title: Prefrontal cortex stimulation induces 2-arachidonoyl-glycerol-mediated suppression of excitation in dopamine neurons.
abstract: Endocannabinoids form a novel class of retrograde messengers that modulate short- and long-term synaptic plasticity. Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are the best characterized transient forms of endocannabinoid-mediated synaptic modulation. Stimulation protocols consisting of long-lasting voltage steps to the postsynaptic cell are routinely used to evoke DSE-DSI. Little is known, however, about more physiological conditions under which these molecules are released in vitro. Moreover, the occurrence in vivo of such forms of endocannabinoid-mediated modulation is still controversial. Here we show that physiologically relevant patterns of synaptic activity induce a transient suppression of excitatory transmission onto dopamine neurons in vitro. Accordingly, in vivo endocannabinoids depress the increase in firing and bursting activity evoked in dopamine neurons by prefrontal cortex stimulation. This phenomenon is selectively mediated by the endocannabinoid 2-arachidonoyl-glycerol (2-AG), which activates presynaptic cannabinoid type 1 receptors. 2-AG synthesis involves activation of metabotropic glutamate receptors and Ca2+ mobilization from intracellular stores. These findings indicate that dopamine neurons release 2-AG to shape afferent activity and ultimately their own firing pattern. This novel endocannabinoid-mediated self-regulatory role of dopamine neurons may bear relevance in the pathogenesis of neuropsychiatric disorders such as schizophrenia and addiction.
authors.affiliation: Center of Excellence Neurobiology of Addiction, Institute of Neuroscience, University of Cagliari, 09042 Monserrato, CA, Italy. myriam@unica.it
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.forename: Simona
authors.initials: S
authors.lastname: Perra
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.forename: Giuliano
authors.initials: G
authors.lastname: Pillolla
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D004558:Electric Stimulation; D063388:Endocannabinoids; D018698:Glutamic Acid / Q000502:physiology; D005989:Glycerides / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000502:physiology; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; D002118:Calcium; D004298:Dopamine