Combined ∆9-tetrahydrocannabinol and moderate alcohol administration: effects on ingestive behaviors in adolescent male rats

Abstract

Rationale-Whereas co-use of alcohol and marijuana is prevalent in adolescents, the effects of such drug co-exposure on ingestive and cognitive behaviors remain largely unexplored. We hypothesized that co-exposure to alcohol and Δ 9-tetrahydrocannabinol (THC), the main psychoactive constitute of marijuana, alters feeding behavior and cognition differently from either drug alone. Methods-Male rats received daily THC (3-20 mg/kg/day) or oil vehicle through subcutaneous injection or consumption of a cookie with access to saccharin or saccharin-sweetened alcohol during adolescence (P30-45). Barnes maze and sucrose preference tests were applied to assess spatial memory and behavioral flexibility and abstinence-related anhedonia, respectively. Results-Subcutaneous THC did not affect alcohol intake, but dose-dependently increased acute (3-h) chow intake and reduced weight gain. Moderate alcohol consumption reduced the acute hyperphagic effect of subcutaneous THC. By contrast, oral THC at a dose > 5 mg/kg robustly reduced alcohol intake without affecting 3-h chow intake. At this dose, some rats stopped consuming the THC-laced cookies. Furthermore, oral THC reduced weight gain, and co-exposure to alcohol alleviated this effect. Chronic subcutaneous, but not oral, THC reduced sucrose intake during abstinence. Neither treatment impaired cognitive behaviors in the Barnes maze. Conclusion-Moderate alcohol and THC consumption can interact to elicit unique outcomes on ingestive behaviors and energy balance. Importantly, this study established a novel model of voluntary alcohol and THC consumption for studying mechanisms underlying the consequences of adolescent onset co-use of the two drugs.

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

“…During the second week, when EtOH intake was highest, consumption of THC dough reduced EtOH intake. This effect was completely driven by mice receiving THC dough after DID and is consistent with decreased EtOH intake when combined with oral THC in rats (Nelson et al., ). What appears to be an increase in EtOH intake in mice receiving THC dough before DID (vs. THC after) is likely explained by a general increase in fluid intake following consumption of THC, as mice had elevated water intake following THC consumption on multiple days.…”

“…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., ).…”

“…Synthetic cannabinoids have been shown to facilitate alcohol drinking in both mice and rats (Colombo et al., ; Linsenbardt and Boehm, ); however, this is in contrast to ∆ 9 ‐tetrahydrocannabinol (THC), which has no effect or reduces alcohol drinking depending on route of administration (Nelson et al., ). This suggests a difference in effects on alcohol drinking between synthetic cannabinoids and the phytocannabinoid THC.…”

“…Edible THC products are becoming increasingly popular (Giombi et al., ; Wang et al., ), and, given their formulations (e.g., cookies, candies), are likely appealing to adolescents. Although viewed as safer by adolescents (Friese et al., ), edible THC administration in rodents induces CB1R‐mediated effects similar to those produced by other routes of administration (Kruse et al., ; Nelson et al., ; Smoker et al., ), and high doses are known to produce adverse reactions in humans (Benjamin and Fossler, ; Bui et al., ; Favrat et al., ; Monte et al., ). It is still unclear to what degree use of edible THC might induce facets of substance use disorder, such as craving or tolerance, but it has been shown to impact CB1R expression in drug reward‐related circuitry (Kruse et al., ).…”

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

“…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.…”