Relapse and Reinstatement
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Questions and Answers

What are the triggering factor for relapse according to the text?

  • Re-exposure to the drug or other drugs
  • The context where drug was usually taken
  • Stress
  • All of the above (correct)

    • In the reinstatement model by De Wit & Stewart, what triggers an increase in responses in rats?

  • Priming with a drug and exposure to known triggers (correct)
  • Stress from light foot shock
  • Presence of discriminative cues
  • Experiencing withdrawal symptoms

    • What is a challenge in studying conditioned withdrawal according to the text?

  • Lack of technological tools for measurement
  • Inability to induce spontaneous withdrawal in animals
  • Difficulty in recruiting subjects for self-report studies
  • Ethical issues in conducting animal studies (correct)

    • Which neurotransmitter is implicated in priming-induced reinstatement?

    <p>A &amp; B</p> Signup and view all the answers

    What type of cues are discrete cues in the context of reinstatement models?

    <p>Cues that are present at the same time as the drug is delivered</p> Signup and view all the answers

    What is Naltrexone?

    <p>Opiate-R antagnoist</p> Signup and view all the answers

    What is the role of DAd1 antagonist infused directly in the NAc core?

    <p>It has no effect on cue-induced reinstatement</p> Signup and view all the answers

    What is the effect of blocking Glu transmission in the NAc core?

    <p>It blocks cue-induced reinstatement</p> Signup and view all the answers

    What is the role of Norepinephrine (NE) in stress-induced reinstatement?

    <p>NE is a critical factor in stress-induced response</p> Signup and view all the answers

    What happens if CRF transmission into BNST is blocked?

    <p>Reinstatement is blocked</p> Signup and view all the answers

    What is the effect of injecting CRF into BNST?

    <p>Reinstatement is induced</p> Signup and view all the answers

    What is the role of DA antagonists in the NAc shell?

    <p>Mild effect on reinstatement if D1 or D2 is blocked</p> Signup and view all the answers

    What is the effect of CRF antagonist injection in the VTA?

    <p>Blocks reinstatement</p> Signup and view all the answers

    What happens when Glu transmission is blocked?

    <p>Blocks reinstatement and increase in DA</p> Signup and view all the answers

    How does acute food deprivation affect stress-induced reinstatement?

    <p>Leptin injection blocks reinstatement</p> Signup and view all the answers

    What happens when CRF transmission into BNST is blocked?

    <p>Reinstatement is blocked</p> Signup and view all the answers

    What is the role of dopamine (DA) antagonists in the NAc shell?

    <p>Increase heroin seeking</p> Signup and view all the answers

    What is the effect of injecting CRF into the VTA?

    <p>Induce reinstatement</p> Signup and view all the answers

    What is the effect of blocking Glutamate (Glu) transmission in the NAc core?

    <p>Block reinstatement and increase in dopamine (DA)</p> Signup and view all the answers

    What is the role of Norepinephrine (NE) in stress-induced reinstatement?

    <p>Causes release of CRF</p> Signup and view all the answers

    What is the effect of injecting kynurenic acid (non-specific DA-R antagonist)?

    <p>Blocks reinstatement</p> Signup and view all the answers

    What is the effect of CRF antagonist injection in the VTA?

    <p>Blocks reinstatement</p> Signup and view all the answers

    What brain area is critical for relapse according to the text?

    <p>Amygdala</p> Signup and view all the answers

    What is the role of Glutamate (Glu) in drug-seeking behavior?

    <p>Increase in Glu leads to an increase in DA</p> Signup and view all the answers

    What happens when CRF is blocked?

    <p>Block increase in Glu &amp; DA</p> Signup and view all the answers

    Is the bed nucleus stria terminalis (BNST) the main target for Dopamine (DA) neurons in the brain?

    <p>False</p> Signup and view all the answers

    Does CRF release as a hormone rather than a neurotransmitter in the brain?

    <p>False</p> Signup and view all the answers

    Is CRF antagonist injection sufficient to block the increase in Glutamate (Glu) and Dopamine (DA) in cocaine-trained rats?

    <p>True</p> Signup and view all the answers

    Is leptin release from fat cells to the brain stronger in animals that are food deprived compared to those that are satiated?

    <p>False</p> Signup and view all the answers

    Is the release of CRF critical for the reinstatement of cocaine but not for heroin-seeking behavior?

    <p>False</p> Signup and view all the answers

    Match the brain region with its role in reinstatement models:

    <p>Bed nucleus stria terminalis (BNST) = Main target for CRF neurons Nucleus accumbens (NAc) shell = Increases heroin seeking Ventral tegmental area (VTA) = Shows CRF release after footshock Amygdala = Inhibited by CRF antagonist injection into BNST</p> Signup and view all the answers

    Match the neurotransmitter with its role in drug-seeking behavior:

    <p>Dopamine (DA) = Blocked by D1 &amp; D2 antagonists to block reinstatement Glutamate (Glu) = Injection of kynurenic acid blocks reinstatement Corticotropin-releasing factor (CRF) = Critical for reinstatement of cocaine Norepinephrine (NE) = Causes release of CRF in stress-induced reinstatement</p> Signup and view all the answers

    Match the experimental manipulation with its effect on reinstatement:

    <p>CRF antagonist injection into VTA = Blocks reinstatement and increase in Glu &amp; DA Leptin injection = Blocks reinstatement in food-deprived animals D-Phe CRF injection into BNST = Induces reinstatement TTX into amygdala = Inhibits amygdala and causes no input for reinstatement</p> Signup and view all the answers

    Acute food deprivation can be used to stress-induced reinstatement - Satiated = ______ release from fat cells to brain to stop eating - Obesity leads to desensitization to ______ (signal is not as strong/null) - If animals injected with ______, it will reduce their feeding - animals trained to SA heroin, extinction, then some are food deprived or satiated - Injection of ______ = block reinstatement in both groups - Same doses of ______ has no e ect on footshock- or priming-induced reinstatement - Drugs “hijack” the natural rewards pathway - CRF probably comes from amygdala (not sure yet) - Common pathway to all triggers of relapse (VTA, mPFC, NAc).

    <p>leptin</p> Signup and view all the answers

    Micro dialysis can be used to add ______ antagonist and diffuse 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 ______ release in the VTA (both cocaine and saline) - Stress response - Not-cocaine/saline then received TTX = no ______ release - ______ release is dependent on APs: no AP = no ______ release - Shows that ______ 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 different in cocaine-trained rats - ______-R antagonist is injected, blocks reinstatement - ______ is critical for the reinstatement of cocaine - ______-R antagonist is injected, blocks increase in Glu & DA ff ff ff ff ff ff - Footshock = increase in ______ - If ______ 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 (affects Rs, not release) - If Glu-R are blocked, block increase in DA - footshock (stress) = increase in ______ = increase in Glu = increase in DA - If blocked Glu transmission = block restatement + block increase in DA - Increase in ______ is not shown in naive animals - Higher sensitivity to ______ may be only in cocaine - Also last very long - ______-R- antagonist = block increase in Glu - infusion of ______ into the VTA = reinstatement (similar to footshock) - If ______ is blocked = block reinstatement - ______ itself is enough to cause reinstatement - If ______ is infused + block Glu R = block reinstatement Shalev et al, 2001

    <p>CRF</p> Signup and view all the answers

    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 effect If d2 blocked = mild effect If blocked d1 & d2 = block reinstatement - DA antagonist injected into the NAc shell - Increases heroin seeking - D1 R antagonist: effect blocked role of CRF Wang et al - micro dialysis can be used to add CRF antagonist and diffuse 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 different 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-specific DA-R antagonist) - Animals that were infused with it = blocks reinstatement - No effect on increase in Glu (affects 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

    <p>dopamine</p> Signup and view all the answers

    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 ______: there will be no input - If its not, you’ll still get effect/reinstatement - Without cross over, has to be parallel

