Cross-Talk Between Cannabinoid and Opiate Systems
Steven R. Goldberg, Ph.D., NIDA Intramural Research Program

Dr. Steven Goldberg described a series of studies demonstrating that both THC, the main psychoactive ingredient in marijuana, and anandamide, an endogenous cannabinoid, can serve as effective reinforcers of drug-taking behavior. These findings provide direct evidence for involvement of endogenous cannabinoid systems in brain reward processes. Additional findings include evidence that THC’s reinforcing effects are reduced by an opioid antagonist and reinstated or potentiated by an opioid agonist, and evidence that THC increases β-endorphin in the ventral tegmental area (VTA) and the shell of the nucleus accumbens. Further, augmented levels of β-endorphins in the VTA may be responsible for previous findings of THC-induced dopamine elevations in the nucleus accumbens.

Presynaptic Effects of Endocannabinoids
Bradley Alger, Ph.D., University of Maryland School of Medicine

Dr. Bradley Alger discussed the discovery of a new mode of cellular communication in which the target (pyramidal) cells may regulate their own state of inhibition by sending a signal backwards across the synaptic junctions (retrograde signaling), causing a temporary inhibition of GABA release. Additionally, Bradley’s team concluded that depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) are produced by short-term retrograde action of endocannabinoids on presynaptic cells. Further, endocannabinoids inhibit calcium influx, increase potassium efflux, and interfere with the quantal release process. Bradley also noted that prolonged activation of CB1Rs can cause long-term depression of glutamate or GABA release, but that there must be another element to it—it cannot be just a cannabinoid, or must be a different cannabinoid, or it may be that there are different ways in which cannabinoid receptors are activated over a long period of time.

Efficacy in CB-1 Cannabinoid Receptor Signal Transduction
Allyn C. Howlett, Ph.D., North Carolina Central University

CB-1 receptors exist as a complex with their associated Gi/0 proteins. Association with Gαi1 and Gαi2 occurs via the third intracellular loop and with Gαo and Gαi3, via the juxtamembrane C-terminal domain (fourth intracellular loop). Allyn Howlett detailed evidence showing that structurally different agonists induce conformational changes within these domains, promoting the selective activation of certain G protein subtypes. This may explain the differences in efficacy between WIN55221-2 and the endocannabinoid analog methanandamide. Howlett hypothesized that such selectivity could result in selective G protein-promoted signal transduction pathways.

Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling
Benjamin Cravatt, Ph.D., The Scripps Research Institute

Dr. Benjamin Cravatt discussed studies involving genetically engineered mice that lack the enzyme fatty acid amide hydrolase (FAAH). The results of these experiments demonstrate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous tone that is essential for normal pain transmission. Therefore, Cravatt proposed, FAAH may represent a pharmaceutical target for the treatment of pain and neuropsychiatric disorders. He described his team’s determination of the three-dimensional structure of FAAH by x-ray crystallography, as well as their development of a proteomic assay to screen FAAH inhibitors against whole tissue/cell extracts.

The Endocannabinoid System and the Regulation of Emotions
Daniele Piomelli, Ph.D., University of California, Irvine

Anandamide is released in selected regions of the brain and is deactivated through a two-step process that consists of transport into cells followed by intracellular hydrolysis. Dr. Daniele Piomelli discussed research that shows that pharmacological blockade of the enzyme fatty acid amide hydrolase (FAAH), which is responsible for intracellular anandamide degradation, produces anxiolytic-like effects in rats without causing the wide spectrum of behavioral responses typical of direct-acting cannabinoid agonists. These findings suggest that anandamide contributes to the regulation of emotion and anxiety and that FAAH might be the target for a novel class of anxiolytic drugs.