Cocaine facilitates craving via an action on sensory processing

Sensory systems play an important role in cocaine addiction, perhaps most clearly demonstrated when stimuli (‘cues’) associated via classical conditioning with the effects of the drug, trigger craving and relapse. It has been shown in previous studies that administration of cocaine can enhance evoked responses in the primary sensory cortex of experimental animals. Given that the speed of learning in classical conditioning is affected by the intensity of the conditioned stimulus (CS), and that cocaine enhances the neural representation of sensory stimuli in the primary sensory cortex in a manner similar to an increase in intensity, we hypothesise that cue-induced craving in human addicts is facilitated by the drug. In short, cocaine speeds the process that leads to craving. This hypothesis is supported by the fact that cocaine enhances sensory responses in humans and leads to an improvement in attention (the putative intermediary between enhanced sensory responses and facilitated learning). Furthermore, cocaine affects neural loci which are known to play a role in learning and facilitates classical conditioning when present during acquisition. In addition, related drugs like d-amphetamine and ecstasy (which themselves produce craving) affect sensory processing and attention, and in the case of d-amphetamine facilitate human learning. It is therefore possible that cocaine itself plays a – previously under-appreciated – role in the formation of associations between drug and drug-related environmental cues by enhancing primary sensory responses. A corollary of this is that, as with other intense CSs, the established association may be particularly resistant to extinction, potentially explaining why cues continue to elicit craving months or even years after the last cocaine use.     

AIDS Rumour,Intellectual Anxiety,and Discursive Empowerment among Cameroonian Tradipractitioners

This article refines established notions of rumour as a strategy of discursive empowerment by differentiating typologies of empowerment. Specifically, I employ terminology from the anthropological literature on witchcraft to distinguish between ‘levelling’ rumour, which seeks to attack the power of others, and ‘accumulative’ rumour, which seeks to increase the power of rumour-tellers. To exemplify this, I explore a rumour that circulated in 2012 and 2013 among practitioners of traditional medicine in West Cameroon, which claimed that the state would kill tradipractitioners working to cure HIV/AIDS. I first outline the likely sociopolitical roots of practitioners’ anxiety regarding their intellectual labour. I then argue that this narrative was simultaneously levelling and accumulative in a national context, yet became accumulative in the more international context of practitioner–anthropologist relations. Ultimately, both forms of empowerment were key to understanding the rumour's favourable positioning of tradipractitioners in an increasingly uncertain, tense, and multinational part of Cameroon.     

Obstetric violence as immigration injustice: A view from the United States and Colombia

In September 2020, Project South, along with numerous other organizations, released a report detailing abuses in a Georgia Detention Center – including forced hysterectomies. Whatever other factors are at play, one of them is an intrinsic connection between obstetric violence against pregnant migrants and immigration injustice. It is not incidental that these acts – in US detention centers, along the US-Mexico border, in Colombian hospitals and clinics – are being perpetrated on immigrant bodies. And it is not accidental or random which immigrant bodies are vulnerable to these violations. Understanding and confronting obstetric violence directed at pregnant migrants, though, requires reconceptualizing the nature of obstetric violence itself. In particular, we must recognize that obstetric violence against pregnant Latin American migrants in the United States and Colombia is a type of immigration injustice, a means to perpetrate immigration injustice, and a product of immigration injustice. As such, bioethicists need to collaborate with immigration scholars to resist it. After providing some background on the nature of obstetric violence and some ways it is perpetuated against pregnant migrants in the United States and Colombia, I will give a brief overview of how I conceptualize immigration justice. From there, I explain how this type of obstetric violence constitutes a type of immigration injustice, a means to perpetrate immigration injustice, and a product of immigration injustice. My hope is that this analysis motivates bioethicists throughout the Americas to engage with immigration scholars and activists to confront the issue more forcefully.     

