Addiction Biology

Li, Feng; Du, Han; Wu, Bo; Wei, Jiayun; Qiao, Yanling; Lai, Miaojun; Zhou, Wenhua; Shen, Haowei; Wang, Youmei; Xu, Peng; Di, Bin

doi: 10.1111/adb.13171pmid: 35470563

2‐Fluorodeschloroketamine (2‐FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2‐FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2‐FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self‐administration and drug discrimination using ketamine as a reference. 2‐FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2‐FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2‐FDCK and ketamine induced locomotor sensitization after withdrawal. 2‐FDCK readily induced self‐administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2‐FDCK dose‐dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2‐FDCK has an abuse potential comparable with ketamine.

Robinson, Alex H.; Chong, Trevor T.‐J.; Verdejo‐Garcia, Antonio

doi: 10.1111/adb.13172pmid: 35470564

People with Methamphetamine Use Disorder (PwMUD) spend substantial time and resources on substance use, which hinders their ability to explore alternate reinforcers. Gold‐standard behavioural treatments attempt to remedy this by encouraging action towards non‐drug reinforcers, but substance use often persists. We aimed to unravel the mechanistic drivers of this behaviour by applying a computational model of explore/exploit behaviour to decision‐making data (Iowa Gambling Task) from 106 PwMUD and 48 controls. We then examined the longitudinal link between explore/exploit mechanisms and changes in methamphetamine use 6 weeks later. Exploitation parameters included reinforcement sensitivity and inverse decay (i.e., number of past outcomes used to guide choices). Exploration parameters included maximum directed exploration value (i.e., value of trying novel actions). The Timeline Follow Back measured changes in methamphetamine use. Compared to controls, PwMUD showed deficits in exploitative decision‐making, characterised by reduced reinforcement sensitivity, U = 3065, p = 0.009, and less use of previous choice outcomes, U = 3062, p = 0.010. This was accompanied by a behavioural pattern of frequent shifting between choices, which appeared consistent with random exploration. Furthermore, PwMUD with greater reductions of methamphetamine use at 6 weeks had increased directed exploration (β = 0.22, p = 0.045); greater use of past choice outcomes (β = −0.39, p = 0.002) and greater choice consistency (β = −0.39, p = 0.002). Therefore, limited computational exploitation and increased behavioural exploration characterise PwMUD's presentation to treatment, while increased directed exploration, use of past choice outcomes and choice consistency predict greater reductions of methamphetamine use.

Abbott, Megan S.; Seaman, Robert W.; Doyle, Michelle R.; Maguire, David R.; Rice, Kenner C.; Collins, Gregory T.

doi: 10.1111/adb.13168pmid: 35470552

Synthetic cathinones, such as 3,4‐methylenedioxypyrovalerone (MDPV), are recreational drugs of abuse often identified in ‘bath salts’ preparations. Humans report compulsive patterns of bath salts use, and previous work suggests that a subset of rats develop unusually high levels of MDPV self‐administration. This study aims to test the hypothesis that high levels of impulsivity (e.g., inability to withhold responding for a sucrose reward) will predispose rats to high levels of MDPV self‐administration relative to rats with lower levels of impulsivity. The 1‐choice serial reaction time task (1‐CSRTT) was used to assess impulsivity (i.e., premature responding) in 10 female and 10 male Sprague Dawley rats. Rats were then allowed to self‐administer 0.032 mg/kg/inf MDPV or 0.32 mg/kg/inf cocaine, after which full dose–response curves for MDPV (0.001–0.1 mg/kg/inf) or cocaine (0.01–1 mg/kg/inf) were generated under a FR5 schedule of reinforcement. After a history of self‐administering MDPV or cocaine, impulsivity was reassessed under the 1‐CSRTT, prior to evaluating the acute effects of MDPV (0.032–0.32 mg/kg) or cocaine (0.1–1 mg/kg) on impulsivity. Level of impulsivity was not correlated with subsequent levels of either MDPV or cocaine self‐administration, and level of drug self‐administration was also not correlated with subsequent levels of impulsivity, although acute administration of MDPV and cocaine did increase premature responding. In failing to find direct relationships between either impulsivity and subsequent drug‐taking behaviour, or drug‐taking behaviour and subsequent assessments of impulsivity, these findings highlight the complexity inherent in the associations between impulsive behaviour and drug‐taking behaviour in both animal models and humans.

Bagley, Jared R.; Khan, Arshad H.; Smith, Desmond J.; Jentsch, James D.

doi: 10.1111/adb.13162pmid: 35470554

Cocaine self‐administration is a complexly determined trait, with a substantial proportion of individual differences being determined by genetic variation. However, the relevant genetic variants that drive heritable differences in cocaine use remain undiscovered. Cocaine intravenous self‐administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Here, we provide information on cocaine (or saline—as a control) IVSA in 84 members of the hybrid mouse diversity panel (HMDP), an array of genetically distinct classical or recombinant inbred strains. We found cocaine IVSA to be substantially heritable in this population, with strain‐level intake ranging for near 0 to >25 mg/kg/session. Though saline IVSA was also found to be heritable, a modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced, at least in part, by unique genetic variants. Genome‐wide association studies (GWAS) of infusions earned in cocaine and saline groups revealed significant quantitative trait loci (QTL) on Chromosomes 3 and 14 for cocaine, but not saline, IVSA. Positional candidates were further prioritized through use of bulk RNA sequencing data that revealed genes with cis‐eQTL and genetic correlation to number of infusions. Additionally, these data identify reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This work is part of an ongoing effort to characterize genetic variation that moderates cocaine IVSA that may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.

Ceccarini, Jenny; Koole, Michel; Van Laere, Koen

doi: 10.1111/adb.13167pmid: 35470551

The established role of dopamine (DA) in the mediation of reward and positive reinforcement, reward processing is strongly influenced by the type 1 cannabinoid receptors (CB1Rs). Although considerable preclinical evidence has demonstrated several functional CB1R–DA interactions, the relation between human CB1R availability, DA release capacity and drug‐reinforcing effects has been never investigated so far. Here, we perform a multitracer [18F]MK‐9470 and [18F]fallypride positron emission tomography (PET) study in 10 healthy male subjects using a placebo‐controlled and single‐blinded amphetamine (AMPH) (30 mg) administration paradigm to (1) investigate possible functional interactions between CB1R expression levels and DA release capacity in a normo‐DAergic state, relating in vivo AMPH‐induced DA release to CB1R availability, and (2) to test the hypothesis that the influence of striatal DAergic signalling on the positive reinforcing effects of AMPH may be regulated by prefrontal CB1R levels. Compared with placebo, AMPH significantly reduced [18F]fallypride binding potential (hence increase DA release; ΔBPND ranging from −6.1% to −9.6%) in both striatal (p < 0.005, corrected for multiple comparisons) and limbic extrastriatal regions (p ≤ 0.04, uncorrected). Subjects who reported a greater dopaminergic response in the putamen also showed higher CB1R availability in the medial and dorsolateral prefrontal cortex (r = 0.72; p = 0.02), which are regions involved in salience attribution, motivation and decision making. On the other hand, the magnitude of DA release was greater in those subjects with lower CB1R availability in the anterior cingulate cortex (ACC) (r = −0.66; p = 0.03). Also, the correlation between the DA release in the nucleus accumbens with the subjective AMPH effect liking was mediated through the CB1R availability in the ACC (c′ = −0.76; p = 0.01). Our small preliminary study reports for the first time that the human prefrontal CB1R availability is a determinant of DA release within both the ventral and dorsal reward corticostriatal circuit, contributing to a number of studies supporting the existence of an interaction between CB1R and DA receptors at the molecular and behavioural level. These preliminary findings warrant further investigation in pathological conditions characterized by hypo/hyper excitability to DA release such as addiction and schizophrenia.

Chan, Amy; Willard, Alexis; Mulloy, Sarah; Ibrahim, Noor; Sciaccotta, Allegra; Schonfeld, Mark; Spencer, Sade M.

doi: 10.1111/adb.13165pmid: 35470560

This study investigated the potential therapeutic effects of the FDA‐approved drug metformin on cue‐induced reinstatement of cocaine seeking. Metformin (dimethyl‐biguanide) is a first‐line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self‐administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue‐induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue‐induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self‐administer cocaine followed by extinction prior to cue‐induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue‐induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue‐induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.

Wood, Elizabeth K.; Lemmon, Dani P.; Schwandt, Melanie L.; Lindell, Stephen G.; Barr, Christina S.; Suomi, Stephen J.; Higley, James Dee

doi: 10.1111/adb.13142pmid: 35470557

It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol‐induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol‐induced and alcohol‐induced change in monoamine activity and their relationship with alcohol intake. Alcohol‐naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6–7 months later, subjects were allowed unfettered access to an aspartame‐sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5–7 weeks. Results showed strong positive correlations between baseline and post‐infusion CSF monoamine metabolite concentrations, indicating a trait‐like response. Low baseline and post‐infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post‐infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol‐induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake.

Honeycutt, Sarah C.; Paladino, Morgan S.; Camadine, Rece D.; Mukherjee, Ashmita; Loney, Gregory C.

doi: 10.1111/adb.13170pmid: 35470562

Opioid use disorder (OUD) and opioid‐related deaths remain a significant public health crisis having reached epidemic status globally. OUDs are defined as chronic, relapsing conditions often characterized by compulsive drug seeking despite the deleterious consequences of drug taking. The use of nicotine‐containing products has been linked to increased likelihood of prescription opioid misuse, and there exists a significant comorbidity between habitual nicotine use and opioid dependence. In rodent models, nicotine administration nearly doubles the amount of opioids taken in intravenous self‐administration paradigms. Here, we examined the effect of acute systemic nicotine administration in male rats on responding for the synthetic opioid remifentanil (RMF) in a contextual punishment paradigm using either an exteroceptive punisher (foot‐shock) or an interoceptive punisher (histamine). Nicotine administration, relative to saline, increased RMF intake in both unpunished and punished contexts, regardless of form of punishment, and resulted in significantly higher motivation to obtain RMF in the previously punished context, as measured by progressive ratio breakpoint. Additionally, regardless of context, nicotine‐treated rats were slower to extinguish RMF responding following drug removal and displayed higher levels of cue‐induced reinstatement than saline‐treated controls. Furthermore, these data support that, compared with histamine adulteration, contingent foot‐shock is a more potent form of punishment, as histamine punishment failed to support contextual discrimination between the unpunished and punished contexts. In contrast to RMF administration, augmentation of responding for an audiovisual cue by nicotine pretreatment was lost following contextual punishment. In conclusion, acute nicotine administration in adult male rats significantly enhances compulsive‐like responding for RMF that persists despite contingent punishment of drug‐directed responding.

Wei, Shoupeng; Li, Yu‐ling; Gong, Qi; Liang, Hui; Bernardi, Rick E.; Liang, Jian‐hui

doi: 10.1111/adb.13163pmid: 35470556

Previous studies have indicated a role for molecular chaperone heat shock protein 70 (Hsp70) in the development of behavioural sensitization to morphine in rodents, suggesting that Hsp70 expression following morphine exposure is involved in molecular changes that may underlie addiction vulnerability. The current study was carried out to investigate the role of Hsp70 in the positive reinforcing properties of morphine using conditioned place preference (CPP) in male rats. An unbiased CPP procedure of three phases (pre‐conditioning: d1–d3; conditioning: d4–d6; and testing: d7) was used. During the conditioning phase, morphine injections (5 mg/kg, subcutaneously) were administered to induce significant place preference. To explore the effect of Hsp70 on the development and expression of morphine CPP, Hsp70 inhibitors (PES, KNK437 and methylene blue) were administered into the lateral ventricle prior to either morphine conditioning sessions or a morphine challenge on the test day. Furthermore, Hsp70 expression within the mesocorticolimbic system was measured after the treatment with KNK437, a transcriptional inhibitor. We found that PES and KNK437, respectively, injected intracerebroventricularly dose‐dependently attenuated both the development and expression of morphine CPP. Methylene blue treatment demonstrated an attenuation of the development, but had no effect on the expression of morphine CPP. Following KNK437 treatment, Hsp70 expression was significantly inhibited in the shell of nucleus accumbens (NAc) during both the development and expression of morphine CPP. The findings suggest that Hsp70 in the NAc shell plays an important role in the reinforcing effects of morphine and may be involved in the development of morphine dependence.

Komarnyckyj, Mica; Retzler, Chris; Cao, Zhipeng; Ganis, Giorgio; Murphy, Anna; Whelan, Robert; Fouragnan, Elsa Florence

doi: 10.1111/adb.13174pmid: 35470555

Alcohol use disorder is characterised by disrupted reward learning, underpinned by dysfunctional cortico‐striatal reward pathways, although relatively little is known about the biology of reward processing in populations who engage in risky alcohol use. Cues that trigger reward anticipation can be categorized according to their learnt valence (i.e., positive vs. negative outcomes) and motivational salience (i.e., incentive vs. neutral cues). Separating EEG signals associated with these dimensions is challenging because of their inherent collinearity, but the recent application of machine learning methods to single EEG trials affords a solution. Here, the Alcohol Use Disorders Identification Test (AUDIT) was used to quantify risky alcohol use, with participants split into high alcohol (HA) (n = 22, mean AUDIT score: 13.82) and low alcohol (LA) (n = 22, mean AUDIT score: 5.77) groups. We applied machine learning multivariate single‐trial classification to the electroencephalography (EEG) data collected during reward anticipation. The LA group demonstrated significant valence discrimination in the early stages of reward anticipation within the cue‐P3 time window (400–550 ms), whereas the HA group was insensitive to valence within this time window. Notably, the LA, but not the HA group demonstrated a relationship between single‐trial variability in the early valence component and reaction times for gain and loss trials. This study evidences disrupted hypoactive valence sensitivity in the HA group, revealing potential neurophysiological markers for risky drinking behaviours which place individuals at‐risk of adverse health events.