Combined treatment with Sigma1R and A2AR agonists fails to inhibit cocaine self-administration despite causing strong antagonistic accumbal A2AR-D2R complex interactions: the potential role of astrocytes

Abstract

Previous studies have indicated that acute treatment with the monoamine stabilizer OSU-6162 (5 mg/kg), which has a high affinity for Sigma1R, significantly increased the density of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes following cocaine self-administration. Ex vivo studies using the A2AR agonist CGS21680 also suggested the existence of enhanced antagonistic accumbal A2AR-D2R allosteric interactions after treatment with OSU-6162 during cocaine self-administration. However, a 3-day treatment with OSU-6162 (5 mg/kg) failed to alter the behavioral effects of cocaine self-administration. To test these results and the relevance of OSU-6162 (2.5 mg/kg) and/or A2AR (0.05 mg/kg) agonist interactions, we administered low doses of receptor agonists during cocaine self-administration and assessed their neurochemical and behavioral effects. No effects were observed on cocaine self-administration; however, marked and highly significant increases using the proximity ligation assay (PLA) were induced by the co-treatment on the density of the A2AR-D2R heterocomplexes in the nucleus accumbens shell. Significant decreases in the affinity of the D2R high- and low-affinity agonist binding sites were also observed. Thus, in low doses, the highly significant neurochemical effects observed upon cotreatment with an A2AR agonist and a Sigma1R ligand on the A2AR-D2R heterocomplexes and their enhancement of allosteric inhibition of D2R high-affinity binding are not linked to the modulation of cocaine self-administration. The explanation may be related to an increased release of ATP and adenosine from astrocytes in the nucleus accumbens shell in cocaine self-administration. This can lead to increased activation of the A1R protomer in a putative A1R-A2AR-D2R complex that modulates glutamate release in the presynaptic glutamate synapse. We hypothesized that the integration of changes in presynaptic glutamate release and postjunctional heteroreceptor complex signaling, where D2R plays a key role, result in no changes in the firing of the GABA anti-reward neurons, resulting in no reduction in cocaine self-administration in the present experiments.

Understanding electrical and chemical transmission in the brain

“…The astrocytes in dominance, can modulate blood flow and mediate transfer of mitochondria to neurons and is the major source of cholesterol (Siracusa et al, 2019). It has become increasingly clear in recent years that integrative receptor-receptor and receptor-protein interactions can exist also in the astrocytes potentially altering the affinity and density of these heterocomplexes (Cervetto et al, 2017;Narvaez et al, 2020;Borroto-Escuela et al, 2023) as previously demonstrated in neurons (Borroto-Escuela et al, 2012, 2014, 2017c, 2018bChruscicka et al, 2019;Di Palma et al, 2020;Chruscicka et al, 2021;Romero-Fernandez et al, 2022).…”

“…Populations of astroglia are important targets for dopaminergic and noradrenergic volume transmission through their contents of dopamine and noradrenaline receptors, including contents of heteroreceptor complexes like A2AR–D2R heterocomplexes ( Cervetto et al, 2017 , 2023 ; Pelassa et al, 2019 ). The monoamine including also serotonin receptors modulate key functions of the astroglia, including microglia ( Fuxe et al, 2012 ; Cervetto et al, 2017 ; Fuxe and Borroto-Escuela, 2018 ; Narvaez et al, 2020 ; Borroto-Escuela et al, 2023 ).…”

Membrane Heteroreceptor Complexes as Second-Order Protein Modulators: A Novel Integrative Mechanism through Allosteric Receptor–Receptor Interactions

“…This important technique (PLA) was developed by Fredriksson, Gullberg, Söderberg and colleagues [58,59]. For recent work on the analysis and quantitation of the GPCR heterocomplexes with in situ PLA (see [57,[60][61][62][63][64][65][66][67][68][69][70][71]).…”

“…In current procedures, the receptor complexes appear as red blobs with a diameter of 0.5 to 1.5 um and their density in sampled fields is determined using confocal laser microscopy. The assay is performed in combination with a Neuro-ChromPan neuronal marker antibody-Alexa488, giving a green fluorescence to the neurons and enabling the study of the link of the red blobs to the neurons [61][62][63][64][65]. Based on different types of glial markers, the link of the red blobs to glial cells can also be established.…”

Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

“…Cocaine-induced reorganization of D2R-S1R complexes may in turn contribute to the formation of adenosine 2A receptor (A2AR)-D2R-S1R heterocomplexes; this is interesting as A2AR agonists have anti-cocaine properties. However, a recent study reported that combined treatment with S1R and A2AR failed to inhibit cocaine self-adminstration [ 90 ], highlighting the need for further work to understand these interactions and their role in psychostimulant outcomes and behaviors. [ 75 , 91 ].…”