ROLE OF CANNABINOID CB1 RECEPTORS IN THE NUCLEUS ACCUMBENS CORE IN STRESS-INDUCED REINSTATEMENT OF COCAINE SEEKING AND CONTEXT-SPECIFIC INCREASE OF EXTRACELLULAR GLUTAMATE

GUZMÁN, A. S.; AVALOS, M. P.; MONGI BRAGATO, B.; DE GIOVANNI, L.N.; SANCHEZ, M. A.; EULIARTE, P. V.; VEDELAGO, G.; BOEZIO, M. J.; RIGONI, D.; VIRGOLINI, M. B.; BOLLATI, F.; CANCELA, L. M.

Villasimius

Conferencia; ADDICTION 2022 Conference; 2022

Universidad de Cagliari

Pharmacological evidence from our lab supports the critical role of glutamatergic neurotransmission within the nucleus accumbens core (NAcore) in stress-induced reinstatement of cocaine-seeking behavior in rodents. Since the cannabinoid type-1 receptor (CB1R) has a crucial role in modulating glutamate release, we evaluated the effects of AM251 and ACEA, a highly selective CB1R antagonist and agonist respectively, on 1) our model of stress-induced reinstatement of cocaine-conditioned place preference (CPP), and 2) changes in extracellular glutamate (eGLU) levels within NAcore by using the in vivo microdialysis technique. Firstly, our results demonstrated that a reinstating stress session (30 min of restraint) induced an increase in eGLU levels within NAcore in animals re-exposed to the drug-paired compartment after the extinction of cocaine-CPP. Interestingly, the microinjection of AM251 (5 nmol/0.5ul/side) or ACEA (0.01 fmol/0.5ul/side) directly into NAcore (but not NAshell) prevented or potentiated, respectively, the stress-induced increase of eGLU and reinstatement of cocaine-CPP. Since reinstatement can be prevented by restoring impaired glutamate homeostasis, we proposed that CB1R could be modulating basal eGLU levels. For this, we perfused increasing doses of ACEA into NAcore by reverse microdialysis showing a reduction in basal eGLU levels in a dose-dependent manner. These in vivo findings are consistent with the canonical CB1R signaling mechanism and suggest that CB1R activation may cause an initial reduction in basal eGLU and a lower presynaptic inhibition by mgluR2/3, favoring subsequent presynaptic glutamate release triggered by stress. Basal eGLU levels and expression of CB1R within NAcore along the CPP protocol complete the discussion of our results.