title: Cannabinoid transmission in the prefrontal cortex bi-phasically controls emotional memory formation via functional interactions with the ventral tegmental area.
abstract: Disturbances in cortical cannabinoid CB1 receptor signaling are well established correlates of various neuropsychiatric disorders, including depression and schizophrenia. Importantly, the ability of cannabinoid transmission to modulate emotional processing is functionally linked to interactions with subcortical DA systems. While considerable evidence demonstrates that CB1 receptor-mediated modulation of emotional processing and related behaviors follows a biphasic functional curve, little is known regarding how CB1 signaling within cortical networks may interact with subcortical DAergic systems involved in emotional behavior regulation. Using a combination of in vivo electrophysiological recordings and behavioral pharmacology in rats, we investigated the relationship between mPFC cannabinoid transmission, fear memory formation, and subcortical DA neuron activity patterns. We report that direct intra-mPFC CB1 activation biphasically modulates spontaneous, subcortical VTA DA neuron activity in a dose-dependent fashion; while lower doses of a CB1 receptor agonist, WIN 55,212-2, significantly increased spontaneous firing and bursting rates of VTA DA neurons, higher doses strongly inhibited spontaneous DA neuron activity. Remarkably, this same dose-related functional difference was observed with the regulation of fear-related emotional memory formation. Thus, lower levels of CB1 activation potentiated the emotional salience of normally subthreshold fear memory, whereas higher levels completely blocked fear memory acquisition. Furthermore, while the potentiation of subthreshold fear memory salience was blocked by DA receptor antagonism, CB1-mediated blunting of suprathreshold fear memory was rescued by intra-VTA administration of a GABAB receptor antagonist, demonstrating that reversal of GABAergic inhibitory mechanisms in the VTA can reverse the inhibitory influence of intra-PFC CB1 transmission on mesolimbic DA activity.
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology.
authors.forename: Brittany
authors.initials: B
authors.lastname: Draycott
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-5915-5627
authors.initials: M
authors.lastname: Loureiro
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology.
authors.forename: Tasha
authors.identifier: http://orcid.org/0000-0001-8746-557X
authors.initials: T
authors.lastname: Ahmad
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology.
authors.forename: Huibing
authors.initials: H
authors.lastname: Tan
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology.
authors.forename: Jordan
authors.initials: J
authors.lastname: Zunder
authors.affiliation: Addiction Research Group, Departments of Anatomy and Cell Biology, Department of Psychiatry, and Department of Psychology, Schulich School of Medicine and Dentistry. University of Western Ontario, London, Ontario, Canada N6A 5C1 steven.laviolette@schulich.uwo.ca.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Laviolette
mesh_terms: D000200:Action Potentials; D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D005239:Fear; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D008297:Male; D008568:Memory; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
chemical_list: D043884:Receptor, Cannabinoid, CB1
keywords: cannabinoids; dopamine; fear memory; prefrontal cortex; ventral tegmental area