Individual differences in the neuropsychopathology of addiction.

Drug addiction or substance-use disorder is a chronically relapsing disorder that progresses through binge/intoxication, withdrawal/negative affect and preoccupation/anticipation stages. These stages represent diverse neurobiological mechanisms that are differentially involved in the transition from recreational to compulsive drug use and from positive to negative reinforcement. The progression from recreational to compulsive substance use is associated with downregulation of the brain reward systems and upregulation of the brain stress systems. Individual differences in the neurobiological systems that underlie the processing of reward, incentive salience, habits, stress, pain, and executive function may explain (i) the vulnerability to substance-use disorder; (ii) the diversity of emotional, motivational, and cognitive profiles of individuals with substance-use disorders; and (iii) heterogeneous responses to cognitive and pharmacological treatments. Characterization of the neuropsychological mechanisms that underlie individual differences in addiction-like behaviors is the key to understanding the mechanisms of addiction and development of personalized pharmacotherapy

Establishing the behavioural limits for countershaded camouflage

Countershading is a ubiquitous patterning of animals whereby the side that typically faces the highest illumination is darker. When tuned to specific lighting conditions and body orientation with respect to the light field, countershading minimizes the gradient of light the body reflects by counterbalancing shadowing due to illumination, and has therefore classically been thought of as an adaptation for visual camouflage. However, whether and how crypsis degrades when body orientation with respect to the light field is non-optimal has never been studied. We tested the behavioural limits on body orientation for countershading to deliver effective visual camouflage. We asked human participants to detect a countershaded target in a simulated three-dimensional environment. The target was optimally coloured for crypsis in a reference orientation and was displayed at different orientations. Search performance dramatically improved for deviations beyond 15 degrees. Detection time was significantly shorter and accuracy significantly higher than when the target orientation matched the countershading pattern. This work demonstrates the importance of maintaining body orientation appropriate for the displayed camouflage pattern, suggesting a possible selective pressure for animals to orient themselves appropriately to enhance crypsis

Is countershading camouflage robust to lighting change due to weather?

Countershading is a pattern of coloration thought to have evolved in order to implement camouflage. By adopting a pattern of coloration that makes the surface facing towards the sun darker and the surface facing away from the sun lighter, the overall amount of light reflected off an animal can be made more uniformly bright. Countershading could hence contribute to visual camouflage by increasing background matching or reducing cues to shape. However, the usefulness of countershading is constrained by a particular pattern delivering ‘optimal’ camouflage only for very specific lighting conditions. In this study, we test the robustness of countershading camouflage to lighting change due to weather, using human participants as a ‘generic’ predator. In a simulated three-dimensional environment, we constructed an array of simple leaf-shaped items and a single ellipsoidal target ‘prey’. We set these items in two light environments: strongly directional ‘sunny’ and more diffuse ‘cloudy’. The target object was given the optimal pattern of countershading for one of these two environment types or displayed a uniform pattern. By measuring detection time and accuracy, we explored whether and how target detection depended on the match between the pattern of coloration on the target object and scene lighting. Detection times were longest when the countershading was appropriate to the illumination; incorrectly camouflaged targets were detected with a similar pattern of speed and accuracy to uniformly coloured targets. We conclude that structural changes in light environment, such as caused by differences in weather, do change the effectiveness of countershading camouflage

Present and future potential of plant-derived products to control arthropods of veterinary and medical significance

The use of synthetic pesticides and repellents to target pests of veterinary and medical significance is becoming increasingly problematic. One alternative approach employs the bioactive attributes of plant-derived products (PDPs). These are particularly attractive on the grounds of low mammalian toxicity, short environmental persistence and complex chemistries that should limit development of pest resistance against them. Several pesticides and repellents based on PDPs are already available, and in some cases widely utilised, in modern pest management. Many more have a long history of traditional use in poorer areas of the globe where access to synthetic pesticides is often limited. Preliminary studies support that PDPs could be more widely used to target numerous medical and veterinary pests, with modes of action often specific to invertebrates. Though their current and future potential appears significant, development and deployment of PDPs to target veterinary and medical pests is not without issue. Variable efficacy is widely recognised as a restraint to PDPs for pest control. Identifying and developing natural bioactive PDP components in place of chemically less-stable raw or 'whole’ products seems to be the most popular solution to this problem. A limited residual activity, often due to photosensitivity or high volatility, is a further drawback in some cases (though potentially advantageous in others). Nevertheless, encapsulation technologies and other slow-release mechanisms offer strong potential to improve residual activity where needed. The current review provides a summary of existing use and future potential of PDPs against ectoparasites of veterinary and medical significance. Four main types of PDP are considered (pyrethrum, neem, essential oils and plant extracts) for their pesticidal, growth regulating and repellent or deterrent properties. An overview of existing use and research for each is provided, with direction to more extensive reviews given in many sections. Sections to highlight potential issues, modes of action and emerging and future potential are also included

Higgs Assisted Q-balls from Pseudo-Nambu-Goldstone Bosons

Motivated by recent constructions of TeV-scale strongly-coupled dynamics, either associated with the Higgs sector itself as in pseudo-Nambu-Goldstone boson (pNGB) Higgs models or in theories of asymmetric dark matter, we show that stable solitonic Q- balls can be formed from light pion-like pNGB fields carrying a conserved global quantum number in the presence of the Higgs field. We focus on the case of thick-wall Q-balls, where solutions satisfying all constraints are shown to exist over a range of parameter values. In the limit that our approximations hold, the Q-balls are weakly bound and parametrically large, and the form of the interactions of the light physical Higgs with the Q-ball is determined by the breaking of scale symmetry.Comment: 24 pages, 6 figures, 1 tabl

An enzymatic approach reverses nicotine dependence, decreases compulsive-like intake, and prevents relapse.

Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)-induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans

Dopamine D3 Receptor Antagonism Reverses the Escalation of Oxycodone Self-administration and Decreases Withdrawal-Induced Hyperalgesia and Irritability-Like Behavior in Oxycodone-Dependent Heterogeneous Stock Rats.

Prescription opioids, such as oxycodone, are highly effective analgesics for clinical pain management, but approximately 25% of patients who are prescribed opioids misuse them, and 5%-10% develop an opioid use disorder (OUD). Effective therapies for the prevention and treatment of opioid abuse and addiction need to be developed. The present study evaluated the effects of the highly selective dopamine D3 receptor antagonist VK4-116 ([R]-N-[4-(4-[3-chloro-5-ethyl-2-methoxyphenyl]piperazin-1-yl)-3-hydroxybutyl]-1H-indole-2-carboxamide) on oxycodone addictive-like behaviors. We used a model of extended access to oxycodone self-administration and tested the effects of VK4-116 on the escalation of oxycodone self-administration and withdrawal-induced hyperalgesia and irritability-like behavior in male and female rats. Pretreatment with VK4-116 (5-25 mg/kg, i.p.) dose-dependently decreased the escalation of oxycodone self-administration and reduced withdrawal-induced hyperalgesia and irritability-like behavior in opioid-dependent rats. These findings demonstrate a key role for D3 receptors in both the motivation to take opioids and negative emotional states that are associated with opioid withdrawal and suggest that D3 receptor antagonism may be a viable therapeutic approach for the treatment of OUD

Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol-Dependent Rats.

GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior