Restoring glutamate homeostasis in the nucleus accumbens via endocannabinoid-mimetic drug prevents relapse to cocaine seeking behavior in rats

Abstract

Impaired glutamate homeostasis is a key characteristic of the neurobiology of drug addiction in rodent models and contributes to the vulnerability to relapse to drug seeking. Although disrupted astrocytic and presynaptic regulation of glutamate release has been considered to constitute with impaired glutamate homeostasis in rodent model of drug relapse, the involvement of endocannabinoids (eCBs) in this neurobiological process has remained largely unknown. Here, using cocaine self-administration in rats, we investigated the role of endocannabinoids in impaired glutamate homeostasis in the core of nucleus accumbens (NAcore), which was indicated by augmentation of spontaneous synaptic glutamate release, downregulation of metabotropic glutamate receptor 2/3 (mGluR2/3), and mGluR5-mediated astrocytic glutamate release. We found that the endocannabinoid, anandamide (AEA), rather than 2-arachidonoylglycerol elicited glutamate release through presynaptic transient receptor potential vanilloid 1 (TRPV1) and astrocytic cannabinoid type-1 receptors (CB1Rs) in the NAcore of saline-yoked rats. In rats with a history of cocaine selfadministration and extinction training, AEA failed to alter synaptic glutamate release in the NAcore, whereas CB1R-mediated astrocytic glutamate release by AEA remained functional. In order to induce increased astrocytic glutamate release via exogenous AEA, (R)-methanandamide (methAEA, a metabolically stable form of AEA) was chronically infused in the NAcore via osmotic pumps during extinction training. Restoration of mGluR2/3 function and mGluR5-mediated astrocytic glutamate release was observed after chronic methAEA infusion. Additionally, priming or cue-induced reinstatement of cocaine seeking was inhibited in methAEAinfused rats. These results demonstrate that enhancing endocannabinoid signaling is a potential pathway to restore glutamate homeostasis and may represent a promising therapeutic strategy for preventing cocaine relapse.

CB1R activation in nucleus accumbens core promotes stress-induced reinstatement of cocaine seeking by elevating extracellular glutamate in a drug-paired context

“…In fact, the neuronal origin of basal extracellular glutamate regulated by CB1R is supported by the previous observation that administration of AM251 alone induced an increase of extracellular glutamate in NA in a TTX-dependent manner 18 . It should be noted that after chronic perfusion of methAEA, a partial agonist of CB1R with a more robust effect on astrocytic CB1R than on presynaptic CB1R, restored the impaired glutamate homeostasis in cocaine-experienced rats, and subsequently prevented reinstatement 75 . This latter mechanism can be proposed as an alternative or indirect pathway to obtain similar results to that proposed for the acute administration of AM251 18 .…”

“…A third hypothesis can be related to the activity of CB1R expressed in astrocytes 75 , 76 . A recent work, using NA slice electrophysiology from cocaine-experienced rats, showed that activation of CB1R causes an excitatory event that typically corresponds to astrocytic glutamate release 75 . However, this mechanism seems not to impact significantly on those in vivo changes in extracellular glutamate detected during the perfusion of ACEA in our study.…”

“…This latter mechanism can be proposed as an alternative or indirect pathway to obtain similar results to that proposed for the acute administration of AM251 18 . In both cases, the inhibition of reinstatement might be an overall consequence of stimulating mgluR2/3, via sustained astrocytic glutamate release by a partial agonist 75 or via the facilitating effect of a potent, selective CB1R antagonist/inverse agonist on neuronal glutamate release 18 . Conversely, glutamate release from astrocytes occurs in those that are reactive 77 apparently in response to drug-associated cues and stress 78 , 79 , and therefore it is likely that the context-specific elevation of extracellular glutamate after restraint stress in our study may be attributed to a summation between glutamate release from reactive astrocytes (mediated by CB1R or mgluR5) and that from presynaptic terminals.…”

Cocaine experience induces functional adaptations in astrocytes: Implications for synaptic plasticity in the nucleus accumbens shell

“…We have not evaluated synaptic NMDA receptors signalling or SICs at long withdrawal intervals, but a number of recent studies indicate that cocaine‐induced increase in extrasynaptic NMDA signalling may be a transient phenomenon. For example, initial upregulation of extrasynaptic NMDA receptors was found to dissipate by 1 month of withdrawal from cocaine 76 and 14 days of extinction training was not associated with differences in SIC frequency in the NAc 81 . Relative abundance of extrasynaptic NMDA receptors may also be synergistic with the effects of dendritic sprouting reported after cocaine because dendritic coverage has been shown to influence duration of synaptic transients 82,83 .…”

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

“…PEA- and OEA-mediated inhibition of astrocyte activation seems to involve PPAR-α [ 161 , 162 ]. Furthermore, AEA has been shown to elicit glutamate release through astrocytic CB 1 receptor activation in the core of nucleus accumbens in rats [ 163 ].…”