Regulation of plasticity of glutamate synapses by endocannabinoids and the cyclic‐AMP/protein kinase A pathway in midbrain dopamine neurons

• Published in: The Journal of physiology Vol. 588; no. 14; pp. 2589 - 2604
• Main Authors: Haj‐Dahmane, Samir, Shen, Roh‐Yu
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 15.07.2010; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Addictive behaviors; Animals; Arachidonic Acids - biosynthesis; Arachidonic Acids - physiology; Calcium Channel Blockers - pharmacology; Calcium Channels, L-Type - physiology; Cannabinoid Receptor Modulators - physiology; Cyclic AMP - physiology; Cyclic AMP-Dependent Protein Kinases - physiology; Dopamine; Dopamine - physiology; Endocannabinoids; Glutamic Acid - physiology; Glycerides - biosynthesis; Glycerides - physiology; Glycerol; Kinases; Long-Term Synaptic Depression - physiology; Male; Mesencephalon - enzymology; Mesencephalon - physiology; Neuronal Plasticity - physiology; Neurons; Neurons - enzymology; Neurons - physiology; Neuroscience; Nifedipine - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Receptors, N-Methyl-D-Aspartate - physiology; Synapses - enzymology; Synapses - physiology; Synaptic Transmission - physiology; Type C Phospholipases - antagonists & inhibitors; Type C Phospholipases - physiology; Ventral Tegmental Area - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2010.190066

Endocannabinoids (eCBs) are lipid signalling molecules which play a key role in the regulation of synaptic transmission and plasticity in the central nervous system. Previous studies have reported that eCBs are released ‘on demand’ in the ventral tegmental area (VTA), a brain region critical for reward learning. However, their role in modulating the long‐term plasticity of glutamate synapses of VTA dopamine (DA) neurons remains unknown. In the present study, we showed that low frequency afferent stimulation paired with moderate postsynaptic depolarization elicited an N‐methyl‐d‐aspartate (NMDA) receptor‐independent long‐term depression (LTD) at glutamate synapses of VTA DA neurons. This form of LTD was caused by a decrease in the probability of glutamate release. Examination of the mechanisms underlying this form of LTD revealed that it was mediated by retrograde eCB signalling. In addition, we found that inhibition of 2‐arachidonoyl glycerol biosynthesis blocked LTD induction, suggesting that 2‐arachidonoyl glycerol is the most likely retrograde eCB messenger mediating LTD. The eCB‐LTD induced at glutamate synapses of VTA DA neurons also required the inhibition of the presynaptic cAMP/PKA pathway. Taken together, these results reveal a critical role of eCBs in controlling the long‐term plasticity of glutamate synapses in VTA DA neurons. Neurons of the ventral tegmental area are part of the brain circuits that regulate reward‐related behaviours and addiction. We show that synaptic transmission here undergoes long‐term depression. This plastic change is mediated by the release of endocannabinoid signalling molecules, which stimulate cannabinoid CB1 receptors. The findings contribute to our understanding of the ability of drugs of abuse to induce persistent alterations of the synaptic communication in the brain reward circuits, which is believed to underlie addictive behaviours.