Lecture 20- Addiction Flashcards
How prevalent is drug use?
-extremely
How prevalents is alcohol and tobacco use? (legal drugs)
-more 13-year-olds have drunk alcohol than not -that’s 350,000 13-year-old drinkers in England and Wales alone
How prevalents is illicit drug use?
•cannabis: 34% aged 14+ have used in lifetime • opioids (inc. heroin): 2.3%, or 384,800 people • amphetamines:9.1%(or,1 in 5 of those aged 20-29)
Is drug use protracted?
-yes -Estimates those aged 50+ seeking drug abuse help will rise from 1.7m in 2000/01 to 4.4m by 2020
How much money do drug and alcohol abuse cost every year in Australia?
-56 billion dollars
What makes drugs attractive?
-reinforcement - first while using the drug get positive, these are the immediate effects, euphoric -then have negative symptoms after the drug taking (hangover) which also incentives further drug use to avoid the negative effects
What are the positive reinforcements?
-Euphoria -anxiolysis -pleasure -Drug taking associated with “happiness” and therefore repeated
What are the negative reinforcements?
-dysphoria, anxiety, depression -Drug taking renewed to prevent occurrence of negative symptoms -sometimes people take drugs to escape the negative effects
What was the experiment looking at dopamine and serotonin levels in a rat that self administered cocaine?
-Release of chemicals in the brain of rats during a 12 hour binge of cocaine self-administration. -Note the reduction to levels below pre-drug basal. -This is thought to act as a cue to re-consume. -Cocaine causes a high degree of psychological dependence -measuring the release of neurotransmitters in nucleus accumbens (dopamine and serotonin) -self administer cocaine, for 12 hours as much as they want. then have increase in dopamine and serotonin, after stopping to take the drug= goes lower than where the neurotransmitter started= at this point if animals given the opportunity to administer then do so!
What is an addiction?
•A chronic relapsing disorder which consists of a compulsive pattern of drug-seeking and drug taking behaviour – takes place at the expense of other activities – persists despite adverse consequences (these can be variable, liver damage, social aspects etc. the consequences are not just to the drug user) -another definition: the loss of control over drug use, or the compulsive seeking and taking of drugs despite adverse consequences
How much of the global burden of diseases comes from alcohol and drugs?
• Almost 10% of the global burden of disease comes from the use of alcohol, tobacco and illicit drugs (WHO, 2002)
What are the risk factors involved in why some people become addicted while others don’t?
- Genetics, environment & biology contribute to addiction
- What are some risk factors involved in addiction?
- these dictate if you become an addict or not
- genetics: very complicated, not a single gene disease
What are some examples of strong candidate genes affecting the likelihood of addiction?
-mutation in the dopamine transported the D2 -many don’t replicate across populations and races etc, -then also trophic factors: BDNF -these are genes that are likely implicated in addiction -5HTT= in depression, alcoholism -protective mutation is= in the Han Chinese population, aldehyde dehydrogenases mutation gene, get drunk really quickly= so lower alcoholism,
How does one become addicted? (cartoon)
-cartoon demonstration of someone going fron an occassional drug user (social drinking) to someone who cannot control it
What is the simplified brain circuitry involved in rewardM
- predominant component is the green (dopamine projections) from the VTA (ventral tegmental area) to nucleus accumbens, dorsal striatum, prefrontal cortex, amygdala and hippocampus
- also critically important: glutamate from prefrontal cortex to nucleus accumbens and striatum
- also cortical tegmental projection: from prefrontal to VTA, regulates dopamine neuorns
- also excitatory from hypothalamus to VTA
What is the mesolimbic dopamine pathway?
• Involved in goal-directed learning • Reinforces behaviours central to the survival of both individual and species (eg. acquiring food, procreation) (dopamine is important for goal directed learning, have to have the dopamine system to learn goal direcetd behaviour, ) • Simplistically, drugs of abuse“hijack”this system. (activate this system more than they would be active naturally) • Rhesus monkeys administer cocaine over food, persisting to the point of death
What do drugs affecting the brain end up doing?
