Sex differences in Δ9-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats

doi:10.1016/J.NEULET.2014.05.057

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Sex differences in Δ9-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats

Journal Article•DOI•

Sex differences in Δ9-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats

Jenny L. Wiley¹, James J. Burston¹•Institutions (1)

Virginia Commonwealth University¹

25 Jul 2014-Neuroscience Letters (NIH Public Access)-Vol. 576, pp 51-55

TL;DR: The present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex Differences in cannabinoid effects across behaviors, and Hormonal and/or pharmacodynamic factors are also likely to play a role.

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About: This article is published in Neuroscience Letters.The article was published on 2014-07-25 and is currently open access. It has received 80 citations till now. The article focuses on the topics: Cannabinoid.

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Journal Article•DOI•

Sex-Dependent Effects of Cannabis and Cannabinoids: A Translational Perspective.

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Ziva D. Cooper¹, Rebecca M. Craft²•Institutions (2)

Columbia University Medical Center¹, Washington State University²

01 Jan 2018-Neuropsychopharmacology

TL;DR: A translational perspective on the sex-dependent effects of cannabis and cannabinoids is provided by synthesizing findings from preclinical and clinical studies focused on sex comparisons of their therapeutic potential and abuse liability, two specific areas of significant public health relevance.

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194 citations

Cites background from "Sex differences in Δ9-tetrahydrocan..."

...…Neuropsychopharmacology REVIEWS THC-induced increase in locomotor activity, and this was observed in females only, at the lowest THC dose tested (Wiley and Burston, 2014)....
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...Tolerance to THC’s cataleptic effect did appear to be greater in adolescent females than males in one of these studies, although group sample sizes were relatively small and the sex difference was not statistically significant (Wiley and Burston, 2014)....
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...…effects (antinociception, locomotor suppression, catalepsy, and hypothermia) in male vs female, adolescent vs adult rats (Wiley et al, 2007; Wiley and Burston, 2014) or in adolescents bred in-house vs shipped (Wiley and Evans, 2009), robust tolerance developed to all four ‘tetrad’…...
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...After acute THC injection, females produce more of the major active metabolite 11-OH-THC than males do (Tseng et al, 2004; Wiley and Burston, 2014; Britch et al, 2017)....
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...This sex difference in 11-OH-THC production is modulated by gonadal hormones (Craft et al, 2017), observed in adolescent as well as adult rats, and increases in magnitude with repeated THC treatment (Wiley and Burston, 2014)....
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Journal Article•DOI•

The Impact of Exposure to Cannabinoids in Adolescence: Insights From Animal Models.

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Tiziana Rubino¹, Daniela Parolaro¹•Institutions (1)

University of Insubria¹

01 Apr 2016-Biological Psychiatry

TL;DR: Modeling the adolescent phase in animals appears to be a useful approach to investigate the impact of cannabis use on the adolescent brain and suggests that it may represent, per se or in association with other hits, a risk factor for developing psychotic-like symptoms in adulthood.

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136 citations

Cites background from "Sex differences in Δ9-tetrahydrocan..."

...This effect was greater in female than in male rats, probably as a result of the recently described different THC metabolism in the sexes (82) and the alleged presence of more efficient receptors in adolescent female rats (83)....
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Journal Article•DOI•

Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC

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Tomáš Hložek¹, Libor Uttl², Lukáš Kadeřábek³, Marie Balíková¹, Eva Lhotková³, Rachel R. Horsley³, Pavlína Nováková³, Klára Šíchová³, Kristýna Štefková³, Filip Tylš³, Martin Kuchař², Tomáš Páleníček³, Tomáš Páleníček⁴ - Show less +9 more•Institutions (4)

First Faculty of Medicine, Charles University in Prague¹, Charles University in Prague², National Institutes of Health³, Institute of Chemical Technology in Prague⁴

01 Dec 2017-European Neuropsychopharmacology

TL;DR: Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications.

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134 citations

Cites background or methods from "Sex differences in Δ9-tetrahydrocan..."

...The doses used in the current study were selected according to animal and clinical studies in which: 1) THC shows behavioural locomotor effects and induces psychotic-like symptoms in animals (El-Alfy et al., 2010; Katsidoni et al., 2013; Nagai et al., 2006; Wiley and Burston, 2014); 2) doses of CBD that were effective in humans to treat schizophrenia, have shown some antagonising effects on THC and have also shown some antipsychotic-like properties in rodents (Bhattacharyya et al....
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...…behavioural locomotor effects and induces psychotic-like symptoms in animals (El-Alfy et al., 2010; Katsidoni et al., 2013; Nagai et al., 2006; Wiley and Burston, 2014); 2) doses of CBD that were effective in humans to treat schizophrenia, have shown some antagonising effects on THC and have…...
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Journal Article•DOI•

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

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Alexa A. Wakley¹, Jenny L. Wiley², Rebecca M. Craft¹•Institutions (2)

Washington State University¹, Research Triangle Park²

01 Oct 2014-Drug and Alcohol Dependence

TL;DR: The results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure, given the importance of drug tolerance in the development of drug dependence.

