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A comprehensive set of questions and answers related to relapse and drug-seeking behavior in the context of addiction. It explores various factors that contribute to relapse, including stress, drug cues, and priming effects. The document also delves into the neurobiological mechanisms underlying relapse, focusing on the role of dopamine and glutamate in specific brain regions. It examines different research methods used to study relapse, including animal models and human studies, highlighting their strengths and limitations. This resource is valuable for students studying addiction psychology, neuroscience, or related fields.
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drug or other drugs: Even a brief re-exposure can prime relapse. Cues associated with drug use: Includes objects (e.g., syringes), places, smells, or people linked to drug use. Stress: A commonly cited reason for relapse, as stress increases cravings. Withdrawal symptoms: Conditioned withdrawal can trigger cravings even after the acute withdrawal phase."
effect occurs when a brief re-exposure to a drug (or a similar substance) reactivates cravings, potentially leading to relapse. For example, medical exposure to opiates in someone with a history of opioid use disorder."
individuals to report drug-related feelings can itself trigger cravings. Analyzing large, variable datasets is also difficult." "What methods are used to study the brain mechanisms of relapse in humans, and what are their
stimulation. These approaches have limited resolution and manipulation capabilities." "Why is craving often used as a proxy for relapse in studies, and what is the limitation of this
not always result in relapse, as individuals can resist cravings."
when a user has been abstinent for a longer time, making the results more pronounced." "What is an alternative method for studying relapse-related factors in abstinent users (Sinha et al
to stress-inducing, personalized scripts, which they develop with the participants. These scripts simulate real-life stressful scenarios that the subjects imagine during testing."
scripts based on real or familiar stressful scenarios. During testing, these scripts are read to participants, who imagine themselves in the scenario. Researchers measure physiological responses like heart rate and cortisol levels (a stress hormone that rises and falls over time). Participants also report their craving levels, which increase after imagining the stressful scenario." "What physiological and psychological effects are observed in abstinent users exposed to stress-
increased heart rate and elevated cortisol levels that peak and decline during the recovery period. Psychologically, participants report heightened craving levels after imagining the stressful scenario."
Ethical restrictions limit the types of manipulations allowed. The population is difficult and expensive to work with, resulting in small sample sizes. Smartphone-based studies to track emotions and cravings provide large datasets but have limited depth and may inadvertently act as triggers."
Stress: Mild footshocks irritate rats, increasing lever pressing. Priming Injection: A single drug dose induces lever pressing even without drug delivery. Cues: Reintroducing drug-associated cues (e.g., tones or lights) strongly reinstates lever pressing."
seeking behavior in animals after extinction. Priming involves administering a small dose of the drug after the extinction phase to see if it reinstates drug-seeking behavior. Cue exposure refers to reintroducing environmental cues (like lights or sounds) previously associated with drug administration. Stress can also act as a powerful trigger for reinstatement, as it mimics conditions that might lead to relapse in humans."
"What is the effect of D2 receptor antagonists on heroin reinstatement (Shalam & Stewart 1996)?
- CORRECT ANSWER D2 receptor antagonists were tested, and even low doses effectively blocked reinstatement of drug-seeking behavior, suggesting that dopamine transmission through D2 receptors is also essential for priming-induced reinstatement." "What is the interpretation of the D1 and D2 receptor findings in reinstatement (Shalam &
rats. Specifically: D1 receptors seem particularly important for priming effects. D2 receptors also play a role, with even low doses blocking reinstatement, highlighting the essential involvement of DA transmission in drug-seeking behavior." "What was the main goal of McFarland & Kalivas (2001) in their study on drug priming and
the role of specific brain regions, particularly the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), in cocaine priming-induced reinstatement of drug- seeking behavior. The study specifically investigated how dopamine (DA) and glutamate within these regions contribute to reinstatement of drug-seeking behavior after extinction." "How does cocaine priming influence reinstatement of drug-seeking behavior in animal models?
extinction of drug-seeking behavior. This priming injection leads to a significant reinstatement of drug-seeking behavior, measured by the number of responses during the extinction phase, indicating that the prior experience with the drug is reactivated by the priming injection." "What neurotransmitters and brain regions are involved in cocaine priming-induced
priming-induced reinstatement is primarily influenced by DA and glutamate in specific brain regions: the VTA, NAc, and PFC. The study focuses on how these areas interact to control the return of drug-seeking behavior following extinction."
reinstatement by preventing dopamine release."