    <p>pathway</p> Signup and view all the answers

    Role of BNST (Erb & Stewart) - main target for ______ neurons: bed nucleus stria terminalis (BNST) - If block ______ transmission into BNST = block reinstatement - If inject ______ into BNST = induce reinstatement

    <p>CRF</p> Signup and view all the answers

    Study Notes

    Relapse and Reinstatement

    • Most addicts will relapse, and it is a big problem of treatment.
    • Replacement therapies, antagonist, and reverse agonist are used to treat addiction.
    • AA/NA (Alcoholics Anonymous and Narcotics Anonymous) have a dramatic drop in abstinence and stabilize at about 25% success rate.

    Triggering Factors

    • Re-exposure to the drug or other drugs can trigger relapse.
    • Priming effect: brief exposure to a drug can prime the behavior.
    • Re-exposure to stimuli associated with drugs can trigger relapse.
    • Cues over time become powerful in guiding behavior (saliency).
    • Immediate/discrete cues: e.g. needle, powder, smell, people, etc.
    • Stress can trigger relapse, leading to an increase in craving.

    The Reinstatement Model (De Wit & Stewart)

    • IV drug self-administration (SA) is used to train rats to press a lever (operant conditioning).
    • An auditory cue is paired with the drug.
    • To study relapse, rats are made abstinent and then exposed to known triggers.
    • Priming reinstatement test: injecting a single dose of the drug and putting the rat back in the chamber.
    • Stress: light foot shock shows an increase in responses.
    • Withdrawal: not a good trigger for reinstatement, but inducing spontaneous withdrawal can trigger responses.

    Mechanisms of Reinstatement

    • Different pathways are involved in different triggers.
    • Overlap between different triggers exists.

    Priming

    • DA, Glu, VTA, NAc, and mPFC are involved in heroin reinstatement.
    • Amygdala and ventral pallidum are also involved.
    • Systemic injections of DA, opioid antagonists, and heroin priming show the role of DA in reinstatement.

    Role of DA in Priming

    • Test 1: animals trained to SA heroin, went through extinction, and received an injection of heroin/saline/naltrexone (priming) before the test.
    • Test 2: animals trained to SA heroin, went through extinction, and received an injection of heroin/saline/raclopride (priming) before the test.
    • Test 3: animals trained to SA heroin, went through extinction, and received an injection of heroin/saline/upenthixol (priming) before the test.

    Role of Glu in PFC (McFarland)

    • Animals trained to SA cocaine, went through extinction, and received an injection of cocaine/saline/ufenanize (priming) before the test.
    • DA in PFC arises from VTA.

    Theories of Reinstatement

    • Theory 1: GABA - Baclofen/muscimol (GABA-B, GABA-A agonist) inhibits neurons.
    • Theory 2: DA - DA in NAc core: no change in reinstatement.
    • Theory 3: Glu - Not DA, but Glu is critical for reinstatement.
    • Theory 4: opioid-R - if block opioid-R, block reinstatement.

    Cues vs Context & DA (Bossert et al 2017)

    • Transmission through DAd1 is highly related to cue-induced reinstatement.
    • Discrete cues: cues that are present at the same time as the drug is delivered.
    • Contextual cues: context where the drug is administered.
    • If d1R are blocked, you can block reinstatement.
    • Where in the brain is this effect happening?Here are the study notes for the text:

    DAd1 Antagonist and Cue-Induced Reinstatement

    • Infusing DAd1 antagonist directly into the NAc core blocks cue-induced reinstatement
    • Infusing DAd1 antagonist into the NAc shell has no effect on reinstatement
    • The NAc core and shell have different functions in cue-induced reinstatement

    Role of Basolateral Amygdala and NAc

    • Transiently shutting down the BLA using TTX blocks cue-induced reinstatement
    • Transiently shutting down the NAc using TTX blocks priming-induced reinstatement
    • The BLA is critical for cue-induced reinstatement, but not for priming-induced reinstatement
    • The NAc is not critical for cue-induced reinstatement, but is critical for priming-induced reinstatement

    Role of Glutamate (Glu)

