The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. Δ9-Tetrahydrocannabinol (Δ9-THC) is the plant's primary psychoactive constituent. Given the abuse liability of Δ9-THC, assessment of the psychoactive effects of minor cannabinoids and other plant constituents is important, especially for compounds that may be used...
The co-use of nicotine and cannabis has been steadily rising in the United States. Rodent studies suggest that delta-9-tetrahydrocannabinol (THC) could increase addictive qualities of nicotine, but whether repeated THC exposure alters self-administration of nicotine has not been tested. We hypothesized that THC would increase the reinforcing effects of nicotine and alter nicotine intake. Adult...
The recent NIH mandate to consider sex as a biological variable in preclinical research has focused attention on delineation of sex differences in behavior. To investigate mechanisms underlying sex differences in Δ9-tetrahydrocannabinol (THC) effects, we examined the effects of sex and gonadal hormones on CB1 receptors in cerebellum, hippocampus, prefrontal cortex, and striatum. Adult...
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 Δ9-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...
Diversion of synthetic cannabinoids from the lab to drugs of abuse has become increasingly prevalent in recent years. Moreover, as earlier synthetic cannabinoids were banned, manufacturers introduced a new supply of novel compounds to serve as replacements. Hence, the chemical diversity of synthetic cannabinoid analogs has also rapidly increased. The present study examined 8 new synthetic...
Psychoactive cannabinoids from the marijuana plant (phytocannabinoids), from the body (endocannabinoids), and from the research lab (synthetic cannabinoids) produce their discriminative stimulus effects by stimulation of CB1 receptors in the brain. Early discrimination work with phytocannabinoids confirmed that Δ9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive constituent of the...
NeuropharmacologyOctober 2017Robert A Owens, Mohammed A Mustafa, Bogna M Ignatowska-Jankowska et al.
Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is...
Women report greater sensitivity to the subjective effects of Δ9-tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. A cumulative dosing THC discrimination procedure was...
Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with...
November 15, 2016Daniel G Barrus, Kristen Capogrossi, Sheryl Cates et al.
Food products containing cannabis extract (edibles) have emerged as a popular and lucrative facet of the legalized market for both recreational and medicinal cannabis. The many formulations of cannabis extracts used in edibles present a unique regulatory challenge for policy makers. Though edibles are often considered a safe, discreet, and effective means of attaining the therapeutic and/or...
Incomplete overlap in the discriminative stimulus effects of Δ-tetrahydrocannabinol (THC) and the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol has been reported in food-reinforced tasks. The aim of this study was to examine cannabinoid discriminative stimulus effects in a nonappetitive procedure. Adult male mice lacking the gene for AEA's major metabolic enzyme, fatty acid...
Whereas the inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the respective major hydrolytic enzymes of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), elicits no or partial substitution for Δ(9)-tetrahydrocannabinol (THC) in drug-discrimination procedures, combined inhibition of both enzymes fully substitutes for THC, as well as produces a...
A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC...
The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e.,...
Synthetic indole-derived cannabinoids, originally developed to probe cannabinoid CB1 and CB2 receptors, have become widely abused for their marijuana-like intoxicating properties. The present study examined the effects of indole-derived cannabinoids in rats trained to discriminate Δ(9)-tetrahydrocannabinol (Δ(9)-THC) from vehicle. In addition, the effects of Δ(9)-THC in rats trained to...
The mechanism through which marijuana produces its psychoactive effects is Δ(9)-tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC׳s psychoactive effects is to...
Synthetic indole-derived cannabinoids have become commonly used recreational drugs and continue to be abused despite their adverse consequences. As compounds that were identified early in the epidemic (e.g., naphthoylindoles) have become legally banned, new compounds have appeared on the drug market. Two tetramethylcyclopropyl ketone indoles, UR-144...
The prototypic cannabinoid type 1 (CB₁) receptor antagonist/inverse agonist, rimonabant, is comprised of a pyrazole core surrounded by a carboxyamide with terminal piperidine group (3-substituent), a 2,4-dichlorophenyl group (1-substituent), a 4-chlorophenyl group (5-substituent), and a methyl group (4-substituent). Previous structure-activity relationship (SAR) analysis has suggested that the...
Δ(9)-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg...
The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Δ9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase...
Adolescents and young adults of both sexes are the primary consumers of "club" drugs; yet, most of the mechanistic preclinical research in this area has been performed in adult male rodents. The purpose of this study was to evaluate the acute and repeated effects of drugs that are commonly abused by adolescents in female adolescent and adult rats in a rodent model of behavioral sensitization....
Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of some of its effects. This study represents a systematic examination of this hypothesis. Salvinorin A was isolated from S. divinorum and was...
Primarily, rats have served as subjects in Delta(9)-tetrahydrocannabinol's (THC) discrimination studies although other species such as monkeys and pigeons have been used. While the introduction of the knockout and transgenic mice has vastly stimulated the study of the discriminative stimulus effects of drugs there is only a single published report of mice trained to discriminate THC. Thus, this...
Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor...
Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Delta(9)-tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids (e.g., cannabidiol (CBD)) has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio...