Relapse and Reinstatement PDF

Relapse and Reinstatement Relapse to drugs - most addicts will relapse - Big problem of treatment - Replacement therapies - Antagonist, reverse agonist - AA/NA - Dramatic drop in abstinence and stable at about 25% - Success rate is not good TRIGGERING FACTORS: - re-exposure to the drug, or other dru...

Relapse and Reinstatement Relapse to drugs - most addicts will relapse - Big problem of treatment - Replacement therapies - Antagonist, reverse agonist - AA/NA - Dramatic drop in abstinence and stable at about 25% - Success rate is not good TRIGGERING FACTORS: - re-exposure to the drug, or other drugs - Priming e ect: prime the behaviour with brief exposure - Re-exposure to stimuli associated with drugs - Very di cult to avoid - Cues over time become powerful in guiding behaviour (saliency) - Immediate/discrete cues: i.e. needle, powder, smell, people, etc. - Stress - Following exposure to stress, there is an increase in craving - Withdrawal (?) - Conditioned withdrawal: - Comes up as a factor, but di cult to show in controlled circumstances or animal studies - Di cult to study: ethical issues - Now: using smartphone apps - Even more di cult to study underlying brain mechanisms - Post mortem, imaging studies - Manipulations are limited: TMS only Cue-induced self-report (Reid) - subject are not abstinent, recruited, and asked to stop using for a short period of time - Exposed to cocaine-associated cues - Craving increases after the cue and after cocaine use - High has a slight increase after the cue and big increase after cocaine use Stress (Sinha) - worked on scrips that describes something that is stressful & imagine that they’re going through the scenario - Heart rate, cortisol goes up (vs neutral script) - Also report a craving increase THE REINSTATEMENT MODEL (DE WIT & STEWART): SA ffi ffi ff ffi ffi - IV drug SA to train the rat to press lever (operant conditioning) - Paired with an auditory cue - To study relapse, need to make the rat abstinent but cannot ask it (unlike humans) - Go through extinction (press lever = no drugs) - Decrease in number of responses (very low, never 0) - Once very low, you can expose the rat to known triggers + priming with a drug - Can be done in di erent setting (di erent chamber) & bring them back to old chamber to reinstate behaviours - On test day, no drug when press lever, no cues - priming reinstatement test: injecting rat with single dose of the drug & put them back in chamber - Shows an increase in responses - Stress: light foot shock - Shows increase in responses - Withdrawal: not a good trigger for reinstatement - But if induce spontaneous withdrawal (randomly stop drug) - Being back the cues (light and noise): will trigger responses - Discriminative cues: cues not directly related to drug, but tell the rat that drugs is available - i.e. particular tone when drug is present, no tone when drug is not available - Tell the rat when the drug is present Priming (de Wit & Stewart) - triggers introduced after extinction phase - Once dose increases, there is an increase in drug-seeking (craving) - Triggered by exposure to the drug they used before Discrete cue-induced (Koya) - animals get cue light when pressing lever and sometimes sound - FR-1 to FR-4 which increases behaviour and proceed to extinction - when exposed to cue associated with heroin induces reinstatement Foot shock (10 min) stress (Shaham) - animals that went through withdrawal didn’t show reinstatement - But stress showed robust reinstatement of behaviour - Showed reinstatement e ect with priming Food deprivation stress (Shalev) - going through food deprivation (24-48h) causes signi cant stress that will show reinstatement THE REINSTATEMENT MODEL: CPP - Trained rats through CPP for morphine and went through extinction - Dropped rats into apparatus to walk around in both conditions (2 months) until stopped showing preference for 1 side or the other - Then were primed: given injection of morphine/saline and dropped into apparatus - Showed reinstatement following “extinction” - Reinstated the memories and showed preference for morphine side - stress: put rats in cold water to swim a little and dropped into the apparatus and preferred fi ff ff ff ff the side they used to prefer - Same e ect THE REINSTATEMENT MODEL: MECHANISMS - di erences in pathways - Overlap between di erent triggers PRIMING Priming: DA, Glu, VTA, NAc, mPFC - more recently: amygdala, ventral pallidum - heroin reinstatement Systemic injections DA (d1, d2, non-speci c), opioid antagonists Heroin priming, footshock stress Role of DA Test 1 - animals trained to SA heroin, went through extinction & then received an injection of heroin/ saline/naltrexone (priming) before the test - Animals that received saline: low response - Animals that received heroin: high response (reinstatement) - Animals that got naltrexone (opiate-R antagonist): blocks the priming e ect = block reinstatement = low response Test 2 - animals trained to SA heroin, went through extinction & then received an injection of heroin/ saline/raclopride (priming) before the test - Injected with Raclopride: DAd1 antagonist: blocked reinstatement - DAd1R seems important for priming-induced reinstatement Test 3 - animals trained to SA heroin, went through extinction & then received an injection of heroin/ saline/ upenthixol (priming) before the test - even low dose of Flupenthixol/DAd2R antagonist - DA transmission important for priming-induced reinstatement Role of Glu in PFC (McFarland) - animals trained to SA cocaine, went through extinction & then received an injection of cocaine/saline/ ufenazine (priming) before the test - In VP: no e ect - In NAc (core): no e ect - In dPFC: blocked reinstatement - Vs saline injection: big increase of response - DA in PFC arises from VTA ff fi ff ff fl ff fl ff Theory 1: GABA - Baclofen/muscimol (GABA-B, GABA-A agonist) = inhibit the neurons - Almost all neurons have GABA-R - Injected in the VTA after cocaine - Blocks reinstatement - Then injected DA directly in dPFC at the same time = reinstatement Theory 2: DA - DA in NAc core: no change in reinstatement - NAc core & shell receives di erent input and have di erent outputs = functionally di erent - VTA > NAc (core, NOT shell) - DA in the shell: block reinstatement Theory 3: Glu - Not DA, but Glu that is critical for reinstatement - Important Glu input is from VTA to NAc through dPFC - Block priming induced reinstatement Theory 4: - if block opiod-R, block reinstatement CUE Cues vs Context & DA (Bossert et al 2017) - transmission through DAd1 is highly related with cue-induced reinstatement - Discrete cues: cues that are present at the same as the drug is delivered - Contextual cues: context where the drug is administered - If d1R are blocked, you can block reinstatement - When cues presented (that usually results in reinstatement) - Where in the brain is this e ect happening? - Infused DAd1 antagonist directly in NAc core - Controls: - Animals that didn’t get the cue had no reinstatement - Animals that got the cue had reinstatement of behaviour - Infused DAd1 antagonist directly in NAc core: - Animals that got a cue, did not show reinstatement - If you infused in the shell, antagonist has no e ect (reinstatement still occurs) - For context-induced reinstatement, infusion of DAd1 antagonist in the NAc shell blocked reinstatement whereas the core didn’t Role of basolateral amygdala & NAc (Grimm & See, 2000) - transiently shut down an area (using neurotoxin: tetrodotoxin) - Blocks Na channels (block APs) = no transmission - When TTX is metabolized, the neurons are functional again - trained 4 groups of rats to SA cocaine - 2 groups also had cannula into BLA + 1 vehicle & 1 TTX - 2 groups had cannula into NAc (shell and core, not speci c) + 1 vehicle & 1 TTX - Animals then underwent extinction - Animals shows extinction burst on rst day (large responses) then sharp drop ff fi ff ff fi ff ff Test 1: animals exposed to cues + TTX in BLA - During training, every time they pressed lever, they got a light cue during drug administration - On test day, they were infused into the BLA (vehicle or TTX [shut down]) - Vehicle: Shows cue-induced reinstatement - TTX (BLA shut down): Didn’t show any response - Animals cannot move, so no behaviours - Went through another day of extinction - They were then primed with cocaine - Both groups show that when presented with cues, there is a reinstatement - Conclusion: BLA plays critical role in cue-induced reinstatement but not in prime-induced - DA in the BLA is important (See) - Blocking DAd1R in mPFC can also block cue-induced reinstatement Test 2: animals exposed to cues + TTX in NAc - During training, every time they pressed lever, they got a light cue during drug administration - On test day, they were infused into the NAc - TTX (NAc shut down): - Doesn’t produce cue-induced reinstatement - Shutting down an area completely - Went through another day of extinction - They were then primed with cocaine - Vehicle: when presented with cues, there is no prime-induced reinstatement - Conclusion: NAc is not critical in cue-induced but is critical for priming-induced reinstatement Role of Glu (Stefanik) - if Glu transmission is blocked in NAc core, block cue-induced reinstatement - If block pathway from mPFC to NAc core using photo-inhibition = - Using Halo, virus infect neurons in mPFC, synthesizing proteins that are expressed on ff neurons in mPFC & will be expressed on the axons projecting into the NAc and express on terminals in the NAc - Hyper polarizing neurons in NAc = inhibition of Glu release in NAc - A ecting only this pathway - Shows dramatic reduction in activity - during cue-reinstatement tests, if pathway is blocked, reinstatement will not occur STRESS Stress response (HPA axis): Hypothalamus releases CRF -> Pituitary releases ACTH -> Adrenal releases Cortisol - by removing adrenal glands, you remove the stress response - train animal to SA drug, extinction, remove adrenal glands, and stress them - Animals still show normal stress-induced reinstatement - Shows you dont need the stress response of HPA axis - Many receptors in the brain for CRF as neurotransmitter - Not only a hormone Role of CRF (Erb) - animals trained to SA cocaine - Before test, injected with CRF antagonist (D-Phe CRF) - Saline + antagonist: low response - Foot shock + antagonist: nice reinstatement unless with CRF antagonist which blocks reinstatement - CRF is critical for stress-induced reinstatement - Priming: weird and messy results Role of Norepinephrine (Highfoeld) - rats trained with speedball (cocaine + heroin) & footshock - Vehicle: reinstatement occurs - If inhibit NE release: dose-response blockage of stress-induced response - Important source of NE: LTA (lateral tegmental area) - Amygdala: source of CRF neurons - Connection between the 2? - can you induce reinstatement by injecting NE or CRF? = YES - If inject NE but block CRF-R = block reinstatement - If inject CRF but block NE = no block of reinstatement - Means there’s a relationship/connection : NE causes release of CRF Role of BNST (Erb & Stewart) - main target for CRF neurons: bed nucleus stria terminalis (BNST) - If block CRF transmission into BNST = block reinstatement - If inject CRF into BNST = induce reinstatement Role of Connection between BNST & Amygdala - CRF antagonist into BNST (one hemisphere) + TTX into amygdala (on other hemisphere) - One side: inhibited amygdala (TTX) - Other side: inhibited BNST (D-PHE CRF) - If its the pathway: there will be no input - If its not, you’ll still get e ect/reinstatement - Without cross over, has to be parallel - Train animal to SA drug + footshock + D-Phe CRF and/or TTX - If you only block one side: reinstatement still happens because the other side still works - If block both sides, you attenuate reinstatement (not blocked entirely) - Pathway is important but not the only one for reinstatement Role of DA (Shalam & Stewart) - if animals are injected with opioid-R antagonist, no blocking of reinstatement If d1 blocked = mild e ect If d2 blocked = mild e ect If blocked d1 & d2 = block reinstatement - DA antagonist injected into the NAc shell - Increases heroin seeking - D1 R antagonist: e ect blocked role of CRF Wang et al - micro dialysis can be used to add CRF antagonist and di use in the synapse - Implanted the probe into VTA - animals trained to SA cocaine or saline, go through extinction - Animals then exposed to footshocks, and reinstatement phase - those that got footshock show a CRF release in the VTA (both cocaine and saline) - Stress response - Not-cocaine/saline then received TTX = no CRF release - CRF release is dependent on APs: no AP = no CRF release - Shows that CRF is released locally, not release as hormone, but as NT - increase in Glu release after footshock ONLY in cocaine-trained rat - Also increase in DA ONLY in cocaine-trained rat - Despite abstinence, brain is di erent in cocaine-trained rats - CRF-R antagonist is injected, blocks reinstatement - CRF is critical for the reinstatement of cocaine - CRF-R antagonist is injected, blocks increase in Glu & DA ff ff ff ff ff ff - Footshock = increase in CRF - If CRF blocked = block increase in Glu & DA = block reinstatement role of Glu - injected kynorinic acid (non-speci c DA-R antagonist) - Animals that were infused with it = blocks reinstatement - No e ect on increase in Glu (a ects Rs, not release) - If Glu-R are blocked, block increase in DA - footshock (stress) = increase in CRF = increase in Glu = increase in DA - If blocked Glu transmission = block restatement + block increase in DA - Increase in CRF is not shown in naive animals - Higher sensitivity to CRF may be only in cocaine - Also last very long - CRF-R- antagonist = block increase in Glu - infusion of CRF into the VTA = reinstatement (similar to footshock) - If CRF is blocked = block reinstatement - CRF itself is enough to cause reinstatement - If CRF is infused + block Glu R = block reinstatement Shalev et al, 2001 - Acute food deprivation can be used to stress-induced reinstatement - Satiated = leptin release from fat cells to brain to stop eating - Obesity leads to desensitization to leptin (signal is not as strong/null) - If animals injected with leptin, it will reduce their feeding - animals trained to SA heroin, extinction, then some are food deprived or satiated - Injection of leptin = block reinstatement in both groups - Same doses of leptin has no e ect on footshock- or priming-induced reinstatement - Drugs “hijack” the natural rewards pathway - CRF probably comes fi ff ff ff from amygdala (not sure yet) - Common pathway to all triggers of relapse (VTA, mPFC, NAc)