Transforming Growth Factor Beta Receptor 1 Is Increased following Abstinence from Cocaine Self-Administration,but Not Cocaine Sensitization

The addicted phenotype is characterized as a long-lasting, chronically relapsing disorder that persists following long periods of abstinence, suggesting that the underlying molecular changes are stable and endure for long periods even in the absence of drug. Here, we investigated Transforming Growth Factor-Beta Type I receptor (TGF-β R1) expression in the nucleus accumbens (NAc) following periods of withdrawal from cocaine self-administration (SA) and a sensitizing regimen of non-contingent cocaine. Rats were exposed to either (i) repeated systemic injections (cocaine or saline), or (ii) self-administration (cocaine or saline) and underwent a period of forced abstinence (either 1 or 7 days of drug cessation). Withdrawal from cocaine self-administration resulted in an increase in TGF-β R1 protein expression in the NAc compared to saline controls. This increase was specific for volitional cocaine intake as no change in expression was observed following a sensitizing regimen of experimenter-administered cocaine. These findings implicate TGF-β signaling as a novel potential therapeutic target for treating drug addiction.     

Gossip-Based Solutions for Discrete Rendezvous in Populations of Communicating Agents

The objective of the rendezvous problem is to construct a method that enables a population of agents to agree on a spatial (and possibly temporal) meeting location. We introduce the buffered gossip algorithm as a general solution to the rendezvous problem in a discrete domain with direct communication between decentralized agents. We compare the performance of the buffered gossip algorithm against the well known uniform gossip algorithm. We believe that a buffered solution is preferable to an unbuffered solution, such as the uniform gossip algorithm, because the use of a buffer allows an agent to use multiple information sources when determining its desired rendezvous point, and that access to multiple information sources may improve agent decision making by reinforcing or contradicting an initial choice. To show that the buffered gossip algorithm is an actual solution for the rendezvous problem, we construct a theoretical proof of convergence and derive the conditions under which the buffered gossip algorithm is guaranteed to produce a consensus on rendezvous location. We use these results to verify that the uniform gossip algorithm also solves the rendezvous problem. We then use a multi-agent simulation to conduct a series of simulation experiments to compare the performance between the buffered and uniform gossip algorithms. Our results suggest that the buffered gossip algorithm can solve the rendezvous problem faster than the uniform gossip algorithm; however, the relative performance between these two solutions depends on the specific constraints of the problem and the parameters of the buffered gossip algorithm.     

Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse

A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 μM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(∞)) required to produce physiological effects has been estimated to be 7.9±2.7 μM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.     

The neurosteroid dehydroepiandrosterone sulfate,but not androsterone,enhances the antidepressant effect of cocaine examined in the forced swim test — Possible role of serotonergic neurotransmission

One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5 mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.     

Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release

Intravenous injections of cocaine HCl are habit-forming because, among their many actions, they elevate extracellular dopamine levels in the terminal fields of the mesocorticolimbic dopamine system. This action, thought to be very important for cocaine''s strong addiction liability, is believed to have very short latency and is assumed to reflect rapid brain entry and pharmacokinetics of the drug. However, while intravenous cocaine HCl has almost immediate effects on behavior and extracellular dopamine levels, recent evidence suggests that its central pharmacological effects are not evident until 10 or more seconds after IV injection. Thus the immediate effects of a given intravenous cocaine injection on extracellular dopamine concentration and behavior appear to occur before there is sufficient time for cocaine to act centrally as a dopamine uptake inhibitor. To explore the contribution of peripheral effects of cocaine to the early activation of the dopamine system, we used brain microdialysis to measure the effects of cocaine methiodide (MI)—a cocaine analogue that does not cross the blood brain barrier—on glutamate (excitatory) input to the dopamine cells. IP injections of cocaine MI were ineffective in cocaine-naïve animals but stimulated ventral tegmental glutamate release in rats previously trained to lever-press for cocaine HCl. This peripherally triggered glutamate input was sufficient to reinstate cocaine-seeking in previously trained animals that had undergone extinction of the habit. These findings offer an explanation for short-latency behavioral responses and immediate dopamine elevations seen following cocaine injections in cocaine-experienced but not cocaine-naïve animals.     

