Van den Oever et al. (2008) Heroin-Seeking Relapse (Edexcel A-Level Psychology): Revision Notes
Van den Oever et al. (2008) Heroin-Seeking Relapse
Study overview
Researchers: Van den Oever et al.
Year: 2008
Focus: Prefrontal cortex AMPA receptor plasticity in cue-induced relapse to heroin-seeking
Participants
Male Wistar rats were used throughout the study, with a series of experiments conducted sequentially, each building on the findings of the previous investigation.
Aim
This study sought to investigate the biological mechanisms underlying relapse to heroin use by examining the immediate physical changes occurring at synapses in the medial prefrontal cortex (mPFC) when individuals are exposed to drug-conditioned stimuli.
The researchers aimed to understand how plasticity (changes in neural pathways and synapses) in the mPFC might be affected by drug use and how this relates to learned environmental cues that trigger relapse.
Background
Physical dependency and relapse
A key indicator of addiction is the failure to maintain abstinence from drugs even after the individual is no longer physically dependent. Physical dependency refers to a state where chronic drug abuse creates a physical need for the drug to function normally, characterised by tolerance and withdrawal symptoms when the drug is absent.
The phenomenon of relapse has been explained through classical conditioning theory. This form of learning occurs when environmental events or stimuli become associated with internal responses. In the context of drug use, environmental cues associated with prior drug taking can trigger renewed addiction even years after last use.
For example, paraphernalia (equipment used for drug consumption), such as items used to smoke crack cocaine, can cause severe cravings and prompt relapse even in individuals who have been drug-free for extended periods. This demonstrates that relapse can occur independently of physical dependency.
The importance of understanding plasticity
The researchers proposed that understanding how the plasticity of the medial prefrontal cortex is affected by drug use, and how this connects to learned cues, could provide insights into the mechanisms underlying relapse.
By investigating brain changes in drug users at the cellular level, it may be possible to identify mechanisms that alter in response to drug use and subsequently contribute to relapse. This understanding could potentially lead to pharmacological treatments that reduce relapse rates.
Procedure
Initial conditioning phase
The rats underwent conditioning to become dependent on heroin through administration via intravenous infusion through a surgically implanted catheter. This delivery occurred in response to nose-poking behaviour.
During conditioning, the rats were simultaneously exposed to environmental stimuli that served as triggers for the nose-poking behaviour. Once the rats became heroin dependent, they underwent extinction training for three weeks. During extinction, the rats were exposed to the drugs or kept in their home cages until they no longer displayed drug-seeking behaviour (nose pokes in the apparatus that previously led to heroin).
The study found that relapse was substantially more likely when the environmental cues associated with drug taking during the conditioning phase were present during the re-exposure phase.
Subsequent investigations
Having established that learned cues associated with drug-taking situations exert powerful influences on relapse, the researchers proceeded to explore the biological mechanisms underlying this phenomenon through a sequence of four investigations.
Investigation 1: Identifying synaptic changes
Procedure
This investigation aimed to identify differences at the synaptic level between rats who had been exposed to cues (and therefore relapsed) and those who had not been exposed to cues.
The rats were immediately euthanised following the relapse trial, and their brains were dissected. Areas of the medial prefrontal cortex were examined microscopically using sensitive mass spectrometry (an analytical technique that identifies the amount and types of chemicals present in a sample).
Findings
Substantial changes linked to endocytosis (the process of taking in extra-cellular materials from outside a cell by fusing with the cell's plasma membrane) were observed in six proteins in the synaptic membranes of AMPA receptors in rats exposed to cues compared to control rats.
AMPA receptors are post-synaptic receptors responsible for glutamate transmission (glutamate is the most prevalent excitatory neurotransmitter in the nervous system). This finding demonstrated that cue-induced heroin seeking alters synaptic functioning and strength in the rat's brain.
Hypothesis
This led to a hypothesis that preventing the endocytosis of specific proteins would reduce cue-dependent heroin-seeking behaviour.
Investigation 2: Testing the role of endocytosis
Procedure
In the next investigation, rats were injected with either an active peptide (a chain of biological molecules containing 50 or fewer amino acids) that would limit endocytosis, or an inactive peptide (serving as a control). The injection occurred 90 minutes before the rats were exposed to a 30-minute session of relapse testing.
Findings
Finding: Active Peptide Effect
Rats given the active peptide and exposed to cues showed substantially less nose-poking behaviour compared to those exposed to cues and given the inactive substance.
Following the relapse trial, the rats were euthanised and slices of the mPFC were examined as before.
Rats exposed to cues and injected with the active peptide showed no difference in synaptic reactivity compared to those not exposed to cues. However, rats exposed to cues and given the control (inactive) peptide showed the same changes as previously observed.
Conclusion
The active peptide successfully stopped the endocytosis, confirming the role of endocytosis in AMPA currents and its contribution to relapse behaviour.
Investigation 3: Locating the effect
Procedure
The researchers then investigated the precise location within the brain where the endocytosis effect on cue-dependent drug seeking occurred.
The active peptide was injected precisely into various areas of the rat brain.
Findings
The active peptide only decreased heroin seeking in the relapse trial when administered to the ventral (top part) areas of the mPFC.
Conclusion
This led to the conclusion that cue-induced relapse to heroin seeking depends on minute chemical changes brought about by endocytosis specifically in the ventral mPFC.
Investigation 4: Testing specificity to drugs
Procedure
The researchers tested whether this effect on the reduction of cue impact would extend to naturally occurring reinforcers, not just drugs.
Rats were trained to nose poke for sucrose solution and tested in the same manner as those trained for heroin.
Findings
While it was found that cues did affect relapse to sucrose-seeking behaviour, the administration of the peptide did not change this effect.
Conclusion
This suggests that the endocytosis effect is drug-specific and does not prevent operant reinforcers (naturally occurring rewards) from affecting learning in general. Operant conditioning refers to learning based on the consequence for the operator of the action performed, where actions that are reinforced are repeated and learned.
Results/findings
Environmental cues presented during drug taking substantially affect the risk of relapse in previously dependent rats, particularly when presented alongside the drug following extinction or abstinence. This occurs even when rats are no longer drug dependent.
This effect can be linked to brain plasticity in the mPFC, where exposure to cues changes the protein (main components of physical metabolic pathways of cells, made up of chains of peptides) composition at AMPA receptors.
Endocytosis leads to these changes and can be blocked by administering a peptide. Blocking endocytosis stops cue-induced relapse, especially when applied to the ventral areas of the mPFC. The peptide does not stop cues acting on other operantly conditioned reinforcers, affecting learning.
Conclusion
Re-exposure to conditioned stimuli associated with prior heroin use can act as a trigger for relapse. The cue in some way triggers a synaptic response that encourages heroin-seeking behaviour to recover following a period of abstinence.
This synaptic response can be blocked to prevent synaptic reactivity, suggesting a possible pharmacological treatment approach for those addicted to drugs.
Evaluation
Strengths
Scientific rigour and objective measurement
The study is highly scientific in its use of specialised equipment to precisely measure changes at the molecular level. This provides objective, quantifiable differences in neurochemistry associated with the effect of cues on relapse. The controlled laboratory conditions and systematic approach through four sequential investigations demonstrate methodological strength.
Consistency with other research
The study is supported by other research, such as Rogers et al. (2008), who found similar results but only investigated the effect of cues and the biological substrate of heroin addiction. The findings have been shown to be consistent with other studies involving cocaine, for example Peters et al. (2008), suggesting the model may have broader applications to substance addiction.
Ethical appropriateness for animal research
Rodents and humans share similar brain areas, making it ethically appropriate to investigate these mechanisms using the highly controlled scientific studies conducted on animals. It would be ethically impossible to conduct such research on humans because researchers would need to expose ex-addicts to cues likely to cause relapse and monitor their brain activity at the cellular level.
Although some such studies have been conducted on humans, they must meet very stringent ethical requirements, tend to be small-scale with few participants, and are typically less invasive than research on non-humans. The findings cited in this study are consistent with less experimental human research on the effects of cues on relapse.
Weaknesses
Validity of extrapolating from rats to humans
The data for this study is gathered from rats, which challenges the validity of extrapolating findings to model human addiction and relapse. Humans have substantially higher levels of choice in their decision making, involving more cognitive functioning than rodents possess. Reducing relapse to the workings of basic neural circuitry present in rats may be misleading.
Additionally, drug taking in humans can be a social activity rather than a purely physical experience, so it cannot be accurately modelled by animal studies. Human addiction involves complex psychological, social, and environmental factors that are difficult to replicate in animal models.
Limited scope of the model
Other substances of abuse may act on different neural substrates, and indeed this study established that naturally occurring reinforcers like sucrose are not affected in the same way. This potentially limits the usefulness of the model of relapse presented here to specific drug addictions rather than providing a universal explanation.
However, the model could be considered useful because of the scale of the drugs problem. US government estimates indicate that relapse back into drug use is between 40 and 60 per cent, stating that drug addiction should be treated like any other chronic illness, with relapse serving as a trigger for renewed intervention.
Ethical considerations of animal research
Whilst animal research was necessary for this type of investigation, it raises ethical concerns about exposing animals to addictive substances and potentially harmful procedures. The animals were made physically dependent on heroin and underwent surgical procedures for catheter implantation, which involves suffering and cannot be fully justified by potential human benefits alone.
Remember!
Key Points to Remember:
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Cue-induced relapse occurs when environmental stimuli associated with drug use trigger drug-seeking behaviour, even after extended periods of abstinence.
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Endocytosis in the ventral mPFC plays a specific role in relapse to heroin-seeking behaviour, involving changes in AMPA receptors at the synaptic level.
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Blocking endocytosis with peptides can prevent cue-induced relapse to heroin specifically, but does not affect responses to naturally occurring reinforcers like sucrose.
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The study provides evidence for potential pharmacological treatments that could reduce relapse rates by targeting specific neurochemical mechanisms.
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Methodological limitations include the challenges of extrapolating from rat models to human behaviour and the ethical considerations of animal research involving addictive substances.