Abstinence & Incubation of Drug-Seeking (PDF)

Abstinence & Incubation of drug-seeking Abstinence Procedure Reinstatement procedure is very useful, but there is one important caveat: EXTINCTION - Pressing lever without getting the drug (doesn’t happen in humans) - brain systems involved in reinstatement following extinction are di erent from th...

Abstinence & Incubation of drug-seeking Abstinence Procedure Reinstatement procedure is very useful, but there is one important caveat: EXTINCTION - Pressing lever without getting the drug (doesn’t happen in humans) - brain systems involved in reinstatement following extinction are di erent from the ones involved in drug-seeking following abstinence - Di erent circuits/areas may be more important in some behaviours than others FORCED ABSTINENCE 1. Training 2. Abstinence: removed from environment - can be days, months 3. Drug-seeking test: put back in same/di erent environment - Baclofen/Muscimol (B/M) and vehicle - B/M: GABA-R agonist = inhibition of area where injected McLaughlin & See / Fuchs et al, 2006 - Animals trained to SA cocaine, then forced abstinence - 15-19 days abstinence or cue- or context-induced reinstatement - Brought back with inactive lever (extinction) - Inactivation B/M of the BLA, dmPFC, dlCPu (dstriatum) - When brought back to environment = higher responses during extinction= cravings - dmPFC shut down: same e ect - BLA shut down: slight decrease but not signi cant - D striatum shut down: signi cant reduction (similar to SA phase) - when exposed to the cues = reinstatement - When TTX injected = block reinstatement - Prelimbic cortex (dPFC) shut down (TTX): reduction of reinstatement - when exposed to di erent context = extinction - Brought back to context A with inactive lever = reinstatement - dmPFC shut down (TTX) = block reinstatement ff fi ff fi ff ff ff ff Conclusion: - BLA and dmPFC play di erent roles in cocaine seeking after abstinence/extinction training - Cocaine seeking after abstinence may have better face validity as a model induced relapse in humans - Closer to actual human experience Incubation of drug seeking - humans will relapse long after abstinence - Craving for drugs increases at the beginning of abstinence and remains stable for a long time - Addicts do not forget about the drug - Animals start extinction after 3 weeks show higher response vs those who started 1 day after INCUBATION OF DRUG SEEKING: HEROIN Shalev et al, 2001 Phase 1: training & extinction - All rats trained to SA heroin, then groups with di erent time-delay to extinction (5 groups) - Group 1: started extinction after 1 day ( 5 extinction sessions over 5 hours) [group 2 = extinction started after 6 days, etc.] - Extinction curve over time - 1 day: equal response and extinction curve - 6/12/25 days: increased response then extinction curve - (inverted U shape) - Starts with increase in abstinence delays correlates with increase in response = craving - The longer you wait, the more the craving and then decreases - Over time, it goes down - Highest delay = lower craving Phase 2: trigger = stress - after extinction (same day) - Footshock - induced reinstatement: - 1 day incubation: little e ect of footshock - Higher e ects for 6/12 days incubations - Stress-induced reinstatement showed more strongly as incubation time is increased - Lower e ects (but higher than day 1) for 25+ days INCUBATION OF DRUG SEEKING: COCAINE Grimm et al., 2001 Phase 1: training and extinction - trained to SA cocaine, then di erent time-delay to extinction (no cues during extinction) - Increase in abstinence delays correlates with increase in response = craving - More and more craving the longer the incubation Phase 2: cue-induced reinstatement - After 6h, responses are low , so they introduced cues - cue-induced reinstatement: keeps increasing over time = craving - Craving incubates: increases over time ff ff ff ff ff ff ff ff - In a di erent study, time-dependent increases were observed even after 3 months - Why di erent vs heroin? Unknown - Underlying mechanisms may be di erent for stimulants and opiates (and alcohol) INCUBATION OF DRUG SEEKING: SUCROSE - Same experiment: SA with sucrose, then extinction without cues - cue-induced reinstatement of sucrose-seeking with di erent time-delays - Shows incubation of craving (similar to heroin) exists for natural rewards - Inverted U shape - Not necessarily caloric foods, simply needs to be sweet INCUBATION OF DRUG SEEKING: SMOKING (HUMANS) - Same experiment: SA with smoking, then extinction without cues - cue-induced reinstatement of smoking with di erent time-delays - Using pictures smoking-related - While holding lit cigarette - Shows incubation craving INCUBATION OF DRUG SEEKING: ALCOHOL (HUMANS) Li et al., 2015 - Same experiment: SA with alcohol, then extinction without cues - cue-induced reinstatement of drinking with di erent time-delays - Using pictures or olfactory cues - Shows incubation of craving (up to 2 months) INCUBATION OF DRUG SEEKING: BRAIN ADAPTATIONS - DA,TH, DAT not related to incubation Cue-induced reinstatement of cocaine seeking: - brain derived neurotrophic factor (BDNF): growth factor involved in synaptic plasticity - Involved in plasticity, maintenance of neurons/synapses - Special