Addiction neuroscience最新文献

We recently reported an economic choice task in which squirrel monkeys chose between differing amounts of remifentanil, a fast-acting opioid, or a food reward to develop a preclinical screen for evaluating potential pharmacotherapies for opioid dependence. Herein, two known opioid addiction treatments were evaluated using this task, as well as a potential new agent, cariprazine, a dopamine D2/D3 receptor partial agonist currently used to treat bipolar disorder and schizophrenia. Preclinical rodent studies suggest this class of compounds may reduce opioid self-administration. Squirrel monkeys were pretreated daily with clinically relevant doses of each compound during the five days of treatment evaluation using the economic choice task. Shifts in drug preference were measured as changes in subjects’ indifference values, where the probability of drug and milk choice are equivalent. Buprenorphine produced a significant shift in indifference value between baseline and treatment weeks, indicating a decrease in drug preference. Subjects treated with methadone and cariprazine did not show any significant shift in drug preference. Differences between the buprenorphine and methadone results likely reflect a lack of opioid dependence in the subjects. The cariprazine results suggest that it does not alter opioid reward in non-dependent primates over a five day period.

Cocaine Use Disorders (CUDs) are associated with an increased risk of human immunodeficiency virus (HIV) infection. Cocaine and the HIV envelope protein gp120 each induce distinct deficits to mesocorticolimbic circuit function and motivated behavior; however, little is known regarding how they interact to dysregulate these functions or how such interactions impact pharmacotherapeutic efficacy. We have previously shown that the selective, weak partial agonist of the dopamine D3 receptor (D3R), MC-25-41, attenuates cocaine-seeking behavior in male rats. Here, we sought to characterize changes in striatal neuroimmune function in gp120-exposed rats across abstinence from operant access to cocaine (0.75 mg/kg, i.v.) or sucrose (45 mg/pellet), and to examine the impact of gp120 exposure on MC-25-41-reduced cocaine seeking. After establishing a history of cocaine or sucrose self-administration, rats received intracerebroventricular gp120 infusions daily the first 5 days of abstinence and were sacrificed either on day 6 or after 21 days of forced abstinence and a cue-induced cocaine seeking test. We demonstrated that MC-25-41 treatment attenuated cue-induced cocaine seeking among control rats but not gp120-exposed rats. Moreover, postmortem analysis of nucleus accumbens (NAc) core neuroimmune function indicated cocaine abstinence- and gp120-induced impairments, and the expression of several immune factors within the NAc core significantly correlated with cocaine-seeking behavior. We conclude that cocaine abstinence dysregulates striatal neuroimmune function and interacts with gp120 to inhibit the effectiveness of a D3R partial agonist in reducing cocaine seeking. These findings highlight the need to consider comorbidities, such as immune status, when evaluating the efficacy of novel pharmacotherapeutics.

Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.

Persons that develop Alcohol Use Disorder (AUD) experience behavioral changes that include compulsion to seek and take alcohol despite its negative consequences on the person's psychosocial, health and economic spheres, inability to limit alcohol intake and a negative emotional/ motivational state that emerges during withdrawal. During all the stages of AUD executive functions, i.e. the person's ability to direct their behavior towards a goal, working memory and cognitive flexibility are eroded. Animal models of AUD recapitulate aspects of action selection impairment and offer the opportunity to benchmark the underlying circuit mechanisms. Here we propose a circuit-based approach to AUD research focusing on recent advances in behavioral analysis, neuroanatomy, genetics, and physiology to guide future research in the field.

Maladaptive behavior in drug addiction is widely regarded as a result of neurocognitive dysfunctions. Recently, there has been a growing trend to adopt computational methods to study these dysfunctions in drug-addicted patients, not least because it provides a quantitative framework to infer the psychological mechanisms that may have gone awry in addiction. We therefore sought to evaluate the extent to which these theory-driven computational models have fulfilled this purpose in addiction research. We discuss several learning and decision-making theories proposed to explain symptoms that characterize impaired control and the intense urge to use drugs in addiction, and outline the computational algorithms frequently used to model these processes. Specifically, impaired behavioral control over drugs have been explained by aberrant reinforcement learning algorithms and an imbalance between model-based and model-free control, whereas the strong desire for drugs might be explained by a neurocomputational model of incentive sensitization and behavioral economic theory. We argue that while theory-driven computational models may appear to be useful tools that generate novel mechanistic insights into drug addiction, their use should be informed by psychological theory, experimental data, and clinical observations.

Background

Cannabis Use Disorder (CUD) is increasingly prevalent in the United States, while perceived addiction risk and treatment-seeking are declining. Emotional salience of cannabis-use-related problems and benefits likely contribute to motivation to change, but measurement of this process has been limited. The present study sought to validate a novel assessment of emotional appraisal of self-referential cannabis-use-related information across subjective and neurophysiological units of analysis.