-increase in dopamine in the brain -act on the connection from the VTA to nucleus accumbens -all increase release of dopamine from nucleus accumbens
How do opiates increase dopamine at nucleus accumbens?
-disinhibt the cell body,normally inhibited by the GABA neuron, now can fire more -Disinhibit DA neuron
PIC4How does nicotine increase dopamine at nucleus accumbens?
- acts in the same way as opiates but direct
- direct stimulation of the dopaminergic neuron
How does caffeine increase dopamine at nucleus accumbens?
-inhibits feedback from GABA neurons
How does cocaine increase dopamine at nucleus accumbens?
-blocks re-uptake of dopamine at the synapse (at the terminal)
How do ethanol and amphetamines increase dopamine at nucleus accumbens?
- evoke release from terminal directly
- in amphetamines: actively pumps the dopamine
What happens in the circuits when someone is addicted?
- normal: motivational limbic circuit driving the motor subcircuit, the connection that is key is the one from prefrontal cortex to nucleus accumbens! key part of the decisiion making cicruitry
- addicted: the circuit is disturbed , the connection between prefrontal cortex and nucleus accumbens
- In the addicted state it is proposed that the PFC regulation of accumbal outlfow is diminished
What are the two competing circuits in the goal directed behaviour?
two competing circuits:
- one is initiating reward seeking going from prelimbic to nucleus accumbens core= addiction
- separare cicruit going from intralimbic cortex to nucleus accumbens shell= inhibition
- the intralimbic (extinction) one is the abstinents one and the prelimbic one is the relapse one
- Note differential role of prelimbic vs infralimbic cortex in relapse vs extinction
What do you see in the prelimbic parts of the brain of an addicted animal?
-Prelimbic cortex neurons are hypoactive in“addict” like rats who are resistant to punishment (go for drug even if punished) -experiment looking at the circuit: -resistant= addict like animals, resistant to punishment -these have hypofrontality, must give more potential to fire an action potential, also synaptic plasticity impaired. LTD is dramatically impaired, this is associazed with reduced expression of glutamate receptors Mglu2 and Mglu3, gportein coupled metabotropic, midulate glutamate neurons, -impaired hypoactive prelimbic neurons -impaired synaptic activation and that is associated with the glut recepotrs -Synaptic plasticity is impaired in prelimbic cortex of “addict” like rats
What do you see in nucleus accumbens in an addicted animal?
-glutamegergic synapse was involved -In rats, cocaine self-administration leads to deficits in NMDA receptor-mediated corticoaccumbal LTD. This recovers in addiction resistant rats (majority), but remains impaired in addiction vulnerable (minority) rats. Suggests transition to addiction related to persistent corticostriatal dysfunction. -Here what happens in the nucleus accumbens : - synaptic plasticity impaired LTD (all animals, addicted and non- the ones resistant to addiction andt he ones prone: - yellow animals (resistant to addiction) have inbuilt recovery mechanism, so impairment in LTD recovers after few months -but in the addiction prone ones= it doesn’t recoevr!
What is the altered glutamate homeostasis in addiction
- it is also caused by neurochemical effects:
- altered glutamate homeostasis
- normal: glutamate released, sucked up by transporter on an astrocytes so the glutamate doesn’t activate receptors that it shouldn’t
- addicted: dramatic downregulation and reduced function of teh glutamate transporter,so extracellular glutamate levels go up, so there is extra opportunity for extrasynaptic activation
- insertion of AMPA recpetors into postsynaoptic neuron membraneinstead of extrasynaptic
What can the disruption in glutamate homeostasis in addiction be corrected by?
drug called N-actelycysteine that can completely restore this system back to normal, it restores the expression and function of the glitamate transporter, restores glutamate levels extracellularly and stops animals relapsing into drug use
What is the N-acetylcysteine trial?
