Addiction Biology

Poore, Holly E.; Hatoum, Alexander; Mallard, Travis T.; Sanchez‐Roige, Sandra; Waldman, Irwin D.; Palmer, Abraham A.; Harden, K. Paige; Barr, Peter B.; Dick, Danielle M.

doi: 10.1111/adb.13319pmid: 37644899

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under‐control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate genome‐wide association studies of an externalizing and an addiction risk factor, respectively. We first evaluated five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two‐factor structures and a bifactor model. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. Finally, we quantified the degree of polygenic overlap between externalizing and addiction risk using MiXeR. We found that the common and two‐factor structures provided the best fit to the data, evidenced by high factor loadings, good factor reliability and no evidence of concerning model characteristics. The two‐factor models yielded high genetic correlations between factors (rgs ≥ 0.87), and between the effect sizes of genetic correlations with external traits (rg ≥ 0.95). Nevertheless, 21 of the 84 correlations with external criteria showed small, significant differences between externalizing and addiction risk factors. MiXer results showed that approximately 81% of influential externalizing variants were shared with addiction risk, whereas addiction risk shared 56% of its influential variants with externalizing. These results suggest that externalizing and addiction genetic risk are largely shared, though both constructs also retain meaningful unshared genetic variance. These results can inform future efforts to identify specific genetic influences on externalizing and SUDs.

Li, Haoyu; Zhao, Haiting; Hu, Ting; Meng, Li; Mo, Xin; Gong, Mengqi; Liao, Yiwei

doi: 10.1111/adb.13326pmid: 37644892

The persistence of maladaptive heroin‐associated memory, which is triggered by drug‐related stimuli that remind the individual of the drug's pleasurable and rewarding effects, can impede abstinence efforts. Cyclin‐dependent kinase 5 (Cdk5), a neuronal serine/threonine protein kinase that plays a role in multiple neuronal functions, has been demonstrated to be involved in drug addiction and learning and memory. Here, we aimed to investigate the role of cdk5 activity in the basolateral amygdala (BLA) in relapse to heroin seeking, using a self‐administration rat model. Male rats underwent 10 days of heroin self‐administration training, during which an active nose poke resulted in an intravenous infusion of heroin that was accompanied by a cue. The rats then underwent nose poke extinction for 10 days, followed by subsequent tests of heroin‐seeking behaviour. We found that intra‐BLA infusion of β‐butyrolactone (100 ng/side), a Cdk5 inhibitor, administered 5 min after reactivation, led to a subsequent decrease in heroin‐seeking behaviour. Further experiments demonstrated that the effects of β‐butyrolactone are dependent on reactivated memories, temporal‐specific and long‐lasting on relapse of heroin‐associated memory. Results provide suggestive evidence that the activity of Cdk5 in BLA is critical for heroin‐associated memory and that the specific inhibitor, β‐butyrolactone, may hold potential as a substance for the treatment of heroin abuse.

Lv, Liying; Yang, Liping; Sun, Yan

doi: 10.1111/adb.13318pmid: 37644898

This work illustrates the accelerated decline in illegal drug use during the COVID‐19 pandemic in China. We first reviewed the global effects of the COVID‐19 pandemic on the situation of illegal drugs. We then compared the data of the pre‐pandemic (2016–2019) and pandemic period (2020–2022) for drug seizures, individuals identified as using drugs, registered and newly discovered illegal drug users and the number of community‐treated drug users to demonstrate the fast decline in the use of illegal drugs in China. We then discussed the possible reasons and additional considerations for these changes. Overall, the COVID‐19 controls in China, such as all‐staff nucleic acid testing and ID‐based dynamic monitoring, substantially reduced illegal drug use. Being wary of a possible rebound in drug use and preventing new types of drug crimes are still essential in post‐COVID China.