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81 citations

Journal Article•DOI•

Cannabis and synaptic reprogramming of the developing brain

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Anissa Bara¹, Jacqueline-Marie N. Ferland, Gregory Rompala, Henrietta Szutorisz, Yasmin L. Hurd - Show less +1 more•Institutions (1)

Icahn School of Medicine at Mount Sinai¹

21 May 2021-Nature Reviews Neuroscience

TL;DR: In this paper, an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes.

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Abstract: Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ9-tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.

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70 citations

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References

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Journal Article•DOI•

Monitoring the Future: National Results on Adolescent Drug Use: Overview of Key Findings

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Lloyd D. Johnston, Patrick M. O'Malley, Jerald G. Bachman

01 Apr 2003

6,571 citations

Journal Article•DOI•

The adolescent brain and age-related behavioral manifestations

[...]

Linda P. Spear¹•Institutions (1)

Binghamton University¹

01 Jun 2000-Neuroscience & Biobehavioral Reviews

TL;DR: Developmental changes in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems likely contribute to the unique characteristics of adolescence.

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4,985 citations

Journal Article•DOI•

Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.

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Billy R. Martin¹, D R Compton¹, Brian F. Thomas¹, W. R. Prescott¹, P. J. Little¹, Raj K. Razdan, M R Johnson², L S Melvin³, Raphael Mechoulam⁴, S. J. Ward⁵ - Show less +6 more•Institutions (5)

Virginia Commonwealth University¹, Research Triangle Park², Pfizer³, Hebrew University of Jerusalem⁴, Rensselaer Polytechnic Institute⁵

01 Nov 1991-Pharmacology, Biochemistry and Behavior

TL;DR: The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.

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Abstract: Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (−)-11-OH-Δ8-THC-dimethylheptyl was 80–1150 times more potent than Δ9-THC. Stereospecificity was demonstrated by its (+)- enantiomer which was more than 1400–7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (−)-11-OH-Δ9-THC-DMH was found to be equipotent with (−)-11-OH-Δ8-THC-DMH. The aldehyde (−)-11-oxo-Δ9-THC-DMH was 15–50 times more potent than Δ9-THC. Surprisingly, (−)-11-carboxy-Δ9-THC-DMH was also active, being slightly more potent than Δ9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to Δ9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.

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416 citations

Journal Article•DOI•

Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats.

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Miriam Schneider¹, Michael Koch¹•Institutions (1)

University of Bremen¹

01 Oct 2003-Neuropsychopharmacology

TL;DR: It is concluded that puberty in rats is a vulnerable period with respect to the adverse effects of cannabinoid treatment, and chronic cannabinoid administration during pubertal development is proposed as an animal model for some aspects of the etiology of schizophrenia.

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402 citations

Journal Article•DOI•

Specific attentional dysfunction in adults following early start of cannabis use.

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Hannelore Ehrenreich¹, Thomas Rinn¹, Hanns Jürgen Kunert¹, Manfred R. Moeller², Wolfgang Poser¹, Lothar Schilling³, Gerd Gigerenzer⁴, Margret R. Hoehe⁵ - Show less +4 more•Institutions (5)

University of Göttingen¹, Saarland University², University of Mannheim³, Max Planck Society⁴, Max Delbrück Center for Molecular Medicine⁵

01 Mar 1999-Psychopharmacology

TL;DR: The data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood, as apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.

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Abstract: Rationale and objective: The present study tested the hypothesis that chronic interference by cann- abis with endogenous cannabinoid systems during peri- pubertal development causes specific and persistent brain alterations in humans. As an index of cannabi- noid action, visual scanning, along with other atten- tional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. Methods: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other past or present drug abuse, or history of neuropsychiatric disease. After an interview, physi- cal examination, analysis of routine laboratory para- meters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working memory. Results : Of the potential pre- dictors of test performance within the user group, including present age, age of onset of cannabis use, degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age of onset turned out to be the only predictor, predicting impaired reaction times exclu- sively in visual scanning. Early-onset users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not di⁄er from controls (n = 49). Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring e⁄ects on specific attentional func- tions in adulthood. Apparently, vulnerable periods dur- ing brain development exist that are subject to persistent alterations by interfering exogenous cannabi- noids.

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383 citations