"How does DA in the dPFC affect cocaine priming-induced reinstatement (McFarland & Kalivas
reinstatement, showing that dopamine activity in the dPFC is critical for reinstatement." "How did researchers shut down the ventral tegmental area (VTA) in this study (McFarland &
muscimol (GABA-A agonist), which activate inhibitory GABA receptors to silence neurons in the VTA. This stopped dopamine release from the VTA and completely blocked cocaine-induced reinstatement." "What happened to cocaine reinstatement when the VTA was shut down (McFarland & Kalivas
that the VTA's activity is necessary for reinstatement, likely through its dopamine projections to various targets like the PFC, NAc, and hippocampus." "What did the researchers demonstrate by injecting dopamine into the PFC after shutting down
showing that DA activity in the PFC alone is sufficient to induce reinstatement, even without dopamine from the VTA targeting other brain regions." "Why was it surprising that a dopamine antagonist in the NAc core did not block reinstatement
mesolimbic dopamine system, so it was unexpected that blocking dopamine in the NAc core had no effect on cocaine priming-induced reinstatement. This finding redirected focus to the role of the PFC and glutamate." "How are the core and shell of the NAc functionally different in addiction (McFarland & Kalivas
The core is more critical for general and priming-induced reinstatement due to its glutamatergic input from the prelimbic cortex. The shell may be more involved in priming-induced reinstatement via dopamine." "What did the Kalivas group demonstrate about the NAc core and reinstatement (McFarland &
priming-induced reinstatement in the NAc core. Blocking glutamatergic input from the prelimbic cortex to the core prevents reinstatement."
In contrast to discrete cue-induced reinstatement, DA D1 receptors in the NAc lateral shell are crucial for context-induced reinstatement. When a DA D1 antagonist is injected into the NAc lateral shell during context exposure (such as placing the animal back in an environment associated with previous drug use), it effectively blocks the reinstatement of drug-seeking behavior. This suggests that the lateral shell plays a key role in processing contextual cues that trigger relapse." "How do the effects of DA D1 antagonists differ between discrete-cue and context-induced
core are important for reinstatement in response to discrete cues. Context-induced Reinstatement: DA D1 receptors in the NAc lateral shell are important for reinstatement in response to contextual cues (environmental context), while the NAc core is not critical in this case."
reinstatement of drug-seeking behavior. However, the specific subarea of the NAc involved (core vs. lateral shell) depends on the type of cue (discrete vs. contextual). DA transmission in the NAc core is vital for discrete-cue reinstatement, while the NAc lateral shell is important for context- induced reinstatement."
used. Discrete cues (such as a light or tone) and contextual cues (such as the environment where the drug is self-administered) engage different neural circuits, leading to different behavioral outcomes." "What is the traditional method for studying the contribution of brain areas to drug-seeking
brain areas, where researchers would destroy neurons in a specific area to observe changes in behavior. This method provides valuable insights but has the drawback of being nonspecific, and it causes permanent damage, making it difficult to draw conclusions about reversible brain functions."
channels and prevents neurons from firing action potentials. This inhibition is temporary, as the toxin is metabolized, and the brain area "comes back online" after a period."
reinstatement of drug-seeking behavior. They used TTX injections to temporarily shut down these brain areas and assess their contribution during cocaine self-administration and extinction." "What were the key findings during the extinction and cue-induced reinstatement phase of the
curve without any noticeable extinction bursts (unlike previous studies where animals showed frustration and an initial burst of responses). Cue-induced reinstatement: Despite shutting down the NAc with TTX during cue exposure, there was no effect on cue-induced reinstatement. The rats responded to the cues (light and tone) as expected, showing typical drug-seeking behavior."
cue-induced reinstatement of drug-seeking behavior. However, it highlights the complexity of interpreting results from inactivation studies because shutting down a brain area with TTX may not always give clear answers—axons passing through the NAc could also be affected, complicating the interpretation."
cocaine injection, the vehicle group showed significant priming-induced reinstatement. However, the TTX-treated group that had their NAc shut down did not show priming-induced reinstatement, indicating that the NAc is critical for this form of reinstatement." "What conclusion was drawn from the experiment regarding the NAc's role in cue-induced and
essential for cue-induced reinstatement but plays a critical role in priming-induced reinstatement. This underscores the idea that different brain areas may be involved in different forms of drug-seeking behavior, depending on whether the behavior is driven by cues or priming." "Why must researchers be cautious when interpreting results from studies that involve shutting
TTX may not only affect the targeted area but also any axons passing through it, which can lead to
Test Day: The animals are exposed to cocaine-associated cues again, leading to reinstatement of cocaine-seeking behavior, which demonstrates typical cue-induced reinstatement." "What is observed when the mPFC-NAc pathway is inhibited by yellow light during the test day
mPFC-NAc pathway, the cocaine-seeking behavior in response to cues is dramatically reduced, showing that this pathway is necessary for cue-induced reinstatement of cocaine-seeking behavior."