Andersen, Freja Drost; Steffensen, Simon Comerma; Vistisen, Simon Tilma; Pinilla, Estefano; Pedersen, Tina Myhre; Matchkov, Vladimir; Simonsen, Ulf; Andersen, Charlotte Uggerhøj

doi: 10.1111/adb.13320pmid: 37644895

Fatal poisonings where both methadone and quetiapine are detected post‐mortem occurs frequently in legal autopsy cases. It is unclear whether quetiapine increases the risk of fatal methadone poisoning or if it is merely detected due to widespread use. We hypothesized that methadone and quetiapine would have additive toxic effects on respiratory rate, blood pressure, and the QTc‐interval. To investigate this hypothesis, we used telemetry implants for measurements of respiratory rate, haemodynamic variables, the velocity of blood pressure changes, temperature, and movement in conscious, freely moving male Wistar rats aged 12–13 weeks. The combined effects of three accumulative i.p. doses of methadone (2.5, 10, 15 mg/kg) and quetiapine (3, 10, 30 mg/kg) were compared to rats treated with the same doses of each drug alone, and a vehicle‐treated group in a randomized investigator blinded study. No additive effects of quetiapine and methadone on respiratory rate, haemodynamic variables, or movement were observed. However, body temperature was significantly lower by approximately 1.5°C on average in the group treated with both methadone and quetiapine (15 + 30 mg/kg) compared to the other groups. This indicates a synergistic effect of quetiapine and methadone on thermoregulation, which may increase the risk of fatal poisoning. We suggest studying this finding further in human settings.

Cheng, Ying‐jie; Deng, Ying‐zhi; Deng, Di; Wu, Man‐qing; Chai, Jing‐rui; Wang, Yu‐jun; Liu, Jing‐gen; Zhao, Min

doi: 10.1111/adb.13323pmid: 37644896

Chronic exposure to methamphetamine (METH) causes severe and persistent cognitive impairment. The present study aimed to investigate the role of dynorphin/κ opioid receptor (KOR) system in the development of METH‐induced cognitive impairment. We found that mice showed significant cognitive impairment in the novel object recognition test (NOR) following daily injections of METH (10 mg/kg) for seven consecutive days. Systemic blockade of KOR prevented METH‐induced cognitive impairment by pretreatment of the selective KOR antagonist norBNI (10 mg/kg, i.p.) or KOR deletion. Then, significant increased dynorphin and KOR mRNA were observed exclusively in prelimbic cortex (PL) other than infralimbic cortex. Finally, microinjection with norBNI into PL also improved cognitive memory in METH‐treated mice using NOR and spontaneous alternation behaviour test. Our results demonstrated that dynorphin/KOR system activation in PL may be a possible mechanism for METH‐induced cognitive impairment and shed light on KOR antagonists as a potential neuroprotective agent against the cognitive deficits induced by drug abuse.

De Aquino, Joao P.; Meyerovich, Julia; Xie, Catherine Z.; Ranganathan, Mohini; Compton, Peggy; Pittman, Brian; Rogan, Michael; Sofuoglu, Mehmet

doi: 10.1111/adb.13317pmid: 37644897

The opioid and cannabinoid receptor systems are inextricably linked—overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta‐9‐tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within‐subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5‐h test sessions. Measures of experimental and self‐reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed‐effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low‐dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self‐reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose‐dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk–benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Baranger, David A. A.; Paul, Sarah E.; Hatoum, Alexander S.; Bogdan, Ryan

doi: 10.1111/adb.13327pmid: 37644894

Alcohol use is a growing global health concern and economic burden. Alcohol involvement (i.e., initiation, use, problematic use, alcohol use disorder) has been reliably associated with broad spectrum grey matter differences in cross‐sectional studies. These findings have been largely interpreted as reflecting alcohol‐induced atrophy. However, emerging data suggest that brain structure differences also represent pre‐existing vulnerability factors for alcohol involvement. Here, we review evidence from human studies with designs (i.e., family‐based, genomic, longitudinal) that allow them to assess the plausibility that these correlates reflect predispositional risk factors and/or causal consequences of alcohol involvement. These studies provide convergent evidence that grey matter correlates of alcohol involvement largely reflect predisposing risk factors, with some evidence for potential alcohol‐induced atrophy. These conclusions highlight the importance of study designs that can provide causal clues to cross‐sectional observations. An integrative model may best account for these data, in which predisposition to alcohol use affects brain development, effects which may then be compounded by the neurotoxic consequences of heavy alcohol use.

