Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2020-01, Vol.45 (2), p.374-383
• Main Authors: Pickel, Virginia M, Bourie, Faye, Chan, June, Mackie, Ken, Lane, Diane A, Wang, Gang
• Format: Article
• Language: English
• Subjects: Adolescents; Age Factors; Animals; Behavioral plasticity; Cannabinoid receptors; Cannabinoids; Cannabis; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Child development; Chronic exposure; Dendrites; Depolarization; Dose-Response Relationship, Drug; Dronabinol - toxicity; Firing rate; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Male; Membrane potential; Mice; Mice, Inbred C57BL; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - metabolism; Neuroplasticity; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - ultrastructure; Protein Subunits - metabolism; Psychotropic Drugs - administration & dosage; Psychotropic Drugs - toxicity; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses; Synapses - drug effects; Synapses - metabolism; Synapses - ultrastructure; Synaptic plasticity; Teenagers; Tetrahydrocannabinol; THC
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-019-0466-9

Adolescence is a vulnerable period of development when limbic connection of the prefrontal cortex (PFC) involved in emotional processing may be rendered dysfunctional by chronic exposure to delta-9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound in marijuana. Cannabinoid-1 receptors (CB1Rs) largely mediate the central neural effects of ∆9-THC and endocannabinoids that regulate NMDA receptor-dependent synaptic plasticity of glutamatergic synapses in the prelimbic prefrontal cortex (PL-PFC). Thus, chronic occupancy of CB1Rs by ∆9-THC during adolescence may competitively decrease the functional expression and activity of NMDA receptors in the mature PL-PFC. We used a multidisciplinary approach to test this hypothesis in adult C57BL/6J male mice that received vehicle or ∆9-THC in escalating doses (2.5-10 mg/kg/ip) through adolescence (postnatal day 29-43). In comparison with vehicle, the mice receiving ∆9-THC showed a hyperpolarized resting membrane potential, decreased spontaneous firing rate, increased current-induced firing threshold, and decreased depolarizing response to NMDA in deep-layer PL-PFC neurons analyzed by current-clamp recordings. Electron microscopic immunolabeling in the PL-PFC of adult mice that had received Δ9-THC only during adolescence showed a significant (1) decrease in the extrasynaptic plasmalemmal density of obligatory GluN1-NMDA subunits in dendrites of all sizes and (2) a shift from cytoplasmic to plasmalemmal distribution of GluN1 in large dendrites receiving mainly inhibitory-type synapses from CB1R-labeled terminals. From these results and concomitant behavioral studies, we conclude that social dysfunctions resulting from excessive intake of ∆9-THC in the increasingly available marijuana products used by male teens may largely reflect circuit defects in PL-PFC networks communicating through endocannabinoid-regulated NMDA receptors.