Independent presynaptic and postsynaptic mechanisms regulate endocannabinoid signaling at multiple synapses in the ventral tegmental area.
Dopamine (DA) neurons in the ventral tegmental area have been implicated in psychiatric disorders and drug abuse. Understanding the mechanisms through which their activity is regulated via the modulation of afferent input is imperative to understanding their roles in these conditions. Here we demonstrate that endocannabinoids liberated from DA neurons activate cannabinoid CB1 receptors located on glutamatergic axons and on GABAergic terminals targeting GABA(B) receptors located on these cells. Endocannabinoid release was initiated by inhibiting either presynaptic type-III metabotropic glutamate receptors or postsynaptic calcium-activated potassium channels, two conditions that also promote enhanced DA neuron excitability and bursting. Thus, activity-dependent release of endocannabinoids may act as a regulatory feedback mechanism to inhibit synaptic inputs in response to DA neuron bursting, thereby regulating firing patterns that may fine-tune DA release from afferent terminals.
Riegel
Arthur C
AC
Cellular Neurobiology Branch, Electrophysiology Unit, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, United States Department of Health and Human Services, Baltimore, Maryland 21224, USA.
Lupica
Carl R
CR
D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D063388:Endocannabinoids; D005071:Evoked Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013569:Synapses / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D024681:Potassium Channels, Calcium-Activated; D043884:Receptor, Cannabinoid, CB1; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002118:Calcium; D004298:Dopamine