Glutamate transmission Brain regions: BLA, CeA, NAc, and mPFC."
is critical for cue-induced reinstatement of cocaine-seeking behavior, as blocking this pathway inhibits reinstatement." "What are the core components of the circuit involved in cue-induced reinstatement of drug-
NAc, Ventral Pallidum, BLA, CeA"
critical role in cue-induced reinstatement, particularly in the NAc, depending on where it is injected (core or shell). The effect of DA varies based on the type of cue (contextual vs. discrete). In general, DA in the NAc is important for triggering reinstatement."
cocaine cue, contextual cue) may involve specific additions to the circuit. Despite this complexity, there appears to be a common pathway out, though the specific route taken can vary depending on the type of trigger." "Why is the role of the HPA axis in stress-induced reinstatement different for heroin and cocaine?
- CORRECT ANSWER In heroin-induced reinstatement, the absence of corticosterone does not affect the reinstatement response. However, in cocaine-induced reinstatement, a baseline level
of corticosterone is needed for the reinstatement to occur, even though the stress-induced increase in corticosterone is not necessary. The exact reasons for this difference are not fully understood."
not only a hormone involved in the HPA axis but also acts as a neurotransmitter in the brain. It is released at synapses and binds to specific CRF receptors. Researchers began to investigate its role in stress-induced reinstatement, as it is implicated in stress responses outside of the hormonal pathway." "How does norepinephrine (NE) contribute to stress-induced reinstatement of drug-seeking
the stress response. It plays a significant role in modulating stress-induced reinstatement of drug- seeking behavior, alongside CRF."
of CRF, NE, DA, and 5-HT (serotonin). These regions and neurotransmitters coordinate to influence the reinstatement of drug-seeking behavior following stress." "What are the major neurotransmitters involved in the stress response related to drug-seeking
Norepinephrine (NE) Dopamine (DA) Serotonin (5-HT)These neurotransmitters interact with brain regions like the BNST and amygdala to modulate stress and drug-seeking behavior."
the role of CRF receptors in stress-induced reinstatement of drug-seeking behavior, specifically following footshock and priming-induced reinstatement of cocaine and heroin seeking in animals."
animals were trained to self-administer cocaine and then underwent extinction training. Before the test, they were injected with a CRF receptor antagonist (D-Phe) at different doses. Some animals received saline (control), while others received different doses of D-Phe before the test."
The animals in the saline group, who went through the test without receiving any CRF receptor
the BNST following reinstatement."
stress-induced reinstatement, showing the critical role of CRF in the BNST for this behavior."
reinstatement, confirming the importance of CRF transmission in the BNST." "What evidence supports the amygdala → BNST CRF pathway's role in stress-induced
Blocking CRF in the BNST prevents reinstatement. Injecting CRF in the BNST induces reinstatement."
reinstatement."
might cause."
highly active following stress-induced reinstatement, highlighting its role in the behavior."
Injecting CRF: Induces reinstatement."
LTA is the important source of NE, with other sources being less critical." "What are the key brain regions and neurotransmitters involved in stress-induced reinstatement?
- CORRECT ANSWER Regions: Bed nucleus of the stria terminalis (BNST), amygdala. Neurotransmitters: CRF, NE, DA."
To test whether the amygdala → BNST pathway is critical for stress-induced reinstatement by using manipulations in both hemispheres."
significant cross-innervation."
Injecting a CRF antagonist in the BNST of the opposite hemisphere." "What happens when only one side of the amygdala → BNST pathway is disrupted (Erb et al
on the other side compensates." "What happens when both the amygdala and BNST are disrupted on opposite sides (Erb et al
importance of the amygdala → BNST pathway." "What does the disconnection study conclude about the amygdala → BNST pathway (Erb et al
pathways prevents the behavior."
manipulations."
pathways."
that effects seen with dual manipulations are specific."
