Context-induced relapse to drug seeking: a review Crombag, Hans S; Bossert, Jennifer M; Koya, Eisuke ...
Philosophical transactions - Royal Society. Biological sciences,
10/2008, Letnik:
363, Številka:
1507
Journal Article
Recenzirano
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In humans, exposure to environmental contexts previously associated with drug intake often provokes relapse to drug use, but the mechanisms mediating this relapse are unknown. Based on early studies ...by Bouton & Bolles on context-induced 'renewal' of learned behaviours, we developed a procedure to study context-induced relapse to drug seeking. In this procedure, rats are first trained to self-administer drug in one context. Next, drug-reinforced lever responding is extinguished in a different (non-drug) context. Subsequently, context-induced reinstatement of drug seeking is assessed by re-exposing rats to the drug-associated context. Using variations of this procedure, we and others reported reliable context-induced reinstatement in rats with a history of heroin, cocaine, heroin-cocaine combination, alcohol and nicotine self-administration. Here, we first discuss potential psychological mechanisms of context-induced reinstatement, including excitatory and inhibitory Pavlovian conditioning, and occasion setting. We then summarize results from pharmacological and neuroanatomical studies on the role of several neurotransmitter systems (dopamine, glutamate, serotonin and opioids) and brain areas (ventral tegmental area, accumbens shell, dorsal striatum, basolateral amygdala, prefrontal cortex, dorsal hippocampus and lateral hypothalamus) in context-induced reinstatement. We conclude by discussing the clinical implications of rat studies on context-induced reinstatement of drug seeking.
Changes in microglial morphology are powerful indicators of the inflammatory state of the brain. Here, we provide an open-source microglia morphology analysis pipeline that first cleans and registers ...images of microglia, before extracting 62 parameters describing microglial morphology. It then compares control and 'inflammation' training data and uses dimensionality reduction to generate a single metric of morphological change (an 'inflammation index'). This index can then be calculated for test data to assess inflammation, as we demonstrate by investigating the effect of short-term high-fat diet consumption in heterozygous Cx3CR1-GFP mice, finding no significant effects of diet. Our pipeline represents the first open-source microglia morphology pipeline combining semi-automated image processing and dimensionality reduction. It uses free software (ImageJ and R) and can be applied to a wide variety of experimental paradigms. We anticipate it will enable others to more easily take advantage of the powerful insights microglial morphology analysis provides.
Background
In the recent case of R v. Taj, the Court of Appeal of England and Wales upheld the conviction of a defendant who, in a psychotic delusional state, mistook his non‐threatening victim to be ...a terrorist, violently attacking him. The law typically allows honest mistakes (even if unreasonable) as a basis for self‐defence (in this case the defence of others). However, because Taj's delusions were found by the court to have been caused by voluntary alcohol consumption, special legal (prior‐fault) intoxication rules were applied to block his defence; Taj was convicted and sentenced to 19 years imprisonment for attempted murder.
Argument
We focus here on the simple question—what does it mean to be intoxicated? On the facts, Taj did not have drugs active in his system at the time of the attack, but the court nonetheless insisted that Taj's delusional mistake was ‘attributable to intoxication’; namely, to drink‐ and drug‐taking in the previous days and weeks. This extended conception of intoxication was questionably distinguished from psychosis induced by withdrawal. Furthermore, the court was unreceptive to evidence of a long‐standing, underlying mental health disorder. We argue that the court's expanded view of intoxication is problematic, in that intoxication‐induced psychosis cannot be sharply distinguished from other causes such as mental disorders; and even if it could be distinguished, it should not give rise to blame and punishment in the same way as does conduct induced by chemically active intoxicants (‘drug‐on‐board’).
Conclusion
The courts’ expansion of the definition of intoxication is both legally and forensically problematic, introducing legal vagaries where the clinical science is already vague; and with intoxication frequently interlocking with historic intoxication and secondary or comorbid mental health conditions, the decision risks inappropriately and/or over‐criminalizing defendants.
•Visual cues briefly paired with sweet taste increased subsequent snack intake.•Visual cues briefly paired with sweet taste attracted attention.•Sweet-paired visual cues were not liked ...more.•Associations between visual cues and reward appear to be driven by changes in incentive motivation.
Most studies that examine responses to food cues use images of actual foods as stimuli. Since foods are rewarding in multiple ways, it then becomes difficult to try and partial out the role of the importance of different aspects of food reward. Here we aimed to evaluate the impact of novel visual cues specifically associated with the immediate sensory reward from a liked sweet taste. In the training phase, one visual cue (CSsweet) was associated with the experience of sweet taste (10%sucrose) and a second, control cue (CSneutral) with a neutral taste (artificial saliva) using a disguised training procedure. In Experiment 1, participants (n = 45) were given an ad libitum snack intake test 30 min post-training, either labelled with CSsweet or CSneutral. Total caloric consumption was significantly higher in the CSsweet (650 ± 47 kcal) than CSneutral (477 ± 45 kcal) condition, but ratings of liking for the snacks did not differ significantly between conditions. In Experiment 2, participants (n = 80) exhibited an overall attentional bias (22.1 ± 9.9 ms) for the CSsweet relative to CSneutral cue (assessed using a dot-probe task), however rated liking for the CSsweet did not change significantly after cue-sweet training. Likewise, measures of expected satiety for drinks labelled with CSsweet did not differ significantly from CSneutral. Overall these two experiments provide evidence that associations between neutral visual cues and the experience of a liked sweet taste leads to cue-potentiated eating in the presence of the CSsweet cue. With no evidence that cue-sweet training altered rated liking for the visual cues, and in keeping with extant literature on the dissociation of hedonic and rewarding properties of food rewards, we propose this potentiation effect to reflect increased incentive salience.
The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable ...preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touch screen based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research.
Animals selectively respond to environmental cues associated with food reward to optimize nutrient intake. Such appetitive conditioned stimulus-unconditioned stimulus (CS-US) associations are thought ...to be encoded in select, stable neuronal populations or neuronal ensembles, which undergo physiological modifications during appetitive conditioning. These ensembles in the medial prefrontal cortex (mPFC) control well-established, cue-evoked food seeking, but the mechanisms involved in the genesis of these ensembles are unclear. Here, we used male
mice that express green fluorescent protein (GFP) in recently behaviorally activated neurons, to reveal how dorsal mPFC neurons are recruited and modified to encode CS-US memory representations using an appetitive conditioning task. In the initial conditioning session, animals did not exhibit discriminated, cue-selective food seeking, but did so in later sessions indicating that a CS-US association was established. Using microprism-based
2-Photon imaging, we revealed that only a minority of neurons activated during the initial session was consistently activated throughout subsequent conditioning sessions and during cue-evoked memory recall. Notably, using
electrophysiology, we found that neurons activated following the initial session exhibited transient hyperexcitability. Chemogenetically enhancing the excitability of these neurons throughout subsequent conditioning sessions interfered with the development of reliable cue-selective food seeking, indicated by persistent, nondiscriminated performance. We demonstrate how appetitive learning consistently activates a subset of neurons to form a stable neuronal ensemble during the formation of a CS-US association. This ensemble may arise from a pool of hyperexcitable neurons activated during the initial conditioning session.
Appetitive conditioning endows cues associated with food with the ability to guide food-seeking, through the formation of a food-cue association. Neuronal ensembles in the mPFC control established cue-evoked food-seeking. However, how neurons undergo physiological modifications and become part of an ensemble during conditioning remain unclear. We found that only a minority of dorsal mPFC neurons activated on the initial conditioning session became consistently activated during conditioning and memory recall. These initially activated neurons were also transiently hyperexcitable. We demonstrate the following: (1) how stable neuronal ensemble formation in the dorsal mPFC underlies appetitive conditioning; and (2) how this ensemble may arise from hyperexcitable neurons activated before the establishment of cue-evoked food seeking.
Debating intoxication: Response to commentaries Crombag, Hans S.; Child, John J.; Sullivan, George R.
Addiction,
December 2020, 2020-12-00, 20201201, Letnik:
115, Številka:
12
Journal Article
Contextual stimuli associated with drug exposure can modulate various effects of drugs, but little is known about their role in relapse to drug seeking. Using a renewal procedure, the authors report ...that drug-associated contextual stimuli play a critical role in relapse to drug-seeking previously maintained by a heroin-cocaine mixture (speedball). Rats were trained to self-administer speedball, after which drug-reinforced behavior was extinguished over 20 days in the self-administration context or in a different context. On the test day, rats exposed to the drug-associated context, after extinction in a different context, reliably renewed drug seeking. The authors suggest that the renewal procedure can be used to study mechanisms underlying relapse to drug seeking elicited by drug-associated contextual stimuli.
We studied the long-term effects of amphetamine self-administration experience (or sucrose reward training) on dendritic morphology (spine density) in nucleus accumbens (Nacc), medial (MPC) and ...orbital prefrontal cortex (OFC), and hippocampus (CA1 and dentate). Independent groups of rats were trained under a continuous schedule of reinforcement to nose-poke for infusions of amphetamine (0.125 mg/kg/inf) or to receive sucrose pellets during 2 h daily test sessions for 14–20 days. One month after the last training session, the brains were collected and processed for Golgi–Cox staining. We found that: (i) amphetamine self-administration experience selectively increased spine density on medium spiny neurons in the Nacc and on pyramidal neurons in the MPC; (ii) in contrast, amphetamine self-administration decreased spine density in the OFC, whereas sucrose-reward training increased spine density; and (iii) both amphetamine self-administration and sucrose-reward experience increased spines in the CA1, but had no effect in the dentate gyrus. Thus, amphetamine self-administration experience produces long-lasting and regionally-selective morphological alterations in rat forebrain — alterations that may underlie some of the persistent psychomotor, cognitive and motivational consequences of chronic drug exposure.
Our aim was to explore how (neuro)scientific understanding of addiction as a brain-disease impacts criminal sentencing decisions in courts in England and Wales, where legal rules concerning ...intoxication, prior-fault and mental disease conflict, and sentencing guidelines lack clarity. We hypothesized that despite significant neuropsychiatric overlap of addiction and other brain-disorders, variables in relation to etiology would moderate magistrates' sentencing decisions in cases involving addicted offenders. Using a questionnaire-based, quantitative design, and combining frequentist and Bayesian analysis approaches, we probed court magistrates' sentencing decisions, and underlying rationale, for defendants presenting with brain damage resulting from a (fictional) disease, addiction to heroin, or more complex, mixed etiologies. When identical neuropsychiatric profiles resulted from disease, but not heroin addiction, prison sentences were significantly reduced. Study 1 (N = 109) found the pivotal factor preventing addiction from mitigating sentences was perceived choice in its acquisition; removing choice from addiction increased the odds of sentence reduction (∼20-fold) and attaching choice to disease aggravated or reversed earlier leniency. Study 2 (N = 276) replicated these results and found that when heroin use led to disease or vice versa, magistrates found middle ground. These differences were independent of the age of first drug use. Finally, evidence of addiction was more likely to evoke punishment considerations by magistrates, rather than rehabilitation. Consistent with legal rules relating to intoxication but running counter to norms around mental-illness and choice, our results demonstrate the need for greater clarity in sentencing guidance on addiction specifically, and mental disorders more generally.
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