Trends in Pharmacological Sciences
OpinionA2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction
Section snippets
Allosteric Receptor–Receptor Interactions in GPCR Homomers and Heteromers
The molecular structure and function of G protein-coupled receptors (GPCRs) was discovered by Nobel Laureates Robert Lefkowitz and Brian Kobilka [1]. Initially, these were regarded to operate as monomers. However, GPCR heteromers (see Glossary) have now been discussed and elucidated by publications for more than two decades 2, 3. In the past few years, their existence has been further established by crystallography, super-resolution imaging, and spatial intensity distribution analysis [4]. A
Formation of Drug Memories in Cocaine Reward and Addiction
Milton and Everitt [10] initially introduced the concept that drug addiction represented a disorder of learning and memory. They proposed that the existence of persistent maladaptive drug memories can be the basis of drug addiction. In this context, our hypothesis on the molecular basis of learning and memory 11, 12 should be mentioned. It states that the dynamic regulation of synaptic and extrasynaptic homo- and heteroreceptor complexes leads to learning or short-term memory and their
Sigma1R-D2R Receptor–Protein Complexes on Exposure to Cocaine
The sigma-1 receptor (Sigma1R) is an intracellular chaperone that has two transmembrane domains and is located at the interface of the endoplasmic reticulum (ER) and the mitochondria 19, 20. Cocaine has the ability to act as a Sigma1R agonist. Upon activation by cocaine, Sigma1R becomes translocated from the ER into the plasma membrane, where it interacts with D1R and D2R and alters their signaling 21, 22. Sigma1R also dynamically interacts with ion channels such as the Kv1.2 channels; this
Changes in Allosteric A2AR-D2R Interactions and A2AR-D2R Heteroreceptor Complexes upon Cocaine Self-Administration
In the sections below, we review the marked changes that develop in the allosteric receptor–receptor interactions of the A2AR-D2R heteroreceptor complexes in the nucleus accumbens upon cocaine self-administration.
Cocaine Reward
To reduce cocaine rewarding properties, the aim is to increase activity in the D2R-positive GABA anti-reward neurons by using A2AR agonists mainly acting at the A2AR protomers of the A2AR-D2R complexes. Brain-penetrant heterobivalent drugs with, for example, A2AR agonist and D2R antagonist pharmacophores can improve treatment by more selective targeting of the A2AR-D2R heteroreceptor complex. The increase in anti-reward (aversion) by these treatments may stop the cocaine use.
Cocaine Addiction
Treatment should,
Concluding Remarks and Future Perspectives
The current research on A2AR-D2R heteroreceptor complexes in the ventral striato-pallidal GABA anti-reward neurons has provided evidence that they play a critical role in cocaine self-administration. Indeed, a reorganization of the A2AR-D2R heteroreceptor complexes with altered antagonistic A2AR-D2R receptor–receptor interactions brings down cocaine reward. This process may lead to an irreversible brake on D2R protomer recognition and signaling in which the Sigma1R also participates. As a
Acknowledgments
This work was supported by the Swedish Medical Research Council (62X-00715-50-3) and Parkinson Fonden to K.F. and by Hjärnfonden (F02018-0286) and Karolinska Institutet Forskningsstiftelser to D.O.B-E. The statutory funds from the Institute of Pharmacology, Polish Academy of Sciences supported the work of K.W. and M.F. D.O.B-E. belongs to the ‘Academia de Biólogos Cubanos’ group.
Glossary
- A2AR
- the adenosine A2A receptor, a member of the GPCR family, is one of several receptor subtypes for adenosine. It is abundant in the basal ganglia and is a major target of caffeine. The activity of A2AR is mediated by Gs protein that activates adenylyl cyclase. A variety of functional A2AR heteroreceptor complexes have been found in the brain, adding a further degree of complexity to the role of adenosine in modulation of neuronal activity.
- Allosteric receptor–receptor interaction
- when the
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2022, Psychiatry ResearchCitation Excerpt :The adenosine A2A receptor (ADORA2A) is highly expressed in the central nervous system, especially the striatum (Svenningsson et al., 1999). It plays a vital role in sleep-wake regulation (Basheer et al., 2004), learning and memory (Orr et al., 2015), drug addiction (Borroto-Escuela et al., 2018), anxiety (Caetano et al., 2017), synaptic plasticity (Flajolet et al., 2008), and growth and development of neurons (Cheng et al., 2002). Additionally, ADORA2A is closely linked to several neurotransmitters.
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2022, Pharmacology Biochemistry and BehaviorCitation Excerpt :There exist strong indications for the existence of adenosine A2 receptor (A2AR)-dopamine D2 receptor (D2R) heteroreceptor complexes in the ventral striatum, especially in the nucleus accumbens shell, and their involvement in the in cocaine use disorder (Borroto-Escuela et al., 2018a; Borroto-Escuela et al., 2018b; Beggiato et al., 2017; Borroto-Escuela et al., 2017; Wydra et al., 2020). These heteroreceptor complexes are mainly located in the ventral striatal-pallidal GABA anti-reward neurons (Borroto-Escuela et al., 2018a; Fuxe et al., 2008; Filip et al., 2012). There are significant pharmacological findings that A2AR agonists can counteract cocaine induce relapse and food seeking (Bachtell and Self, 2009; O'Neill et al., 2012; Wydra et al., 2015).
GPCR oligomerization as a target for antidepressants: Focus on GPR39
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2021, Pharmacological ResearchCitation Excerpt :Thus, the heterodimeric interaction would lead to a switch from Gαs/olf-cAMP cascade to PLC during A2AR dominant stimulation and from Gαi/o-cAMP signaling to β-arrestin-dependent cascade (internalization) in the case of D2R dominant stimulation [98,99]. Studies have shown that the A2AR-D2R heterodimeric interaction is highly implicated in cocaine addiction [100,101]. It was demonstrated that the ventral striato-pallidal GABA pathways which are regarded as the anti-reward pathway, express D2 receptors.
Non-canonical interplay between glutamatergic NMDA and dopamine receptors shapes synaptogenesis
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