"Why is stress-induced reinstatement not completely blocked when the amygdala → BNST
pathways or contributors are likely involved in stress-induced reinstatement, as demonstrated by the persistent effect of footshock even after disrupting the amygdala → BNST pathway."
using optogenetics or chemogenetics, which allow for precise manipulation of specific pathways, such as the amygdala → BNST pathway, without affecting other regions."
priming involves the opioid system."
seeking after 21 hours of food deprivation."
Blocking these receptors reduces stress-induced heroin-seeking behavior."
"What was the effect of injecting a DA D1 receptor antagonist into the NAc shell (Tobin et al. 2013
acute food deprivation, indicating the importance of D1 receptors in the NAc shell." "How does the effect of systemic DA antagonist injections compare to localized NAc shell
also block stress-induced reinstatement, but the specific targeting of D1 receptors in the NAc shell provides more precise evidence of the receptor's role." "What does acute food deprivation (21 hours) do to heroin-seeking behavior (Tobin et al. 2013
DA D1 receptor antagonist in the NAc shell."
"What was the role of flupenthixol in stress-induced reinstatement studies (Tobin et al. 2013
induced reinstatement of heroin seeking when administered systemically."
the NAc shell specifically reduces heroin-seeking behavior during acute food deprivation, highlighting the importance of the mesolimbic dopamine pathway."
areas also contribute to stress-induced reinstatement, highlighting a broader network involvement."
infuse substances, like a CRF antagonist, into specific brain regions to study their effects."
probe was implanted into the VTA to infuse CRF antagonist, allowing researchers to investigate how blocking CRF affects stress-induced drug-seeking behavior."
crucial for reward and stress-related behaviors. Manipulating CRF or dopamine in this area can affect stress-induced reinstatement of drug seeking."
glutamate play key roles in stress-induced reinstatement."
stress response. This release occurs in both cocaine-trained and cocaine-naive rats."
naive rats. This glutamate release activates the mesolimbic dopamine system, triggering reinstatement."
"What procedure was followed for studying stress-induced reinstatement in cocaine-trained rats
underwent extinction (drug removal), and were then exposed to footshock to test reinstatement." "What happens when a CRF receptor antagonist (α-H-CRF) is infused in cocaine-trained rats
seeking behavior is blocked, indicating that CRF release is critical for reinstatement." "What does the blocking of reinstatement by a CRF receptor antagonist demonstrate (Wang et al
for triggering the reinstatement of cocaine-seeking behavior." "How does a CRF receptor antagonist affect glutamate levels in the VTA after footshock (Wang et
induced increase in glutamate levels in cocaine-trained rats." "How does a CRF receptor antagonist affect dopamine levels in the VTA after footshock (Wang et
in dopamine levels in cocaine-trained rats."
independent of the rats' history with cocaine."
trained rats."
resulting in increased dopamine levels in the VTA."
the reinstatement of cocaine-seeking behavior."
which are necessary for the reinstatement of cocaine-seeking behavior in trained rats." "How are glutamate and dopamine responses different in cocaine-trained vs. naive rats during
occur only in cocaine-trained rats, highlighting cocaine-induced neural adaptations."
Dopamine release → Reinstatement of cocaine-seeking behavior." "How does footshock-induced glutamate release differ between cocaine-trained rats and naive
significant increase in glutamate release, which is not observed in naive animals. While naive rats experience a stress response, they do not show the glutamate increase seen in trained animals, indicating that cocaine history modifies glutamate system responses." "What was the outcome of infusing a nonspecific glutamate receptor antagonist (Kynurenic acid)
blocked reinstatement of cocaine-seeking behavior following footshock. The antagonist inhibits postsynaptic glutamate receptors, preventing glutamate's action, but it does not affect glutamate release itself." "How does Kynurenic acid affect glutamate and dopamine responses to footshock in cocaine-
the increase in glutamate because it only targets postsynaptic receptors, leaving presynaptic glutamate release unaffected. Dopamine: Blocking glutamate receptors prevents the downstream increase in dopamine levels, which is crucial for reinstatement." "Why does glutamate release remain unchanged even when postsynaptic receptors are blocked
receptor blockade. All groups exposed to footshock show an increase in glutamate release." "What happens to DA levels if glutamate receptors are blocked during footshock exposure (Wang
dopamine, which is critical for reinstatement of cocaine-seeking behavior."