Attenuation of Cocaine and Methamphetamine Neurotoxicity by Coenzyme Q10

The neurotoxic effects of cocaine and methamphetamine (METH) were studied in mice brain with a primary objective to determine the neuroprotective potential of coenzyme Q₁₀ (CoQ₁₀) in drug addiction. Repeated treatment of cocaine or METH induced significant reduction in the striatal dopamine and CoQ₁₀ in mice. Cocaine or METH-treated mice exhibited increased thiobarbituric acid reactive substances (TBARs) in the striatum and cerebral cortex without any significant change in the cerebellum. Complex I immunoreactivity was inhibited in both cocaine and METH-treated mice, whereas tyrosine hydroxylase (TH) immunoreactivity was decreased in METH-treated mice and increased in cocaine-treated mice. Neither cocaine nor METH could induce significant change in α-synuclein expression at the doses and duration we have used in the present study. CoQ₁₀ treatment attenuated cocaine and METH-induced inhibition in the striatal ¹⁸F-DOPA uptake as determined by high-resolution microPET neuroimaging. Hence exogenous administration of CoQ₁₀ may provide neuroprotection in drug addiction.     

Deadly secret: situating the unknowing and knowing of the source of the Ebola epidemic in Northern Uganda

This article critically examines the unknowing of the source of the Ebola epidemic in Northern Uganda, in 2000/1, by asking how this unknowing has been achieved and has shaped the disease situation. Specifically, this article follows my informants’ explanation that soldiers of the Uganda People's Defence Force had brought the disease from the Democratic Republic of the Congo to Uganda. This account is widely rejected as a rumour by scientists, who insist that the source of the epidemic remains unknown. By contrast, I suggest that following these stories, as embodied experiences of the multiple connections between war and epidemics, human and nonhuman lives, provides crucial insights into the political ecology of Ebola in the wider region – a region where, even today, conflict and Ebola outbreaks are intricately interwoven. Understanding how unknowing is achieved and shapes a disease situation directs attention to forms of silent knowing, which illuminate what preparedness means in the political ecology of Ebola.     

Moral failure: a jeremiad of the war on drugs in Guatemala

The current consensus among social scientists and political pundits is that the war on drugs failed, with a raft of failed programmes, failed interventions, failed policies, and even failed states. But these critics have tended to overlook a more existential form of failure that plays a key role in the ongoing effects of the war on drugs. This failure, which anthropologists of Christianity are well positioned to understand, is the perceived failure of Pentecostal Christians to make right with the Lord. Based on extensive fieldwork in Guatemala, a country profoundly transformed by the illicit movement of cocaine from the Andes to the United States, this article assesses how and to what effect a sense of moral failure among the country's Christian communities sustains a now expansive network of Pentecostal drug rehabilitation centres. Reading one such centre's archive of intake forms as a jeremiad – a Christian lament that bemoans the failures of society to keep its covenant with God – this article concludes that a sense of moral failure sustains the fading edges of today's war on drugs.     

Review. Positron emission tomography imaging studies of dopamine receptors in primate models of addiction

Animal models have provided valuable information related to trait and state variables associated with vulnerability to drug addiction. Our brain imaging studies in monkeys have implicated D2 receptors in cocaine addiction. For example, an inverse relationship between D2 receptor availability and rates of cocaine self-administration has been documented. Moreover, environmental variables, such as those associated with formation of the social hierarchy, can impact receptor availability and sensitivity to the abuse-related effects of cocaine. Similarly, both D2 receptor availability and cocaine self-administration can be altered by chronic drug administration and fluctuations in hormone levels. In addition, cocaine self-administration can be altered in an orderly fashion by presentation of an acute stressor, such as acting as an intruder into an unfamiliar social group, which can shift the cocaine dose-response curve to the left in subordinate monkeys and to the right in dominant animals, suggesting an interaction between social variables and acute stressors. Conversely, irrespective of social rank, acute environmental enrichment, such as increasing the size of the living space, shifts the cocaine dose-response curve to the right. These findings highlight a pervasive influence of the environment in modifying the reinforcing effects of cocaine and strongly implicate brain D2 receptors.     