Rs - If inject BDNF directly in NAc = increase responses to cues associated with sucrose - Nerve growth factor (NGF): Experimental control growth factor because it is not colocalized with mid-brain DA neurons Grimm et al., 2003 Phase 1: training & extinction - trained rats to SA cocaine Group 1: tested 1 day after SA training Group 2: 30 day abstinence Group 3: 3 months abstinence Then brains tested in vitro ff ff ff ff Results: - using western blotting to measure level of di erent proteins (BDNF & NGF [Control]) - NGF: would change every protein in the brain - Amygdala: - BDNF levels increase as incubation time increases - NGF: same level (almost decrease) as incubation time increases - i.e. change does not happen to every growth factor - NAc & VTA: - BDNF levels increase as incubation time increases - NGF: same level (almost decrease) as incubation time increases - i.e. change does not happen to every growth factor - Changes in BDNF correlated with the change in behaviour Lu et al., 2004 - inject BNDF directly in VTA - 10 days of cocaine SA, then received an injection BNDF directly in VTA - Tested after 3 days or after 10 days Results: - Day 3: show higher number of responses (more craving) - By increasing the amount BNDF in VTA = induce craving - Even greater increase in response on day 10 - Animals are responding more under extinction - BDNF is at least involved in the increase of craving over time when abstinent - How? Unknown INCUBATION GO COCAINE SEEKING (SIMILAR MECHANISMS FOR OPIOIDS [OXY]) - Long-term adaptation in NAc AMPA Conrad et al., 2008 Phase 1: training & extinction - cocaine SA/saline for 10 days - Saline: not a lot of response - Abstinence for 1 day or 45 days Phase 2: cue-induced reinstatement - increase level of responses (nose-pokes) at 1 days, even greater at 45 days Phase 3: in vitro - collected NAc tested with western blotting - Quantify total levels of AMPAR & amount of subunits of AMPAR - GluA1: increase from day 1 to day 45 - GluA2: no increase from day 1 to day 45 (similar to saline) - GluA3: no increase from day 1 to day 45 (similar to saline) - Allowed to measure levels of AMPAR already imbedded into the membrane (surface) - Functional R: - GluA1: no change - GluA2: reduced amount from day 1 to day 45 (similar to saline) - More R that are GluA2 lacking (permeable to calcium = more excitable) - GluA3: no change - AMPAR in membrane are most likely GluA2-lacking fi Phase 4: - use of antagonist speci c to AMPAR GluA2-lacking (Naspm) - Increase in responses from day 1 to day 45 for animals receiving vehicle - Reduction of responses (reduced incubation) from day 1 to day 45 with Naspm - Probably because there are not many GluA2-lacking Rs on membrane - Cocaine/sucrose responses are the same regardless if they get Naspm - Naspm e ect on craving , not REWARD itself Other relapse models (voluntary) - Reinstatement procedure is very useful but in humans, no real extinction phase - Good face validity - Poor predictive validity: ability for model to predict if particular manipulation will work in clinical studies - Because of extinction phase, model doesn’t translate into human condition - Try to cause animals to voluntary decide to stop using the drug - Alternative reward - Punishment ALTERNATIVE REWARD (CONTINGENCY MANAGEMENT): FOOD, SOCIAL INTERACTION - O er alternative: palatable food, social interaction, Borges et al., 2022 Phase 1: - animals trained to press speci c lever to open a screen door connecting to adjacent space with another rat without crossing over - Animals will work very hard for that - animals trained to press di erent lever for drugs - then provide choice: both levers come out - If drug = no access to rat - If rat = no access to drug - Opportunity to choose again next time Results: - big signi cant exclusivity to social interaction over drugs - Heroin, meth - Through that, you can have rats voluntarily abstain Phase 2: reinstatement - introduce trigger to see if rats will choose drugs PUNISHMENT-INDUCED ABSTINENCE ff fi ff ff fl ff fi ff - model negative e ects of drug taking/seeking - Big reason for people to abstain - In rats: punish drug seeking - Lever for drugs = foot shock - Separating drug seeking to drug taking: seek-take procedure - Seeking has exibility - Taking: very rigid, same way of taking drugs, same e ects Phase 1: seek-take procedure - animals press of seek lever: VI: animals doesn’t know how many times to press to get drugs - At end of ratio, seek lever leaves, take lever comes in to get drugs Phase 2: punishment - once animal has learned - Introduction of punishment for seeking, not for taking - When pressing seek lever: 30% of time = foot shock instead of take lever - Seek lever now has risk - If foot shock is strong enough: rats stop/reduce seeking drugs - Voluntary abstinence - But some are very persistent Phase 3: reinstatement - when animals have voluntary abstained, introduction of triggers to induce relapse - In this case stress: food deprivation - Provide them the seek lever - Hungry: ignore risks and increase responses - Relapse Results: - shock/punishment resistant: will need very high levels of shocks to stop drug seeking - Shock/punishment sensitive: will need little intensity of shocks to stop drug seeking