Cerebellar-dependent learning as a neurobehavioral index of the cannabinoid system

Delta-9-tetrahydrocannabinol (THC) is the primary psycho-active ingredient in Cannabis spp., the most widely used illicit drug in the United States. THC is an exogenous agonist of the central cannabinoid receptor (CB1), one of the most abundant G-coupled receptors in the mammalian brain. Although CB1 receptors are distributed throughout the brain, they are found at very high levels in the cerebellum. Despite the variety of disturbances associated with acute cannabis intoxication, including altered short-term memory, dissociation of thoughts, motor impairments, and paranoia, among others, a reliable index of cannabinoid system function has in large part eluded scientists. Thus, there is a demand in contemporary clinical neuroscience for methods sensitive to cannabinoid system function, not only for assessing how cannabis use influences human information processing, but also to assess the involvement of the endocannabinoid system (ECS) in clinical disease and evaluate the effects of CB1-based drug therapies. The purpose of the present article, therefore, is to address this current need by integrating two separate literatures. The first literature demonstrates that the ECS mediates synaptic plasticity, specifically, long-term depression (LTD) of parallel fibers at the parallel fiber-Purkinje junction in the cerebellar cortex. The second literature suggests that LTD at this junction is necessary for the acquisition of the primary dependent variable in delay eyeblink conditioning (EBC)--the exhibition of temporally measured conditioned responses. These two literatures are integrated by proposing an updated EBC circuit that incorporates the CB1 receptor and the endogenous cannabinoids. Finally, the implications of the model is discussed in consideration of recent evidence from CB1 knockout mice, human cannabis users, and schizophrenia patients, with the expectation that translational research on the cannabinoid system will be advanced.