Evaluation of reinforcing and aversive effects of voluntary Δ9-tetrahydrocannabinol ingestion in rats

Abstract

Edible cannabis-infused products are an increasingly popular method of using cannabis in the United States. Yet, preclinical research to determine mechanisms underlying abuse of Δ-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, has focused primarily on the effects of parenteral administration. The purpose of this study was to examine the rewarding and aversive effects of oral THC in a novel rodent voluntary ingestion model. Adult male and female Sprague Dawley rats were given access to sucrose-sweetened solutions during daily sessions. A range of THC concentrations, each paired with a unique flavor previously tested alone, was introduced into these solutions for four-session exposure periods and drinking volumes were measured. Injected (i.p.) THC doses were also paired with unique flavors to compare the effects of route of THC administration on drinking. Introduction of THC into sucrose solutions dose-dependently decreased drinking upon initial exposure, though drinking generally increased in subsequent sessions. By contrast, i.p. THC produced sustained dose-dependent decreases in drinking in rats of both sexes. Subsequent exposure to paired flavors in the absence of THC resulted in further decreases in drinking, suggesting route-specific aversion. Additional testing using saccharin-sweetened solutions in a two-bottle choice paradigm was also conducted, with THC producing sustained dose-dependent decreases in drinking after initial exposure in rats of both sexes. Though self-administration of ingested THC was not demonstrated, evidence of route-specific THC aversion was observed, which suggests that certain routes and/or rates of THC administration may mitigate some of its aversive effects.

Self-administration of edible Δ9-tetrahydrocannabinol and associated behavioral effects in mice

“…Although cannabinoid self-administration, including THC, has previously been demonstrated (Fattore et al, 2001;Justinova et al, 2003;Martellotta et al, 1998;Melis et al, 2017;Spencer et al, 2018;Wakeford et al, 2017), this study is among the first to do so using an oral route of administration and without food deprivation, invasive surgery, restraint, or prior cannabinoid exposure. In this respect, it is in line with demonstrations of oral THC self-administration in rats (Barrus et al, 2018;Nelson et al, 2018). However, there are notable differences among the three studies, including the species used and the method of ingestion.…”

“…Conversely, experimenter administration of cannabinoids has several drawbacks, including the stress associated with administration, routes of administration not used by humans, and its involuntary nature. Considering the increase in oral use of THC by humans and the limitations of current animal models, two recent studies have had explored oral selfadministration of THC in rats using cookies (Nelson et al, 2018) or sweetened solutions (Barrus et al, 2018). In this study, we sought to develop a mouse model of THC selfadministration with the following aims: voluntary oral self-administration in mice of a behaviorally-effective dose(s), repeated self-administration of a behaviorally-effective dose(s), and CB1 receptor mediation of behavioral effects.…”

Indirect and Direct Cannabinoid Agonists Differentially Affect Mesolimbic Dopamine Release and Related Behaviors

“…A two-bottle choice test for a sweet liquid can be utilized to explore the role of drug administration on anhedonia, and saccharin a non-nutritive sweet liquid can be rewarding [67,68] CB1R-knockout on D1R expressing neurons mildly reduced sucrose preference [69]. THC administration induced a conditioned taste aversion to sucrose and saccharin [70][71][72]. However, the aversive nature of cannabinoids with regards to taste preference may be time dependent as pretreatment every other day for 12 days with THC attenuated the THC conditioned taste aversion to saccharin [71].…”

Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain

“…One major challenge to long-term administration of cannabinoids in preclinical models is that most have historically relied on experimenter administration, which does not closely resemble intake patterns of humans in either route of administration, dose, or timing. Efforts have recently been made to model human cannabinoid consumption in rodents more closely, including use of vapor chambers (Nguyen et al, 2016;Javadi-Paydar et al 2018), or sweetened, orally consumed solutions (Barrus et al, 2018). However, in these models, intake was still limited to a relatively short period or was not voluntary.…”