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Rationale Taking high and increasing amounts of cocaine is thought to be necessary for the development of addiction. Consequently, a widely used animal model of drug self-administration involves giving animals continuous drug access during long sessions (LgA), as this produces high and escalating levels of intake. However, human cocaine addicts likely use the drug with an intermittent rather than continuous pattern, producing spiking brain cocaine levels. Objectives Using an intermittent-access (IntA) cocaine self-administration procedure in rats, we studied the relationship between escalation of cocaine intake and later incentive motivation for the drug, as measured by responding under a progressive ratio schedule of cocaine reinforcement. Results First, under IntA, rats escalated their cocaine use both within and between sessions. However, escalation did not predict later incentive motivation for the drug. Second, incentive motivation for cocaine was similar in IntA-rats limited to low- and non-escalating levels of drug intake (IntA-Lim) and in IntA-rats that took high and escalating levels of drug. Finally, IntA-Lim rats took much less cocaine than rats given continuous drug access during each self-administration session (LgA-rats). However, IntA-Lim rats later responded more for cocaine under a progressive ratio schedule of reinforcement. Conclusions Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern—even in small amounts—is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.

In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75 mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100 mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75 mg/kg, p.o.) and reference drugs; acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.

Cannabinoid CB 2 receptor (CB 2 ) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB 2 ; however, the involvement of CB 2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB 2 agonist JWH133 in wild-type and knockout mice lacking CB 2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB 2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB 2 knockouts and was increased in mice defective in neuronal CB 2 knockouts suggestive of increased spontaneous pain. Interestingly, CB 2 -positive lymphocytes infiltrated the injured nerve and possible CB 2 transfer from immune cells to neurons was found. Lymphocyte CB 2 depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB 2 that protects against spontaneous and evoked neuropathic pain.

Aims Opioid use disorder (OUD) remains a serious public health problem. Opioid maintenance treatment is effective but under‐utilized, hard to access under existing federal regulations, and, once patients achieve OUD stability, challenging to discontinue. Fewer than 2% of persons with OUD stop using opioids completely. There have been calls from public advocacy groups, governmental agencies, and public health officials for new treatments for OUD. Dezocine, a non‐scheduled opioid previously used in the United States and currently widely prescribed in China for pain management, could be a candidate for a novel OUD treatment medication in the U.S. Nonetheless, to date, there have been no reviews of the clinical and preclinical literature detailing dezocine's abuse potential, a key consideration in assessing its clinical utility. Discussion There are no English language reports of human abuse, dependence, or overdose of dezocine, despite years of extensive clinical use. There are a few case reports of dezocine abuse in the Chinese literature, but there are no reports of overdose deaths. Dezocine is perceived as an opioid and is “liked” by opioid‐experienced human and non‐human primates, properties that are not dose‐dependent and are mitigated by ceiling effects—higher doses do not result in more “liking.” There is little withdrawal, spontaneous or precipitated, in humans, monkeys, rats, or mice treated chronically with dezocine alone. However, at some doses, dezocine can precipitate withdrawal in humans and monkeys dependent on other opioids. In rodents, dezocine reduces the severity of morphine withdrawal and the rewarding properties of other opioids. Conclusions Although dezocine is reinforcing in humans and monkeys with prior or concurrent opioid use within a restricted dose range, there are only a few anecdotal reports of dezocine abuse despite of the long history of use in humans. Given the evidence of dezocine's limited abuse potential, it could be useful both as a treatment for OUD. However, in‐depth studies would be required for dezocine to be re‐considered for clinical use. Dezocine is a partial MOR agonist previously used clinically in the USA and currently in China. It has been proposed that dezocine be reintroduced to clinical use in the USA, as an analgesia and/or an additional tool to treat opioid use disorder. To consider the clinical reintroduction of dezocine knowing its abuse liability is important. In this review, we found no reports of abuse, dependence or overdose in the English literature, and a small number of cases of dependence in the Chinese literature. If it is less or non‐addictive than other opioids, its short half‐life would allow it to bridge to other medication assisted therapies, facilitate tapering of opioid use and perhaps be used as a rescue medication in those trying to reduce opioid use.

Addiction treatment has not been appreciably improved by neuroscientific research. One problem is that mechanistic studies using rodent models do not incorporate volitional social factors, which play a critical role in human addiction. Here, using rats, we introduce an operant model of choice between drugs and social interaction. Independent of sex, drug class, drug dose, training conditions, abstinence duration, social housing, or addiction score in Diagnostic & Statistical Manual IV-based and intermittent access models, operant social reward prevented drug self-administration. This protection was lessened by delay or punishment of the social reward but neither measure was correlated with the addiction score. Social-choice-induced abstinence also prevented incubation of methamphetamine craving. This protective effect was associated with activation of central amygdala PKCδ-expressing inhibitory neurons and inhibition of anterior insular cortex activity. These findings highlight the need for incorporating social factors into neuroscience-based addiction research and support the wider implantation of socially based addiction treatments.

