Exogenous and Endogenous Cannabinoids Control Synaptic Transmission in Mice Nucleus Accumbens

Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex-NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate-mediated transmission through presynaptic activation of presynaptic K+ channels and GABA-mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long-term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB-LTD). Induction of eCB-LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine-sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB-LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB-mediated synaptic plasticity. These data suggest a major role of the eCB system in long-term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.