Synaptic plasticity is the process whereby connections between neurons can be altered in an experience dependent manner. For example, drugs of abuse alter plasticity in the ventral tegmental area (VTA) of the midbrain. A large amount of research has been applied to uncovering the mechanism whereby synapses on the reward signaling dopamine cells is altered, however, less is known regarding the VTA inhibitory GABA neurons. Our objective was to examine the ability of GABA neurons to exhibit plasticity, and determine how drugs of abuse could influence it. Here we report a novel type of plasticity of excitatory neurotransmission onto VTA GABA cells. This plasticity is dependent on the metabotropic glutamate receptor 5, to signal for diacylglycerolipase alpha to make the endocannabinoid 2-arachadonoyl glycerol to signal via cannabinoid receptor 1 (CB1). Marijuana and cocaine are drugs of abuse that have been shown to alter the endocannabinoid system. Tetrahydrocannabinol is the active ingredient in marijuana, and is a known agonist of CB1, and cocaine is able to attenuate endocannabinoid signals. We tested the effects of these drugs on VTA GABA plasticity and found that it can be blocked by chronic injections of tetrahydrocannabinol, as well as acute and chronic injections of cocaine. If VTA GABA neurons are depressing excitatory inputs, that could lead to less inhibition onto VTA dopamine cells, and therefore, more reward signaling in the brain. This new type of plasticity could be an additional mechanism whereby cocaine and marijuana exert their rewarding and addictive effects. Another brain structure known to exhibit use-dependent plasticity is the hippocampus, which is involved in learning and memory. The stratum oriens is a layer of inhibitory interneurons in the hippocampus that is involved in feedback inhibition onto the principle excitatory cells in the stratum pyramidale. Our goal was to determine whether oriens interneurons were capable of producing an endocannabinoid signal, and if so, whether they could influence plasticity. We identified 2 major subtypes of oriens interneurons, oriens lacunosum-moleculare cells, and parvalbumin-positive basket cells, which are capable of receiving and producing an endocannabinoid signal. Furthermore, we demonstrated that one such endocannabinoid, anandamide, is responsible for signaling for synaptic plasticity. This plasticity is also dependent on CB1, and is unique in that there are few examples of CB1 signaling for potentiation rather than depression. Collectively, these experiments demonstrate two mechanisms of endocannabinoid mediated synaptic plasticity, which could influence reward signaling, addiction and memory.

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