Spencerism and the Causal Theory of Reference

Spencer’s heritage, while almost a forgotten chapter in the history of biology, lives on in psychology and the philosophy of mind. I particularly discuss externalist views of meaning, on which meaning crucially depends on a notion of reference, and ask whether reference should be thought of as cause or effect. Is the meaning of a word explained by what it refers to, or should we say that what we use a word to refer to is explained by what concept it expresses? I argue for the latter view, which I call ‘Darwinian’, and against the former, ‘Spencerian’ one, assuming conceptual structures in humans to be an instance of adaptive structures, and adaptive relations to an environment to be the effect rather than the cause of evolutionary novelties. I conclude with the deficiency – both empirically and methodologically – of a functionalist study of human concepts and the languages they are embedded in, as it would be undertaken in a paradigm that identifies meaning with reference or that gives reference an explanatory role to play for what concepts we have.     

Relationship between gestational cocaine use and pregnancy outcome: a meta-analysis.

Despite a growing number of studies that have investigated the reproductive effects of maternal cocaine use, a homogeneous pattern of fetal effects has not been established and there is little consensus on the adverse effects of the drug. We used meta-analysis to evaluate the reproductive risks of cocaine. We reviewed the 45 scientific papers published in the English language dealing with effects of cocaine used during pregnancy on pregnancy outcome in humans, and identified 20 papers eligible for meta-analysis (cocaine use in pregnancy, pregnancy/fetal outcome studies, human studies, original work, cohort or case control studies, control group present, English language). Our analysis revealed that very few adverse reproductive effects could be shown to be significantly associated with cocaine use by polydrug users when compared to control groups of polydrug users not using cocaine [genitourinary malformations; odds ratio of 6.08 (95% CI 1.18-31.3); gestation age: Cohen's d 0.37 (CI 0.2-0.55)]. When the control groups consisted of no drug users, the polydrug users abusing cocaine had a higher risk for spontaneous abortions [odds ration 10.50 (CI 11.74-64.1)]. Similarly, comparison of users of cocaine alone or no drug users revealed a higher risk for in utero death, in addition to genitourinary tract malformations. Analysis of continuous variables (head circumference, gestational age, birth weight and length) revealed that the effect size was dependent upon the nature of the comparison. Comparison of cocaine users to no drug users consistently yielded a medium effect size (Cohen's d) between 0.50 and 0.58, while comparison of polydrug/cocaine users to polydrug/no cocaine users provided effect sizes small to non existent (0.06-0.37). These discrepancies suggest that a variety of adverse reproductive effects commonly quoted to be associated with maternal use of cocaine may be caused by confounding factors clustering in cocaine users.     

Civil war and the non-linearity of time: approaching a Mozambican politics of irreconciliation

At least 1 million people died during the Mozambican civil war (1976/7-92). Unfolding after gaining independence from Portugal (1975) and alongside experiments with Afro-socialism in the 1980s, the war, despite its brutality, has not been subjected to global templates of reconciliation processes. Thus it comprises a unique case to probe what irreconciliation might mean – both as a political horizon and as an analytical concept. This text juxtaposes ethnographic material from rural, central Mozambique from the late 1990s and early 2000s emphasizing reconciliation with material from the same spaces from the 2010s onwards, where I identify what I term a ‘politics of irreconciliation’. I will make three arguments. First, informed by Hannah Arendt, I approach irreconciliation as fundamentally about the rejection of a world of violence in search of a world shared in common. Second, drawing on recent anthropological theorizing about temporal regimes and chronopolitics, I argue for the salience of a non-linear understanding of the politics of irreconciliation to grapple with the fact that civil war violence is understood as dangerously uncontained rather than nominally past. Third, within the context of Mozambique, forgiveness and its other, irreconciliation, are not only intimately tied to the temporally past or present; they are also, as I show, produced by a tangible and intense absence of a productive future.     

