The cool thing about the endocannabinoid system is that it breaks most  previously accepted neuroscience dogma.  General teaching emphasizes that information processing in the brain is unidirectional, with the signal arising in the presynaptic neuron, travelling across the synapse, and binding to a receptor in the postsynaptic neuron.  In contrast, endocannabinoids function as a retrograde inhibitory signal, meaning they arise in the postsynaptic neuron and travel across the synapse to bind to the presynaptic neuron (see Figure 1 at bottom of page).  The signal is inhibitory as it prevents the presynaptic neuron from signalling any further with the postsynaptic neuron by inhibiting neurotransmitter release in the presynaptic neuron.  Depolarization of the postsynaptic  neuron causes the release of endocannabinoids, which bind to a presynaptic cannabinoid receptor.  The CB1 (cannabinoid 1) receptors are the most abundant receptors in the brain and are also present in the peripheral tissue.

After THC was identified and isolated as the biologically active ingredient in marijuana, numerous synthetic analogs, or similar molecules to elicit similar bioactivity and effects of THC, were created.  In 1974, a synthetic analog was demonstrated to have a similar in vivo analgesic effect (meaning a rat was given a dose of a molecule similar to THC and ceased feeling almost all pain).  The agonists also inhibited adenylyl cyclase.  Adenylyl cyclase  catalyses the conversion of ATP (the body’s form of energy) to cyclic AMP, which acts as a second messenger to regulate many of a cell’s processes.  Adenylyl cyclase is often controlled by a G-protein-coupled receptor.  G-protein coupled receptors are proteins in the cell membrane that are known to be involved in signal transduction from extracellular mechanisms to intracellular mechanisms. G-protein coupled receptors can also affect depolarization.

In 1991 a radioligand (a radioactive biochemical substance) was used to identify the places in the brain that recognize THC.  Using the radioligand, the Cannabinoid Receptors were identified as a G-Protein coupled receptor.  Two types of cannabinoid receptors were identified as CB1 and CB2.  CB1 receptors are the most abundant receptors in the mammalian brain, but are also present at much lower concentrations in peripheral tissues and cells.  CB2 is primarily expressed in cells of the immune and hematopoietic (affects or promotes the formation of blood cells) systems, but also known to be abundant in the brain.   CB1 is primarily responsible for the behavioral and psychoactive effects of marijuana and CB2 is primarily responsible for the immune and blood effects of marijuana.  Most ligands (substances that bind to the cannabinoid receptors such as THC) will bind to both cannabinoid receptors without distinguishing between the two receptors.  A third cannabinoid receptor appears to exist and have many of the same functions as CB1, as shown by its function in CB1 knockout mice.  However, this receptor has not of yet been identified.

DSI is depolarization-induced suppression of inhibition and DSE, depolarization-induced suppression of excitation is the predominant action for which endocannabinoids are responsible.  The story begins with GABA, the main inhibitory neurotransmitter in the central nervous system, which inhibits the postsynaptic cell from firing.  When the GABA receptors on the postsynaptic neuron are activated, chloride ions are let into the cell, which results in a build-up of negative charge, making that cell less likely to fire an action potential.  The excitation of postsynaptic GABA receptors results in the release of postsynaptic endocannabinoids which diffuse back across the synaptic space, and bind to the CB1 receptor, the G-protein Coupled Receptor.  The endocannabinoid binding to CB1 activates a G-protein mediated response to inhibit further release of GABA.  The postsynaptic cell is no longer inhibited by GABA, meaning the postsynaptic cell releases its neurotransmitter (either excitatory or inhibitory) without having to overcome the same extent of hyperpolarization induced by GABA binding to the GABA membrane receptors.  The same story can be told for glutamate, an excitatory neurotransmitter, which will be released to excite an action potential in the postsynaptic neuron.  The CB1-induced suppression of Glutamate released is calle depolariztion-induced suppression of excitation. The behavioral consequences of DSI and DSE remain unclear.  Selective knockout of CB1 receptors from GABAergic interneurons was found to abolish DSI and long-term Depression of inhibitory synapses.  This may have major implications for extinction of fear responses.  However, the classic behavioral responses of THC remained unaffected in the knockout of DSI, indicating a large role of DSE for behavioral affects of THC (Pacher, 2005).

The endocannabinoid system is exceedingly complex, and research on this system has led to many counterintuitive findings, which have led scientists to question many previously held beliefs about not only cannabinoids and their internal receptors, but also the nervous system in general.  For example, endocannabinoids go "upstream" in neurons, meaning that they travel through neurons in the opposite direction of other chemicals.  The consequences of this are not well understood at this time, but is interesting nonetheless.  Scientists have succesfully synthesized several other chemicals that function in the same way as naturally occuring THC in marijuana.  And have also isolated two seperate cannabinoid receptors (CB1 and CB2), which are located throughout the body, with particularly high concentrations in the brain. Endocannabinoid receptors are also present in a wide variety of very important bodily tissues including the gonads (ovaries and testes), and have extensive if not fully understood effects on the immune system as well as the circulatory system.

schematic representation of mechanisms underlying CB1 receptor

(image from

Figure 1:  A schematic representation of the retrograde movement of endocannabinoids.

The movement of cannabinoids is opposite that of other chemicals that move through neurons.