GABA neurons in the ventral tegmental area of the midbrain are important components in the brain's reward circuit. Long term changes in this circuit occur through the process of synaptic plasticity. It has been shown that high frequency stimulation, as well as treatment with endocannabinoids, can cause GABA neurons in the ventral tegmental area to undergo long term depression, a form of synaptic plasticity that decreases excitability of cells. The present study elaborates on the mechanism whereby high frequency stimulation can result in long term depression of ventral tegmental area GABA neurons. Using the whole cell patch clamp technique in acute brain slices, we recorded excitatory currents from ventral tegmental area GABA neurons in GAD-GFP expressing CD1 mice and observed how the excitatory currents changed in response to different treatments. We confirm that high frequency stimulation causes long term depression, and the cannabinoid type 1 receptor antagonist AM-251 blocks this effect. Long term depression is also elicited by treatment with the cannabinoid type 1 receptor agonist 2-arachidonylglycerol. It is inconclusive whether treatment with 2-arachidonylglycerol occludes further long term depression by high frequency stimulation. We also demonstrate that activation of group I metabotropic glutamate receptors by DHPG produces long term depression. These results support the model that at these excitatory synapses, high frequency stimulation causes the release of glutamate from presynaptic terminals, activating group I metabotropic glutamate receptors, causing production of 2-arachidonylglycerol. 2-arachidonylglycerol in turn acts on presynaptic cannabinoid type 1 receptors to decrease release of glutamate onto GABA neurons. This model can be tested by further research, which should include cannabinoid type 1 receptor knockout mice. This study provides more insight into how drugs of abuse such as tetrahydrocannabinol, the active component of marijuana that activate cannabinoid type I receptors, can corrupt the natural reward mechanisms of the brain.



College and Department

Life Sciences; Physiology and Developmental Biology



Date Submitted


Document Type





VTA, GABA, plasticity, LTD, electrophysiology, endocannabinoids, 2-AG