The Rhodococcus sp. cocaine esterase: a bacterial candidate for novel pharmacokinetic-based therapies for cocaine abuse

Cocaine is a powerful central nervous stimulant and among the most abused of drugs. Despite decades of efforts, however, no effective pharmacological treatments are available against cocaine addiction or toxic effects. Classical receptor-antagonist therapeutic approaches have not yielded significant effects, although cocaine targets are well known, thus fostering development of alternative therapeutic strategies. Recent evidence indicates that a sensible approach for treatment of cocaine abuse could be to interfere with cocaine pharmacokinetics, i.e. by preventing the drug from reaching the receptors responsible for its biological effects. Administration of cocaine binding antibodies as well as catalytic antibodies and enzymes that hydrolyze cocaine represent potential alternative therapeutic approach(es). The discovery of the cocaine esterase from the strain MBI of the bacterium Rhodococcus sp. (cocE) could be a major breakthrough in this field; cocE hydrolyzes cocaine faster than any known cocaine esterase and catalytic antibody.     

Lmo4 in the nucleus accumbens regulates cocaine sensitivity

An estimated 2 million Americans use cocaine, resulting in large personal and societal costs. Discovery of the genetic factors that contribute to cocaine abuse is important for understanding this complex disease. Previously, mutations in the Drosophila LIM‐only (dLmo) gene were identified because of their increased behavioral sensitivity to cocaine. Here we show that the mammalian homolog Lmo4, which is highly expressed in brain regions implicated in drug addiction, plays a similar role in cocaine‐induced behaviors. Mice with a global reduction in Lmo4 levels show increased sensitivity to the locomotor stimulatory effects of cocaine upon chronic cocaine administration. This effect is reproduced with downregulation of Lmo4 in the nucleus accumbens by RNA interference. Thus, Lmo genes play conserved roles in regulating the behavioral effects of cocaine in invertebrate and mammalian models of drug addiction.     

Acute effects of cocaine on the neurobiology of cognitive control

Compromised ability to exert control over drug urges and drug-seeking behaviour is a characteristic of addiction. One specific cognitive control function, impulse control, has been shown to be a risk factor for the development of substance problems and has been linked in animal models to increased drug administration and relapse. We present evidence of a direct effect of cocaine on the neurobiology underlying impulse control. In a laboratory test of motor response inhibition, an intravenous cocaine administration improved task performance in 13 cocaine users. This improvement was accompanied by increased activation in right dorsolateral and inferior frontal cortex, regions considered critical for this cognitive function. Similarly, for both inhibitory control and action monitoring processes, cocaine normalized activation levels in lateral and medial prefrontal regions previously reported to be hypoactive in users relative to drug-naive controls. The acute amelioration of neurocognitive dysfunction may reflect a chronic dysregulation of those brain regions and the cognitive processes they subserve. Furthermore, the effects of cocaine on midline function suggest a dopaminergically mediated intersection between cocaine's acute reinforcing effects and its effects on cognitive control.     

Mechanisms of Metabonomic for a Gateway Drug: Nicotine Priming Enhances Behavioral Response to Cocaine with Modification in Energy Metabolism and Neurotransmitter Level

Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. ¹H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.     

Familiarity with Interest Breeds Gossip: Contributions of Emotion,Expectation, and Reputation

Although gossip serves several important social functions, it has relatively infrequently been the topic of systematic investigation. In two experiments, we advance a cognitive-informational approach to gossip. Specifically, we sought to determine which informational components engender gossip. In Experiment 1, participants read brief passages about other people and indicated their likelihood to share this information. We manipulated target familiarity (celebrity, non-celebrity) and story interest (interesting, boring). While participants were more likely to gossip about celebrity than non-celebrity targets and interesting than boring stories, they were even more likely to gossip about celebrity targets embedded within interesting stories. In Experiment 2, we additionally probed participants'' reactions to the stories concerning emotion, expectation, and reputation information conveyed. Analyses showed that while such information partially mediated target familiarity and story interest effects, only expectation and reputation accounted for the interactive pattern of gossip behavior. Our findings provide novel insights into the essential components and processing mechanisms of gossip.