Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice

Trexler, Kristen R.; Nass, Sara R.; Gross, Joshua; Jones, Margaret S.; McKitrick, Austin W.; Siderovski, David P.; Kinsey, Steven G.

doi:10.1016/j.drugalcdep.2018.05.029

Cited by 30 publications

(36 citation statements)

References 63 publications

(95 reference statements)

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“…1C). This dose was based on previous studies using low to high ranges of THC in mice (Trexler et al, 2018;Kasten et al, 2019). Moreover, this dose used has been shown to elevate plasma levels of THC in rodents (> 100 ng/mL) similar to those found in humans smoking cannabis (Huestis, 2007;Zuurman et al, 2008;Nguyen et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Iemolo

Nur

Montilla‐Perez

et al. 2020

Preprint

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Heavy and frequent use of cannabis during adolescence increases the risk of developing psychiatric disorders. However, the neurobiological mechanisms underlying this vulnerability remain largely unknown. Here, we explore whether adolescent vulnerability to long-term behavioral effects of cannabis is modulated by Reelin, a gene implicated in the development of the brain and of psychiatric disorders. To this aim, heterozygous Reeler (HR) mice, that express reduced level of Reelin, were chronically exposed during adolescence to high doses (10mg/kg) of Δ9-tetrahydrocannabinol (THC), a major psychoactive component of cannabis. Mice were tested in early adulthood with multiple behavioral assays, including working memory, social interaction, locomotor activity, anxiety-like responses, stress reactivity, and pre-pulse inhibition. Compared to wild-type (WT), HR mice treated with THC showed, impaired social behaviors, elevated disinhibitory phenotypes and increased responsiveness to aversive situations, in a sex-specific manner. Independent of THC exposure, HR mice also spent more time exploring unfamiliar objects, indicating that Reelin modulates novelty seeking behavior. To identify the neuronal ensemble underlying this elevated novelty seeking in HR mice, we mapped the regional brain expression of the immediate early gene, Fos, in mice exposed to novel objects. HR mice exhibited reduced neuronal activation in the lateral septum, a subcortical brain structure implicated in emotions, cognition and reward processes. Overall, these findings show that (1) Reelin deficiency influences behavioral abnormalities caused by heavy consumption of THC during adolescence, and (2) that Reelin plays a role in the neurobiological mechanisms underlying disinhibitory behaviors, such as novelty seeking.

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Section: Methodsmentioning

confidence: 99%

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Iemolo

Nur

Montilla‐Perez

et al. 2020

Preprint

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“…Mice were weighed daily and injected subcutaneously (s.c.) with AB-FUBINACA (1 or 3 mg/kg; Canazza et al, 2017 ; Wiley et al, 2017 ) or vehicle every 12 h for 5 days, as described previously ( Falenski et al, 2010 ; Schlosburg et al, 2009 ; Trexler et al, 2018 ). Subcutaneous (s.c.) injection was used for repeated administration in lieu of intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…After 30 min, mice received an i.p. injection of rimonabant (3 mg/kg) ( Lichtman et al, 2001 ; Trexler et al, 2018 ) to precipitate withdrawal.…”

Section: Methodsmentioning

confidence: 99%

“…More commonly, chronic drug use results in physical dependence. There is evidence, in both preclinical models and from case reports, that repeated use of SCRAs induces dependence, typically evidenced by the development of tolerance and withdrawal following cessation of use ( Aceto et al, 2001 ; Nacca et al, 2013 ; Sampson et al, 2015 ; Trexler et al, 2018 ). The goals of the present study were to evaluate the acute cannabimimetic effects of the new generation SCRA AB-FUBINACA.…”

Section: Introductionmentioning

confidence: 99%

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The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice

Trexler

Vanegas

Poklis

et al. 2020

Drug and Alcohol Dependence

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Background: Recent years have seen a rise in the diversity and use of synthetic cannabinoids. The present study evaluated the behavioral effects of the third-generation indazole-3-carboxamide-type synthetic cannabinoid, AB-FUBINACA. Methods: Adult male and female C57BL/6J mice were treated with AB-FUBINACA (0–3 mg/kg, i.p.) and tested repeatedly in the tetrad battery measuring catalepsy, antinociception, hypothermia, and locomotor activity. Mice treated with AB-FUBINACA (≥2 mg/kg, i.p.) displayed classic cannabinoid effects in the tetrad that were blocked by the CB 1 receptor selective antagonist rimonabant. To address tolerance and withdrawal effects, a second group of mice was injected with AB-FUBINACA (3 mg/kg, s.c.) or vehicle consisting of 5% ethanol, 5% Kolliphor EL, and 90 % saline every 12 h and tested daily in modified tetrad over the course of 5 days. On the 6th day, withdrawal was precipitated using rimonabant (3 mg/kg, s.c.), and somatic signs of withdrawal (i.e., head twitches and paw tremors) were quantified. Results: Although mice did not develop tolerance to AB-FUBINACA or cross-tolerance to Δ 9 -tetrahydrocannabinol (THC; 50 mg/kg, i.p.), somatic precipitated withdrawal signs were observed. Repeated tetrad testing up to 48 h post injection indicated that AB-FUBINACA effects are relatively short-lived, as compared with THC. Brain levels of AB-FUBINACA, as quantified by UHPLC-MS/MS, were undetectable 4 h post injection. Conclusions: These data indicate that the cannabinoid effects of AB-FUBINACA are relatively short-lived, yet sufficient to induce dependence in mice.

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“…In contrast to alcohol, self‐administration of edible THC produced notable short‐term effects 1 day after the final exposure, including an impairment in baseline rotarod performance and a reduction in THC‐induced hypothermia; however, whole‐brain CB1R expression was unaltered. Repeated exposure to THC leads to both spontaneous and antagonist‐precipitated withdrawal (Cook et al., ; Cutando et al., ; Trexler et al., ; Tzavara et al., ). Given that baseline rotarod performance was measured beyond the time of expected acute effects of orally administered THC (Anderson et al., ; Hložek et al., ; Kruse et al., ; Smoker et al., ), the impairment in motor coordination seen in mice having consumed edible THC is possibly due to its induction of withdrawal.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆⁹‐Tetrahydrocannabinol in Adolescent Male Mice

Smoker

Hernández

Zhang

et al. 2019

Alcoholism Clin & Exp Res

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IIBackground: Cannabinoids and their principle psychoactive target, the cannabinoid type 1 receptor (CB1R), impact a number of alcohol-related properties, and although alcohol and cannabis are often co-used, particularly in adolescence, few animal models of this phenomenon exist. We modeled the couse of alcohol and Δ 9 -tetrahydrocannabinol (THC) in adolescent mice using ingestive methods popular during this developmental period in humans, namely binge-drinking and edible THC. With this model, we assessed levels of use, acute effects, and tolerance to each substance.Methods: Adolescent male C57BL/6J mice had daily, limited access to 1 of 2 edible doughs (THC or control), to 1 of 2 fluids (ethanol (EtOH) or water), and in 1 of 2 orders (dough-fluid or fluiddough). Home cage locomotor activity was recorded both during access and after access. On the day following the final access session, a subset of mice were assessed for functional and metabolic tolerance to alcohol using accelerating rotarod and blood EtOH concentrations, respectively. The remaining mice were assessed for tolerance to THC-induced hypothermia, and whole-brain CB1R expression was assessed in all mice.Results: EtOH intake was on par with levels previously reported in adolescent mice. Edible THC was well-consumed, but consumption decreased at the highest dose provided. Locomotor activity increased following EtOH intake and decreased following edible THC consumption, and edible THC increased fluid intake in general. The use of alcohol produced neither functional nor metabolic tolerance to an alcohol challenge. However, the use of edible THC impaired subsequent drug-free rotarod performance and was associated with a reduction in THC's hypothermic effect.Conclusions: Adolescent mice self-administered both alcohol and edible THC to a degree sufficient to acutely impact locomotor activity. However, only edible THC consumption had lasting effects during short-term abstinence. Thus, this adolescent co-use model could be used to explore sex differences in self-administration and the impact substance co-use might have on other domains such as mood and cognition.

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Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice

Abstract: Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.

Cited by 30 publications

References 63 publications

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice

Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆⁹‐Tetrahydrocannabinol in Adolescent Male Mice

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Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice

Abstract: Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.

Cited by 30 publications

References 63 publications

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice

The short-acting synthetic cannabinoid AB-FUBINACA induces physical dependence in mice

Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice

Contact Info

Product

Resources

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Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆⁹‐Tetrahydrocannabinol in Adolescent Male Mice