    • Blocking Glu transmission in the NAc core blocks cue-induced reinstatement
    • Blocking the pathway from mPFC to NAc core using photo-inhibition also blocks cue-induced reinstatement
    • Inhibiting Glu release in the NAc blocks cue-induced reinstatement

    Stress and Reinstatement

    • Removing the adrenal glands removes the stress response, but does not prevent stress-induced reinstatement
    • CRF is critical for stress-induced reinstatement
    • Inhibiting NE release blocks stress-induced reinstatement

    Triggering Factors for Relapse

    • Re-exposure to the drug or other drugs can trigger relapse
    • Priming, re-exposure to stimuli associated with drugs, and stress can trigger relapse
    • Cues over time become powerful in guiding behaviour
    • Immediate/discrete cues, such as needle, powder, smell, and people, can trigger relapse

    The Reinstatement Model

    • Train the rat to self-administer a drug using operant conditioning
    • Pair the drug with an auditory cue
    • Make the rat abstinent and then expose it to known triggers (cues, stress, etc.) to study relapse
    • The reinstatement model can be used to study the neural mechanisms of relapse### Reinstatement Models
    • The reinstatement model uses CPP (conditioned place preference) to train rats for morphine and then goes through extinction phase.
    • After extinction, rats are primed with an injection of morphine/saline and dropped into the apparatus, showing reinstatement of the memories and preference for the morphine side.
    • Stress can also trigger reinstatement, such as putting rats in cold water to swim, which leads to reinstatement of the preferred side.

    Priming

    • Priming triggers an increase in drug-seeking behavior and craving following exposure to the drug.
    • Priming involves the activation of dopamine (DA), glutamate (Glu), ventral tegmental area (VTA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC).
    • Heroin priming involves the activation of the amygdala and ventral pallidum.

    Mechanisms of Reinstatement

    • Differences in pathways trigger reinstatement, with overlap between different triggers.
    • Priming, cue-induced, and stress-induced reinstatement have distinct mechanisms.

    Role of DA in Reinstatement

    • DA is involved in priming-induced reinstatement, with DA receptors (DAd1 and DAd2) playing a crucial role.
    • Blockade of DA receptors (DAd1 and DAd2) blocks reinstatement.
    • DA transmission in the prefrontal cortex (PFC) is important for priming-induced reinstatement.

    Role of Glu in Reinstatement

    • Glu is involved in cue-induced reinstatement, with blockade of Glu transmission in the NAc core blocking reinstatement.
    • Glu input from the VTA to the NAc through the PFC is critical for reinstatement.

    Role of Cues in Reinstatement

    • Cues can trigger reinstatement, with discrete cues (e.g., light and sound) being more effective than contextual cues.
    • DA transmission in the NAc core is involved in cue-induced reinstatement, with blockade of DAd1 receptors in the NAc core blocking reinstatement.

    Role of Basolateral Amygdala and NAc in Reinstatement

    • The basolateral amygdala (BLA) plays a critical role in cue-induced reinstatement, with blockade of DA receptors in the BLA blocking reinstatement.
    • The NAc is involved in priming-induced reinstatement, with blockade of DA receptors in the NAc shell blocking reinstatement.

    Role of Stress in Reinstatement

    • Stress can trigger reinstatement, with the activation of the hypothalamic-pituitary-adrenal (HPA) axis.
    • Removing the adrenal glands does not prevent stress-induced reinstatement, suggesting that the HPA axis is not necessary for reinstatement.
    • CRF (corticotropin-releasing factor) is a critical neurotransmitter for stress-induced reinstatement, with blockade of CRF receptors blocking reinstatement.
    • Norepinephrine (NE) is also involved in stress-induced reinstatement, with blockade of NE release blocking reinstatement.

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    Test your knowledge of neuroscience and behavioral psychology with this quiz on the effects of DAd1 antagonists on cue-induced reinstatement of behavior in animal studies. Explore the impact of infusions in the NAc core and shell, and deepen your understanding of context-induced reinstatement.

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