Method

Non-treatment-seeking individuals with DSM-5 severe CUD (N = 42) completed a task that presented auditory self-referential, personalized cannabis-use-related problem and benefit statements, as well as neutral self-referential statements, during electroencephalography recording. The late positive potential (LPP) was used as a neurophysiological measure of emotional salience. Valence/arousal ratings of each statement, along with their motivational importance in sustaining vs. reducing cannabis use, were also obtained.

Results

As predicted, valence and arousal ratings significantly differentiated cannabis-use-related problems and benefits from neutral statements. Partially consistent with predictions, the LPP to cannabis-use-related benefits was significantly larger than LPPs to cannabis-use-related problems and neutral statements, which did not differ from each other. Bonferroni-adjusted exploratory correlations revealed that the LPP to cannabis-use-related problems was sensitive to recent cannabis use frequency.

Conclusion

These results provide some support for the validity of this novel multi-method assessment of emotional reactivity to personalized cannabis-use-related self-referential information in non-treatment-seeking individuals with severe CUD. The dissociation between subjective and neurophysiological reactivity to self-referential cannabis-related problem statements should be further explored.

Rodent models are useful for understanding the mechanisms that underlie opioid addiction, but most preclinical studies have focused on rewarding and consummatory aspects of opioids without components of dependence-induced escalation of drug taking or seeking. We characterized several opioid-related behaviors in mice using a model of vaporized fentanyl self-administration. Male and female C57BL/6J mice were assigned to short-access (ShA; 1 h, nondependent) or long-access (LgA; 6 h, dependent) fentanyl vapor self-administration and subsequently tested in a battery of behavioral tests, followed by blood collection during withdrawal. Compared with mice in the ShA group, mice in the LgA group escalated their fentanyl intake, were more motivated to work to obtain the drug, exhibited greater hyperalgesia, and exhibited greater signs of naloxone-precipitated withdrawal. Principal component analysis indicated the emergence of two independent behavioral constructs: “intake/motivation” and “hyperalgesia/punished seeking.” In mice in the LgA condition only, “hyperalgesia/punished seeking” was associated with plasma levels of proinflammatory interleukin-17 (IL-17), chemokine (C-C motif) ligand 4 (CCL-4), and tumor necrosis factor α (TNF-α). Overall, the results suggest that extended access to opioids leads to addiction-like behavior, and some constructs that are associated with addiction-like behavior may be associated with levels of the proinflammatory cytokines/chemokines IL-17, TNF-α, and CCL-4 in blood.

Males and females exhibit differences in motivated and affective behavior; however, the neural substrates underlying these differences remain poorly understood. In the paraventricular nucleus of the thalamus (PVT), sex-related differences in neuronal activity have been identified in response to motivated behavior tasks and affective challenges. Within the PVT, the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is highly expressed and is also involved in motivated and affective behavior. The purpose of this study was to compare the expression of PACAP mRNA and peptide in the PVT of males and females. Analysis with quantitative real-time PCR in mice revealed that females had significantly higher levels of PACAP mRNA than males in the whole PVT, but no differences in the neuropeptides enkephalin or corticotropin releasing factor (CRF) in this brain region. While in rats, females demonstrated a trend for greater gene expression than males in the anterior/middle and middle/posterior PVT, they again showed no differences in enkephalin or CRF. Analysis with immunofluorescent histochemistry revealed that female mice had significantly more PACAP-containing cells than males as a function of area throughout the PVT, and that female rats had significantly more PACAP-27 and PACAP-38-containing cells than males, both as a percentage of total cells and as a function of PVT area. For PACAP-27, this specifically occurred in the anterior PVT, and for PACAP-38, it occurred throughout the anterior, middle, and posterior PVT. These results suggest that sex-related differences in PVT PACAP may underly some of the established sex-related differences in motivated and affective behavior.

The unprecedented proliferation of novel psychoactive substances (NPS) in the illicit drug market has been a public health concern since their emergence in the 2000s. Their consumption can pose severe health risks as their mechanism of action is poorly understood and their level of toxicity is high mainly due to the diffusion of very potent synthetic cannabinoid receptor agonists and synthetic opioids. This study systemically analyses the evolution of the scientific literature on NPS to gain a better understanding of the areas of major research interests and how they interlink. Findings indicate that the published evidence covers clusters focused on classes of NPS that have received widespread media attention, such as mephedrone and fentanyl, and have largely been concerned with the pharmacological and the toxicological profiles of these substances. This scientometric perspective also provides greater insight into the knowledge gaps within this new and rapidly growing field of study and highlights the need for an interdisciplinary approach in tackling the NPS epidemic.