Addiction is a brain disease, and it doesn’t matter: prior choice in drug use blocks leniency in criminal punishment

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

Debating intoxication: response to commentaries

The lack of scientific or clinical clarity faced by courts dealing with cases involving intoxicated criminal defendants is unavoidable, but introducing further legal ambiguity to meet policy goals introduces ever greater risk of problematic (including unjust) legal outcomes

Prior fault and contrived criminal defences: coming to the law with clean hands

The concept of ‘prior fault’ presents a number of significant challenges for the criminal law. The focus of criminal law (offences and defences) is necessarily event specific; we target and assess liability in relation to a snap-shot moment in time or a short series of acts, not as a judgement of prior or more general culpability or character. Therefore, prior fault should be largely an irrelevance at the liability stage. However, remaining faithful to this narrow focus in all circumstances would lead to considerable unfairness, creating an opportunity for defendants to manipulate legal rules to their own advantage. Some of the clearest examples of this arise in so-called contrived defence cases. Let’s take the example of self-defence, a general and complete defence where the defendant’s (D’s) use of force against the victim (V) is both necessary and reasonably proportionate. The standard operation of this defence is largely uncontroversial; people should be empowered to defend themselves from unlawful attack. However, what if D manufactures the circumstances of that ‘attack’ in order to use the law of self-defence to ‘justify’ her pre-planned use of force against V. For example, D wants to kill V. D hands V a knife and then goads V continuously until V (as anticipated) lashes out at D. D shoots and kills V in self-defence. In order to understand and analyse examples such as the one above, we must distinguish two points in time within each potential criminal event. First, and standardly, we must look at the time where the potential criminal offence is committed (T2), asking whether the elements of the potential offence are completed, and if so, whether the elements of a potential defence can be found. In our example above, it is likely that the offence of murder was committed by D, but D would also be able to raise self-defence because of the attack from V. Secondly, we must look at D’s conduct prior to the potential crime (T1), to ask if D has done anything to undermine her future use of a defence at T2. In our example, this could be D’s prior fault in planning, and in manipulating V, in order to create the circumstances of her own defence. It is at this second stage, looking back to T1, that legal rules relating to prior fault must be identified and applied. Issues of prior fault are (potentially) relevant across every criminal defence, and this has given rise to a variety of legal rules designed to prevent the application of contrived defences. However, the legal rules relating to prior fault are often unclear and inconsistent between different defences. Basic questions about what D must have done at T1, what she must have intended, and how this can impact liability at T2, all require investigation. In this article, we provide such an investigation. In Part 1 we explore the application of legal rules relating to prior fault within the current law, exposing areas of inconsistency and incoherence. Part 2 discusses the academic response to this inconsistency, including different models of prior fault that have been recommended in an effort to bring coherence to this area of law. Finally, in Part 3, building upon the academic analysis, we set out our own model of legal rules relating to prior fault; a model that we believe can (and should) be applied across all criminal defences. It is contended that the issue of prior fault can be addressed consistently, and that such rules should form part of any codification project

Regional differences in striatal neuronal ensemble excitability following cocaine and extinction memory retrieval in Fos-GFP mice

Learned associations between drugs of abuse and the drug administration environment play an important role in addiction. In rodents, exposure to a drug-associated environment elicits conditioned psychomotor activation, which may be weakened following extinction learning. While widespread drug-induced changes in neuronal excitability have been observed, little is known about specific changes within neuronal ensembles activated during the recall of drugenvironment associations. Using a cocaine conditioned locomotion procedure, the present study assessed the excitability of neuronal ensembles in the nucleus accumbens core and shell (NAccore and NAcshell), and dorsal striatum (DS) following cocaine conditioning and extinction in Fos-GFP mice that express green fluorescent protein (GFP) in activated neurons (GFP+). During conditioning, mice received repeated cocaine injections (20 mg/kg) paired with a locomotor activity chamber (Paired) or home cage (Unpaired). 7-13 days later both groups were re-exposed to the activity chamber under drug-free conditions, and Paired, but not Unpaired, mice exhibited conditioned locomotion. In a separate group of mice, conditioned locomotion was extinguished by repeatedly exposing mice to the activity chamber under drugfree conditions. Following the expression and extinction of conditioned locomotion, GFP+ neurons in the NAccore (but not NAcshell and DS) displayed greater firing capacity compared to surrounding GFP– neurons. This difference in excitability was due to a generalized decrease in GFP– excitability following conditioned locomotion, and a selective increase in GFP+ excitability following its extinction. These results suggest a role for both widespread and ensemble-specific changes in neuronal excitability following recall of drug-environment associations

An open-source pipeline for analysing changes in microglial morphology

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

Extinction of cue-evoked food seeking recruits a GABAergic interneuron ensemble in the dorsal medial prefrontal cortex of mice

