Preclinical Research @ CSL -

The Division of Behavioral Biology

How can preclinical research inform us about cannabis science?

Our research focuses on the behavioral pharmacology of cannabis constituents such as the well-known cannabinoids, Δ9-tetrahydracannabinol (THC) and cannabidiol (CBD), and secondary cannabinoids such as cannabigerol (CBG), cannabinol (CBN) cannabichromene (CBC). We also are interested in terpenes found in cannabis and other natural sources such as citrus and hops, which impart distinct aromas and flavors, and may produce pharmacological effects on their own or in interaction with cannabinoids (i.e., ‘the entourage effect’). By testing isolated compounds and cannabinoids-terpenes combinations in range of behavioral tests we can increase understanding of the potential medical benefits and potential harms of cannabis and products containing cannabis constituents.

Vaporized cannabinoid administration

Inhalation (vaping and smoking) is the primary route of administration for cannabis and cannabinoid products. Our group has been working on developing methods for the administration of vaporized cannabinoids, starting with THC, in rodents.

Video (left) shows passive vaporized drug administration to a freely moving rat inside of a sealed rodent cage connected to a vacuum pump for continuous air exchange. Chambers are manufactured by La Jolla Alcohol Research Inc.

Schematic of the passive vapor exposure chamber

Evaluation of cannabis constituents for alleviating pain

Cannabis and certain cannabinoid constituents, such as THC, have been shown to have therapeutic benefits for pain. In a recent survey of medical cannabis users, the primary reasons for cannabis product use was to alleviate pain (61%). Our early studies demonstrated that acute doses of THC when vaped or ingested orally reduced pain sensitivity (antinociception) in a dose-related manner, although sex and strain differences were also observed. Future projects will evaluate other cannabis constituents, including minor cannabinoids and terpenes

Photo (right) shows a rat habituating on a test platform; von Frey hairs are then applied to the rat’s hindpaw in order to assess mechanical sensitivity threshold.

Our studies also often include screens of cannabinoids and cannabinoid combinations on standard tests of cannabinoid-receptor 1 mediated effects: the cannabinoid tetrad (tests of pain, hypothermia, locomotion, catalepsy). The test is grounded in early studies on the pharmacological validation of THC and synthetic CB1R agonists in rodents. THC and other cannabinoids produce phenotypic responses of antinociception, hypothermia, hypolocomotion, and catalepsy.

Cannabinoid reward and reinforcement

The abuse liability of a substance is predicted using drug reward and reinforcement procedures. The ‘gold standard’ procedures for the evaluation drug reward and reinforcement are place conditioning (e.g., conditioned place preference, CPP) and operant drug self-administration. Our current research is developing rodent e- vape self-administration and place conditioning models for the purposes of increasing our understanding of the rewarding/reinforcing effects and potential differences in abuse liability of cannabinoids and other cannabis constituents. These rat models allow for medications development and assessment for cannabis use disorder.

Photo (left) shows a rat responding for vaporized drug delivery on a fixed-ratio 1 schedule of reinforcement. Chambers are manufactured by La Jolla Alcohol Research, Inc.

In a recently completed project, we assessed the conditioned rewarding effects of THC vapor in male and female rats. In this study, male and female rats showed an exposure-dependent preference for the THC vapor-paired chamber, and sex differences were observed in the THC amount needed to produce CPP, as well as the time to extinction. Conditioned place aversion was not observed at any of the THC vapor conditions tested. A preprint of this study is available on BioRxiv (1) and is currently undergoing peer review.

In an ongoing project, we are assessing self-administration of THC vapor or propylene glycol vehicle under various schedules of reinforcement and at varying drug concentrations.

Neurocognitive effects of cannabis constituents

Acute administration of cannabis and THC can produce motor and neurocognitive impairments, such as deficits in sustained attention and working memory. Neurocognitive performance after acute and chronic administration of cannabinoids using a series of tests, including the rodent Psychomotor Vigilance Test (rPVT) and the Y-Maze Spontaneous Alternation Test. The rPVT was designed to track the same types of performance variables as the human Psychomotor Vigilance Test (PVT), which is commonly utilized as an objective risk assessment tool to quantify basic attention and neurocognitive function in laboratory, clinical, and operational settings. The Y-maze is a widely used behavioral test for studying spatial learning and memory in rodents.

Photo (right) shows a the Y-maze test of spontaneous alternation behavior; analysis software is Ethovision XT.

In an ongoing study, we are testing the effects of oral THC and CBD, alone and in combination, using the rodent Psychomotor Vigilance Task (rPVT). This is a sustained attention test that requires rats to monitor the location of a light stimulus that appears infrequently and to respond as quickly as possible to the onset of the light stimulus by depressing a nose-poke key; food reinforcement is earned for correct responses. A well documented side effect of acute administration of cannabis and THC is deficits in cognition and attention. CBD, a non-intoxicating constituent of cannabis, may modulate THC’s impairing effects. A publication from this project is in preparation.