path to brain
huge surface area for absorption
risks: emphysema, COPD
injection
10-20 second onset
2-4hr duration
i.v. = 100% bioavailability
2nd shortest circulatory path
subcutaneous and I.M absorption depends on diffusion into tissue and blood flow
risks: necrosis, track marks, infection
insufflation
10-45 min onset
5-8 hr duration - extended release
up to 80% bioavailability
longer pathway to the BBB
risks (snorting cocaine): erosion of upper palate
ingestion
20-45 min onset
6+ hour duration
5-99% bioavailability
first pass metabolism; stomach pH can alter chemistry, degrade
risks: irritation, emesis
drugs must…
reach brain to bind receptors → effects
route affects bioavailability
abuse potential
quicker onset triggers greater euphoria
very high: heroin IV, crack
very low: hallucinogens, ingested drugs
dose response curve
describe relationship between drug concentration and effects
efficacy
maximal response to drug
Emax
potency
highest effect at lowest dose (concentration dependence)
lower ED50 = more potent
therapeutic index
difference in quantitative response - beneficial vs toxic response
LD50/ED50
changes in the presence of other drugs
synergism
additive effects - effect of multiple drugs is greater than individual effects
antagonism
decreased overall response
compete for binding with agonist
drug half-life
time to remove 50% of [drug] from circulation
kinetics
describe elimination - zero order, first order
change with repeated use → tolerance
zero order
linear curve of elimination
first order
exponential curve of elimination