Beldjoud, Hassiba; Avelar, Alicia; Guglielmo, Giordano; Kallupi, Marsida; Sedighim, Sharona; Velarde, Nathan; Boomhower, Brent; Rizo, Nathan; Carrette, Lieselot L. G.; George, Olivier

doi: 10.1111/adb.13316pmid: 37644893

Anxiety is a critical component of the development and maintenance of drug addiction; however, anti‐anxiety medications such as benzodiazepines and beta‐blockers (β‐adrenergic receptor antagonists) are not used for the treatment of substance use disorder, except for the management of acute withdrawal syndrome. Preclinical studies have shown that beta‐blockers may reduce stress‐induced relapse; however, the effect of beta blockers on the escalation and maintenance of drug intake has not been tested. To address this issue, we chronically administered the β‐adrenergic receptor antagonist propranolol during the escalation or maintenance of cocaine intake in a model of extended access (6 h) to cocaine self‐administration (0.5 mg/kg). The behavioural specificity of propranolol was tested using a non‐drug reward (saccharin). Daily administration of propranolol (15 mg/kg) prevented the development of escalation of cocaine self‐administration and partially reversed self‐administration after the establishment of escalation of intake. Moreover, propranolol dose‐dependently decreased the motivation for cocaine tested under a progressive ratio schedule of reinforcement during the development of escalation and after maintenance. Finally, propranolol administration had no effect on the escalation and maintenance of saccharin self‐administration. These results demonstrate that chronic treatment with propranolol provides therapeutic efficacy in reducing cocaine self‐administration during the development and after the establishment of escalation of cocaine self‐administration in an animal model relevant to cocaine use disorder. These results suggest that beta blockers should be further investigated as a target for medication development for the treatment of cocaine use disorder.

doi: 10.1111/adb.13193pmid: N/A

Song, Hongxiu; Lu, Xue; Du, Demin; Peng, Yaqin; Pan, Weichao; Xu, Xing; Fan, Yu; Yang, Xin; Ge, Feifei; Guan, Xiaowei

doi: 10.1111/adb.13314pmid: 37644891

Methamphetamine (Meth) withdrawal elicits anxiety, which is a public health concern with limited therapeutic options. Previous studies implied a strong correlation between mPFC and Meth withdrawal. Here, we examined the role of Gegen‐Qinlian decoction (GQD) in Meth withdrawal anxiety and explored potential therapeutic targets in mPFC. We found that intra‐gastric administration of GQD during the withdrawal period efficiently alleviated anxiety‐like behaviours in Meth‐withdrawn mice. Further, GQD could restore Meth withdrawal‐triggered pathway of GABAergic interneurons (GABA IN)‐pyramidal neurons (PN) in the mPFC of Meth‐withdrawn mice, especially the prelimbic cortex (PrL) sub‐region and PV‐positive GABA IN. While, GQD had no obvious effects on the glial cells in the mPFC of Meth‐withdrawn mice. By transcriptomic analysis and validation of several gene candidates, we found that genes in the MAPK signalling pathway, especially those related to heat shock proteins, including Hspa1a, Hspa1b and Hspb1, might be GQD‐targeting genes in mPFC to treat Meth withdrawal anxiety, as indicated that these genes were up‐regulated by Meth withdrawal but rescued by GQD in mPFC. Collectively, our findings identified for the first time that GQD could efficiently alleviate Meth withdrawal anxiety, partially through regulating the local GABA IN‐PN pathway and transcriptomic profile of mPFC. The present study confirms that TCM, such as GQD, will be a desirable therapeutic approach in the treatment of drug addiction and related emotional deficits.