-“For the 16 subjects who completed the study, 9 subjects terminated use of cocaine completely during the medication phase, 5 subjects substantially decreased their use, and 2 demonstrated no change in cocaine use.” -give them the drug and see what happens
How can you model drug seeking behaviour in animals experimentally?
• Self-administration – Continual access – Restricted access – Operant responding • Conditioned place preference (Pavlovian conditioning) • Extinction / reinstatement – “relapse” • Sensitization (drug-induced plasticity) • Withdrawal syndrome
How can the mouse self-administer?
-operant responding -the mouse self administer: -presses lever, light comes on and then delivery of ethanol -in 20 mins will press it 140 times -from this can model the circuitry and relapse
How do you model relapse in animals?
- Modelling relapse in animals: extinction - reinstatement
- How do you model relapse?
- allow the animal to acquire the self administering behaviour
- then put into rehab, when pressing lever the light doesn’t come on now
- then representing the cue with drug, small amount of drug and see dramatic increase in drug seeking, starts pressing the lever more
What is the circuitry model of drug seeking?
- the base circuitry involved in relapse
- final common pathway: prefrontal cortex, nc, vpalid, implicated in all forms of relapse
- other parts of the brain implicated in other parts of the relapse
How does lateral hypothalamus connect to VTA?
orexin (or HCRT)
- neuropeptide
- lateral hypothalamus has a strong excitatory projection to the VTA
- utilize orexin and glutamate
- orexin release onto VTA is critical for psychostimulant induced synaptic plasticity and rives drug seeking
What are orexins?
The Orexins (Orexin A and Orexin B) are neuropeptides involved in arousal, appetite & reward
What do orexins act on?
orexin acts on two GPCRs = orexin A onOX1R and orexin B on OX2R
Will animals reinstate drug-seeking following extinction & protracted abstinence?
- train animals to self administer alcohol, then go through extinction, then 5 months abstinence
- would they reinstate?
- would they remember the significance of the cue and is orexin involved= yes and yes
- (i) Early reinstatement straight after extinction
- (ii) Late reinstatement, 5 months withdrawal after extinction
What is implicated in the relapse behaviour?
-animals reinstate drug seeking behaviour even after extinction and protracted abstinence and OX1 receptors are implicated at both time points -even after delay: touches the lever to get ethanol -if orexin blocked= no reinstatement
When are orexin-containing neurons activated?
-Orexin-containing neurons are activated during cue-induced reinstatement to alcohol-seeking
Where does the orexin system interact with the final common pathway?
-Layer V cells in prelimbic cortex express Orexin1 receptors that are postsynaptic to OxA input -in prelimbic cortex= direct monosynaptic projection from the lateral hypothalamic orexin containing neurons, up to layer 2, 3 cells in the prelimbic cortex and mainly layer 5 cells -(lateral hypothalamus also projects to nucleus accumbens)
Anatomic Loci for OX receptor modulation of reward-seeking?
-inputing the orexin on the final common pathway -does the orexin act on the prefrontal cortex directly?
What is the SB334867?
-antagonist to orexin
Does Intra-PrL SB334867 reduce cue induced reinstatement of sucrose seeking?
-no it does not -it is reward specific -anatomically and reward specific
Does Intra-VTA SB334867 reduces cue-induced reinstatement of alcohol seeking?
-yes
What are the potential anatomic loci for the orexin input into the final common pathway?
- not only is the VTA is an important loci where orexin is implicated in reward conected behaviour
- also active in prefrontal cortex for integration of the salience of the cue
- they were using an antagonist to the receptors, if the endogenous
- cue salience, cue integration and reactivity
Summary?
• Addiction essentially represents a state of drug- induced neural adaptation of specific pathways • Epigenetic consequences of long-term drug use • Clinically, relapse is the major problem • Full circuitry still to be established