Animals must quickly adapt food-seeking strategies to locate nutrient sources in dynamically changing environments. Learned associations between food and environmental cues that predict its availability promote food-seeking behaviors. However, when such cues cease to predict food availability, animals undergo 'extinction' learning, resulting in the inhibition of food-seeking responses. Repeatedly activated sets of neurons, or 'neuronal ensembles', in the dorsal medial prefrontal cortex (dmPFC) are recruited following appetitive conditioning and undergo physiological adaptations thought to encode cue-reward associations. However, little is known about how the recruitment and intrinsic excitability of such dmPFC ensembles are modulated by extinction learning. Here, we used in vivo 2-Photon imaging in male Fos-GFP mice that express green fluorescent protein (GFP) in recently behaviorally-activated neurons to determine the recruitment of activated pyramidal and GABAergic interneuron mPFC ensembles during extinction. During extinction, we revealed a persistent activation of a subset of interneurons which emerged from a wider population of interneurons activated during the initial extinction session. This activation pattern was not observed in pyramidal cells, and extinction learning did not modulate the excitability properties of activated neurons. Moreover, extinction learning reduced the likelihood of reactivation of pyramidal cells activated during the initial extinction session. Our findings illuminate novel neuronal activation patterns in the dmPFC underlying extinction of food-seeking, and in particular, highlight an important role for interneuron ensembles in this inhibitory form of learning

Changes in appetitive associative strength modulates nucleus accumbens, but not orbitofrontal cortex neuronal ensemble excitability

Cues that predict the availability of food rewards influence motivational states and elicit food-seeking behaviors. If a cue no longer predicts food availability, animals may adapt accordingly by inhibiting food seeking responses. Sparsely activated sets of neurons, coined neuronal ensembles, have been shown to encode the strength of reward-cue associations. While alterations in intrinsic excitability have been shown to underlie many learning and memory processes, little is known about these properties specifically on cue-activated neuronal ensembles. We examined the activation patterns of cue-activated orbitofrontal cortex (OFC) and nucleus accumbens (NAc) shell ensembles using wild-type and Fos-GFP mice following appetitive conditioning with sucrose and extinction learning. We also investigated the neuronal excitability of recently activated, GFP+ neurons in these brain areas using whole-cell electrophysiology in brain slices. Exposure to a sucrose cue elicited activation of neurons in both the NAc shell and OFC. In the NAc shell, but not the OFC, these activated GFP+ neurons were more excitable than surrounding GFP– neurons. Following extinction, the number of neurons activated in both areas was reduced and activated ensembles in neither area exhibited altered excitability. These data suggest that learning-induced alterations in the intrinsic excitability of neuronal ensembles is regulated dynamically across different brain areas. Furthermore, we show that changes in associative strength modulate the excitability profile of activated ensembles in the NAc shell

Drunk, dangerous and delusional: how legal concept-creep risks overcriminalization

Background In the recent case of R v Taj, the Court of Appeal of England & 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). But 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 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 conduct induced by chemically active intoxicants (‘drug‐on‐board’) does. 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 co‐morbid mental health conditions, the decision risks inappropriately and/or over‐criminalising defendants

The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine

The environmental context in which psychostimulant drugs are administered can have a large effect on both their acute psychomotor activating effects and their ability to induce the psychomotor sensitization associated with repeated drug administration. For example, the acute effects of amphetamine and the development of psychomotor sensitization to amphetamine and cocaine are enhanced when they are administered in a distinct and relatively novel test environment, relative to when they are given in the home cage, in the absence of any environmental stimuli predictive of drug administration. The experiments reported here were designed to further examine this phenomenon and to test the hypothesis that the ability of a distinct context to promote robust psychomotor sensitization is due to its ability to reliably signal (cue) drug administration. Specifically, we compared the ability of contextual cues (a distinct test environment) and discrete cues (light, tone and/or odor), which both reliably predict drug administration, to promote the induction of sensitization. The psychomotor stimulant effects (rotational behavior) of repeated intravenous infusions of 0. 5 mg/kg amphetamine were assessed in rats for whom drug treatments were signaled either: (1) by placement into a distinct test environment; (2) by presentation of discrete cues; or (3) rats for whom drug treatments were given in the home environment in the absence of any environmental cues. Amphetamine produced robust sensitization when given in association with placement into a distinct test environment. The same treatment failed to produce sensitization when the drug was given unsignaled in the animal's home cage. Most importantly, signaling drug administration by presenting discrete cues was not sufficient to promote the robust sensitization seen when treatments were given in a distinct test environment. These results confirm that the induction of psychomotor sensitization can be powerfully modulated by environmental context and further establish that, although contextual stimuli associated with a distinct test environment promote robust sensitization, discrete cues that merely predict drug administration do not have this property. Possible reasons for the difference in the ability of contextual versus discrete environmental cues to promote sensitization are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61933/1/crombagBBR00.pd

Acute, but not longer-term, exposure to environmental enrichment attenuates Pavlovian cue-evoked conditioned approach and Fos expression in the prefrontal cortex in mice.

Funder: The University of Sussex Strategic Development FundsFunder: Sussex Neuroscience 4‐year PhD programmeExposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose-associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker "Fos." Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non-contingent or "forced" exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward-seeking across species