Social reinforcement-based treatments are effective for many, but not all, people with addictions to drugs. We recently developed an operant rat model that mimics features of one such treatment, the community-reinforcement approach. In this model, rats uniformly choose social interaction over methamphetamine or heroin. Abstinence induced by social preference protects against the incubation of drug-seeking that would emerge during forced abstinence. Here, we determined whether these findings generalize to cocaine and whether delaying or increasing effort for social interaction could reveal possibly human-relevant individual differences in responsiveness. We trained male and female rats for social self-administration (6 days) and then for cocaine self-administration, initially for 2-h/day for 4 days, and then for 12-h/day continuously or intermittently for 8 days. We assessed relapse to cocaine seeking after 1 and 15 days. Between tests, the rats underwent either forced abstinence or social-choice-induced abstinence. After establishing stable social preference, we manipulated the delay for both rewards or for social reward alone, or the response requirements (effort) for social reward. Independent of cocaine-access conditions and sex, operant social interaction inhibited cocaine self-administration and prevented incubation of cocaine seeking. Preference for social access was decreased by the delay of both rewards or social reward alone, or by increased response requirements for social reward, with notable individual variability. This choice procedure can identify mechanisms of individual differences in an animal model of cocaine use and could thereby help screen medications for people who are relatively unresponsive to treatments based on rewarding social interaction.

Background and rationale Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. Objective In this review, we first summarize recent (2009–present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model. Conclusions Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving.

The nutritional and economic potentials of livestock systems are compromised by the emergence and spread of antimicrobial resistance. A major driver of resistance is the misuse and abuse of antimicrobial drugs. The likelihood of misuse may be elevated in low- and middle-income countries where limited professional veterinary services and inadequately controlled access to drugs are assumed to promote non-prudent practices (e.g., self-administration of drugs). The extent of these practices, as well as the knowledge and attitudes motivating them, are largely unknown within most agricultural communities in low- and middle-income countries. The main objective of this study was to document dimensions of knowledge, attitudes and practices related to antimicrobial use and antimicrobial resistance in livestock systems and identify the livelihood factors associated with these dimensions. A mixed-methods ethnographic approach was used to survey households keeping layers in Ghana (N = 110) and Kenya (N = 76), pastoralists keeping cattle, sheep, and goats in Tanzania (N = 195), and broiler farmers in Zambia (N = 198), and Zimbabwe (N = 298). Across countries, we find that it is individuals who live or work at the farm who draw upon their knowledge and experiences to make decisions regarding antimicrobial use and related practices. Input from animal health professionals is rare and antimicrobials are sourced at local, privately owned agrovet drug shops. We also find that knowledge, attitudes, and particularly practices significantly varied across countries, with poultry farmers holding more knowledge, desirable attitudes, and prudent practices compared to pastoralist households. Multivariate models showed that variation in knowledge, attitudes and practices is related to several factors, including gender, disease dynamics on the farm, and source of animal health information. Study results emphasize that interventions to limit antimicrobial resistance should be founded upon a bottom-up understanding of antimicrobial use at the farm-level given limited input from animal health professionals and under-resourced regulatory capacities within most low- and middle-income countries. Establishing this bottom-up understanding across cultures and production systems will inform the development and implementation of the behavioral change interventions to combat antimicrobial resistance globally.

RationaleReducing nicotine content of inhaled tobacco products may prevent nicotine addiction, but the threshold for nicotine reinforcement has not been systematically evaluated in controlled human laboratory studies.ObjectivesThe current study uses a novel double-blind placebo-controlled intravenous (IV) nicotine self-administration (NSA) model to determine threshold for subjective effects of nicotine and nicotine reinforcement using a forced choice self-administration procedure.MethodsYoung adults (n = 34) had 5 laboratory sessions after overnight nicotine abstinence. In each session, participants sampled and rated the subjective effects of an IV dose of nicotine (0.0125, 0.025, 0.05, 0.1, or 0.2 mg nicotine/70 kg bodyweight) versus saline (placebo), then were given a total of 10 opportunities to self-administer either the IV dose of nicotine or placebo.ResultsMixed effect models revealed a significant effect of nicotine dose for positive (i.e., “stimulatory” and “pleasurable”; p < .0001) effects, but not “aversive” effects during sampling period. Post hoc comparisons showed that higher doses (i.e., 0.1 and 0.2 mg) were associated with greater stimulatory, pleasurable, and physiological effects than placebo and lower doses. Mixed effect models revealed that only the highest dose (i.e., 0.2 mg) was consistently preferred over placebo. Sex differences were generally weak (p = .03–.05).ConclusionsUsing our IV nicotine NSA model, the threshold for detecting positive effects of nicotine in young adult smokers is about 0.1 mg, but a higher dose of nicotine, 0.2 mg, is required to produce a consistent nicotine reinforcement. Regarding the regulatory impact, our findings further support the value of nicotine reinforcement threshold as a tobacco regulatory target.

Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion 1 – 4 . The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N -methyl- d -aspartic acid (NMDA) receptor (NMDAR) antagonism 5 , 6 . Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability. Experiments in mice show that although ketamine has positive reinforcement properties, which are driven by its action on the dopamine system, it does not induce the synaptic plasticity that is typically observed with addiction.