The Balance of MU-Opioid, Dopamine D2 and Adenosine A2A Heteroreceptor Complexes in the Ventral Striatal-Pallidal GABA Antireward Neurons May Have a Significant Role in Morphine and Cocaine Use Disorders

Abstract

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories formed during the development of substance use disorders like morphine and cocaine use disorders. In cocaine use disorder it was found that irreversible A2AR-D2R complexes with an allosteric brake on D2R recognition and signaling are formed in increased densities in the ventral enkephalin positive striatal-pallidal GABA antireward neurons. In this perspective article we discuss and propose how an increase in opioid heteroreceptor complexes, containing MOR-DOR, MOR-MOR and MOR-D2R, and their balance with each other and A2AR-D2R complexes in the striatal-pallidal enkephalin positive GABA antireward neurons, may represent markers for development of morphine use disorders. We suggest that increased formation of MOR-DOR complexes takes place in the striatal-pallidal enkephalin positive GABA antireward neurons after chronic morphine treatment in part through recruitment of MOR from the MOR-D2R complexes due to the possibility that MOR upon morphine treatment can develop a higher affinity for DOR. As a result, increased numbers of D2R monomers/homomers in these neurons become free to interact with the A2A receptors found in high densities within such neurons. Increased numbers of A2AR-D2R heteroreceptor complexes are formed and contribute to enhanced firing of these antireward neurons due to loss of inhibitory D2R protomer signaling which finally leads to the development of morphine use disorder. Development of cocaine use disorder may instead be reduced through enkephalin induced activation of the MOR-DOR complex inhibiting the activity of the enkephalin positive GABA antireward neurons. Altogether, we propose that these altered complexes could be pharmacological targets to modulate the reward and the development of substance use disorders.

Molecular Integration in Adenosine Heteroreceptor Complexes Through Allosteric and De-Phosphorylation (STEP) Mechanisms and its Role in Brain Disease

“…Also by the observation that A2AR mediated synaptic depression was counteracted not only by an A2AR antagonist but also by a dopamine D2R antagonist. This can be explained by the fact these two receptors are primarily located in the dorsal and ventral striatal pallidal GABA neurons mediating motor inhibition and antireward, respectively ( Borroto-Escuela et al, 2021a ; Borroto-Escuela et al, 2021b ).…”

“…The D2R activation markedly inhibits the firing of these two types of neurons via its inhibitory Gi/o coupling of the D2R, causing increases in motor activity and reductions of anti-reward. The striatal-pallidal GABA neurons are enriched in A2AR-D2R heterocomplexes in which the activated A2AR protomer strongly blocks the D2R protomer mediated signaling through allosteric inhibition of the D2R protomer ( Borroto-Escuela et al, 2021b ) ( Figure 1 ). It should be noted that the work of the Italian group in 2020 takes place in striatum, which may be further defined as to the possible inclusion also of the ventral striatum or if it only involved the dorsal striatum.…”

“…It should be noted that the work of the Italian group in 2020 takes place in striatum, which may be further defined as to the possible inclusion also of the ventral striatum or if it only involved the dorsal striatum. Robert Yasuda indicates the relevance of these antagonistic A2AR-D2R interactions in the A2AR-D2R heterocomplexes of the ventral striatal-pallidal GABA neurons for the A2AR mediated inhibition of cocaine self-administration ( Borroto-Escuela et al, 2021a ; Borroto-Escuela et al, 2021b ). Disruption of this receptor complex with an interface interfering peptide in fact blocks the A2AR mediated inhibition of cocaine self-administration ( Borroto-Escuela et al, 2018b ).…”

“…Furthermore, a molecular basis for learning and memory was proposed to be formed through reorganization of available adenosine homo- and heteroreceptor complexes as to structural functions and/or by resetting the multiple allosteric receptor-receptor interactions in these complexes. Based on this evidence, this Opinion article is focused on the underlying relevance of adenosine heteroreceptor complexes in the brain and their integrative mechanisms at the molecular level, involving allosteric receptor-receptor interactions and dephosphorylation mechanisms through Striatal-Enriched Protein Tyrosine Phosphatase (STEP) ( Franco et al, 2020b ; Yasuda, 2020 ; Borroto-Escuela et al, 2021a ; Barresi et al, 2021 ; Borroto-Escuela et al, 2021b ; Beggiato et al, 2021 ; Domenici et al, 2021 ).…”

Contribution of the Adenosine 2A Receptor to Behavioral Effects of Tetrahydrocannabinol, Cannabidiol and PECS-101

“…Interestingly, preclinical studies indicate significant interactions between type 1 cannabinoid receptors (CB1R) and adenosine A2 receptors (A2AR). Both CB1R and A2AR are highly expressed in the striatum, and multiple studies have demonstrated that CB1R and A2AR can form heterodimers [ 13 ]. There is functional evidence for interactions between the two systems; for example, the hypolocomotor and rewarding effects of CB1R agonists are diminished by A2AR antagonism [ 14 ].…”