The loss of NMDAR‐dependent LTD following cannabinoid self‐administration is restored by positive allosteric modulation of CB1 receptors

Abstract

Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self-administration. We used intravenous self-administration of two constituents of cannabis, Δ 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue-induced cannabinoid-seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self-administration. Surprisingly, when rats underwent cue-induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self-administration and the cues predicting cannabis availability.

Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood

“…The reappearance of eCB-LTD and TBS-LTP in the presence of enhanced 2-AG levels achieved via pre-incubation with the potent and selective MAGL inhibitor, JZL184, may owe to a previously demonstrated relationship between presynaptic NMDA receptors and CB1R which have been shown to detect co-incident pre-and post-synaptic activation during certain forms of both LTD and LTP at deep layer synapses of the PFC 48 . Interestingly, elsewhere in the brain, NMDAR-LTD in the nucleus accumbens has also been found to require the participation of CB1R 49 . Here, NMDAR-LTD is abolished following repeated cannabinoid self-administration and is later rescued through enhanced CB1R signaling achieved via the application of a CB1R positive allosteric modulator.…”

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…Unfortunately, due to long-term restrictions on cannabis research in the US and past difficulties in modeling cannabis use with self-administration models in rodents (Panlilio et al, 2015), much less is known about the impact of cannabis relative to other drugs. The development of novel methods of cannabis selfadministration in animals, including oral self-administration of 9-tetrahydrocannabinol (THC)-containing gelatin (Kruse et al, 2019), self-administration of vaporized THC and cannabidiol (CBD) (Freels et al, 2020), and intravenous self-administration of THC and CBD (Neuhofer et al, 2019) will help facilitate the preclinical study of cannabis use disorder, as well as enable us to better understand the consequences of polydrug use involving cannabis.…”

“…Repeated THC administration weakens glutamatergic signaling from the mPFC to the NAc (Spencer et al, 2018;Hwang and Lupica, 2019;Neuhofer et al, 2019) but strengthens input from the basolateral amygdala and ventral hippocampus to the NAc shell (Hwang and Lupica, 2019), suggesting a rewiring of excitatory input to the NAc following long-term cannabinoid exposure. Notably, repeated THC administration also occludes CB 1 -mediated LTD on VTA GABA neurons (Friend L. et al, 2017), indicating a loss of local inhibitory drive on VTA DA neurons.…”

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders

“…The NAcc receives glutamatergic projections from the VTA ( Yamaguchi et al, 2011 ) and other regions involved in the addictive process such as PFC, amygdala, and HIPP ( Koob and Volkow, 2010 ; Floresco, 2015 ; Heinsbroek et al, 2020 ). The acquisition of drug reward associations depends on the convergence of dopaminergic and glutamatergic signaling in the NAcc ( Neuhofer et al, 2019 ). Thus, glutamatergic neurotransmission plays an important role in the functional regulation of relevant brain structures involved in the neurocircuitry of drug addiction.…”