The Endocannabinoid System

In our previous column (in the February ABT), we reviewed the impact of two key factors that precipitate relapse: (1) priming (introduction of small amounts of the drug), which acts on the mesolimbic dopamine pathway in the brain; and (2) stress, which acts on a variety of neural pathways. As our exploration of addiction and the brain continues, the endocannabinoid system contributes additional pieces of information to enhance our understanding of addiction.

Who ever would have thought that the active ingredient in marijuana, tetrahydrocannabinol (THC), had receptor sites ready and waiting in our brains? The plant that gives us marijuana, Cannabis sativa, has been known for thousands of years. Its psychoactive properties have been used over the centuries and across the world. Once the chemical structure of THC was identified, the research began (Gaoni & Mechoulam, 1964).

There have been three major breakthroughs in cannabinoid research, the discovery of (1) two receptors that bind THC: CB1R and CB2R; (2) two endogenous cannabinoids, or “endocannabinoids” (eCBs), AEA and 2-AG; and (3) retrograde signaling (Hashimotodani et al., 2007).

Because CB1R is widely available in the central nervous system, it is likely responsible for the psychoactive nature of Cannabis. CB2R is found mainly in the immune system. Its function is not yet known.

Not only do we have these receptor sites for THC in our brains, but our bodies also produce endogenous forms of THC: anandamide (AEA) and 2-Arachidonoyl-glycerol (2-AG). They are produced “on demand” rather than stored in synaptic vesicles like many neurotransmitters. AEA and 2-AG are synthesized from phospholipids in the post-synaptic cell. It is important to remember that drugs are most likely to have an influence on our behavior when they are structurally similar to chemicals that have a natural role in body function.

After 15 years of continuous research, eCBs were established as neuromodulators that play a key role in synaptic function throughout the central nervous system, regulating a wide range of neural functions and behaviors (Castillo et al., 2012). This range includes many possible roles for eCBs in physiological processes: learning and memory, anxiety, depression, appetite and feeding behavior, pain, neuroprotection, stress and addiction (Kano et al., 2009). Neurotransmitters, which are stored in synaptic vesicles, generally send their messages forward, from the end of an axon terminal across the synapse to the next neuron’s receptors. This is called anterograde transmission (Figure 1). However, the eCBs influence neurotransmission through the process of retrograde signaling. Neuromodulators can increase or decrease the amount or extent of neurotransmitter release within the synapse. For example, AEA and 2-AG are released in a backward direction (retrograde transmission) from the post-synaptic cell, where they are synthesized and released into the synaptic space. At this point, they can act on the presynaptic CB1 receptors, modulating neurotransmission to keep our systems in balance.

Figure 1.

Neurotransmission: anterograde. As an electrical impulse arrives at the terminal, it triggers vesicles that contain a neurotransmitter such as dopamine (in blue) to move toward the terminal membrane. The vesicles fuse with the terminal membrane to release their contents (in this case, dopamine). Once inside the synaptic cleft (the space between the two neurons), the dopamine can bind to specific proteins called dopamine receptors (in pink) on the membrane of a neighboring neuron. (Source: http://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-i-introduction-to-brain/7-synapse-synaptic-neurotransmissio)

Figure 1.

Neurotransmission: anterograde. As an electrical impulse arrives at the terminal, it triggers vesicles that contain a neurotransmitter such as dopamine (in blue) to move toward the terminal membrane. The vesicles fuse with the terminal membrane to release their contents (in this case, dopamine). Once inside the synaptic cleft (the space between the two neurons), the dopamine can bind to specific proteins called dopamine receptors (in pink) on the membrane of a neighboring neuron. (Source: http://www.drugabuse.gov/publications/teaching-packets/neurobiology-drug-addiction/section-i-introduction-to-brain/7-synapse-synaptic-neurotransmissio)

The role of eCBs in synaptic modulation is safely assumed to be significant (Chevaleyre et al., 2006). The eCBs are major players in “synaptic plasticity,” defined as the ability of the synapse to modify what it does; it can change its strength (firing and release patterns) depending on the input it receives from many neural sources. Synaptic plasticity is likely to have an important role as well in the addiction process, especially craving and relapse (A. Horita, unpubl. data).

As Chevaleyre commented (Chevaleyre et al., 2006), “The difficult task of future studies is to determine specifically how transient and enduring eCB-mediated changes in synaptic efficacy contribute to experience-dependent modification of behavior.” As researchers continue to unravel the secrets of the brain, our understanding of these phenomena will hopefully translate into helpful practices to aid in recovery from addiction. Our next column will examine the mechanisms of action and effects of marijuana, an activator of the endocannabinoid system.

References

References
Castillo, P.E., Younts, T.J., Chávez, A.E. & Hashimotodani, Y. (2012). Endocannabinoid signaling and synaptic function. Neuron, 76, 70–81.
Chevaleyre, V., Takahashi, K.A. & Castillo, P.E. (2006). Endocannabinoid-mediated synaptic plasticity in the CNS. Annual Review of Neuroscience, 29, 37–76.
Gaoni, Y. & Mechoulam, R. (1964). Journal of the American Chemical Society, 86, 1646–1647.
Hashimotodani, Y., Ohno-Shosaku, T. & Kano, M. (2007). Endocannabinoids and synaptic function in the CNS. Neuroscientist, 13, 127–137.
Kano, M., Ohno-Shosaku, T., Uchigashima, M. & Watanabe, M. (2009). Endocannabinoid-mediated control of synaptic transmission. Physiological Reviews, 89, 309–380.