New vistas on cannabis use disorder

Abstract

Cannabis sativa preparations are the most consumed illicit drugs for recreational purposes worldwide, and the number of people seeking treatment for cannabis use disorder has dramatically increased in the last decades. Due to the recent decriminalization or legalization of cannabis use in the Western Countries, we may predict that the number of people suffering from cannabis use disorder will increase. Despite the increasing number of cannabis studies over the past two decades, we have gaps of scientific knowledge pertaining to the neurobiological consequences of long-term cannabis use. Moreover, no specific treatments for cannabis use disorders are currently available. In this review, we explore new research that may help fill these gaps. We discuss and provide a solution to the experimental limitation of a lack of rodent models of THC self-administration, and the importance this model can play in understanding the neurobiology of relapse and in providing a biological rationale for potential therapeutic targets. We also focus our attention on glial cells, commenting on recent preclinical evidence suggesting that alterations in microglia and astrocytes might contribute to the detrimental effects associated with cannabis abuse. Finally, due to the worrisome prevalence rates of cannabis use during pregnancy, we highlight the associations between cannabis use disorders during pregnancy and congenital disorders, describing the possible neuronal basis of vulnerability at molecular and circuit level.

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

“…Obstacles in establishing a model of cannabis use that closely mimics the human experience have limited our ability to study the neural mechanisms and impact of cannabis use [1,32]. In the current study, we present evidence supporting the feasibility of a novel preclinical model of cannabis self-administration that employs response-contingent delivery of vaporized cannabis extracts.…”

“…Following passive intravenous THC administration, humans report aversive effects that are most often associated with the dose and infusion rate employed [17]. Thus, it is perhaps unsurprising that intravenous THC delivery generally fails to support self-administration in rodents (see [32] for review). The cannabis extracts used in the current study contain THC, CBD, and other naturally-occurring phytocannabinoids, and these Cannabis vapor self-administration phytocannabinoids may mitigate the aversive effects of THC [42].…”

Cannabinoid disruption of learning mechanisms involved in reward processing

“…We also suggest that the impairment of both learning and motivational network function by cannabinoids may partly explain the difficulty in establishing reliable self-administration models in rodents. Although at present the absence of these models has limited our knowledge of the dynamics of cannabinoid addiction, and by analogy CUD, alternate approaches toward establishing self-administration models, such as using combined Δ 9 -THC/cannabidiol preparations (Melis et al 2017;Spencer et al 2018), may prove useful in the future. Given the increasing use of Δ 9 -THC and synthetic cannabinoids for both medicinal and recreational purposes, it is important to continue to investigate these issues so that we may more fully understand the neurobiological consequences of long-term exposure to cannabinoid drugs.…”

“…Despite their ability to evoke NAc DA release (Wise and Bozarth 1987;Koob 1992;Tanda et al 1997;Oleson and Cheer 2012), and their voluntary use in humans, there has been considerable difficulty in developing reliable rodent models of cannabinoid selfadministration (Justinova et al 2005;Panlilio and Justinova 2018). Although, as has been suggested, the lack of solubility of these hydrophobic compounds and other pharmacodynamic issues may limit their efficacy in these models (Melis et al 2017), we propose that the ability of cannabinoids to act to disrupt the function of widespread neural networks may also contribute to this problem. As we discuss above, exogenous cannabinoids like Δ 9 -THC likely act at several sites to disrupt ongoing network activity, and strong evidence demonstrates that output from hippocampal CA3 and CA1 subfields impinge on major midbrain DA nuclei that contribute to both drug-seeking behavior and to assigning salience to environmental cues (Vorel et al 2001;Luo et al 2011;McGlinchey and Aston-Jones 2018).…”

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

“…Furthermore, in individuals with an alcohol use disorder, co‐use of cannabis is highest among all illicit drugs (Falk et al., ). While there are many models of alcohol self‐administration in animals (Bell et al., ; Rhodes et al., ; Samson, ), models of cannabinoid self‐administration have only more recently been established (Barrus et al., ; Justinova et al., ; Kruse et al., ; Melis et al., ; Panagis et al., ; Smoker et al., ; Spencer et al., ; Wakeford et al., ), and models of alcohol‐cannabinoid coadministration are sparse (Nelson et al., ).…”