On the role of homo and heteroreceptor complexes balance and their allosteric receptor-receptor interactions in voluntary alcohol intake and cocaine use disorder

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Borroto-Escuela DO1, Pintsuk J1, Narváez M2, Feltmann K3, Filip M4, Ferraro L5, Hansson A6, Steensland P3 and Fuxe K1
1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
3 Department of Physiology, School of Medicine, University of Malaga, Málaga, Spain.
3 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
4 Laboratory of Drug Addiction Pharmacology, Polish Academy of Sciences, Kraków, Poland.
5 Department of Pharmacology, University of Ferrara, Ferrara, Italy.
6 Inst.Psychopharmacology, Central Institute of Mental Health, Mannheim, Germany.

Allosteric receptor-receptor interactions in neuronal heteroreceptor complexes represent a novel biological principle to modulate the plasticity and function of the neural networks. Such interactions in multiple homo-and heteroreceptor complexes in neuronal networks may form the molecular basis of learning and memory. This principle is illustrated by showing how cocaine abuse in rats can alter the adenosine A2AR-dopamine D2R heteroreceptor complexes and their receptor-receptor interactions and hereby neural plasticity in the basal ganglia. Pharmacological studies with A2AR agonists and antagonists using cocaine self-administration procedures indicate that antagonistic allosteric plasticity in A2AR-D2R heteroreceptor complexes of the ventral striato-pallidal GABA pathway plays a significant role in reducing cocaine induced reward and motivation and in cocaine seeking. The anti-cocaine actions of A2AR agonists appear to be dependent on the strength of the antagonistic allosteric A2AR-D2R interaction and the number of A2AR-D2R and A2AR-D2R-sigma1R heteroreceptor complexes present in the ventral striato-pallidal GABA neurons, an anti-reward system inhibited by D2R receptors. It involves a differential cocaine-induced increase in sigma1 receptors in the ventral versus the dorsal striatum. In contrast, the allosteric brake on the D2R receptor protomer signaling in the A2AR-D2R heteroreceptor complex of the dorsal striato-pallidal GABA neurons is lost upon cocaine self-administration, potentially due to differences in composition and allosteric plasticity of these complexes versus those in the ventral striato-pallidal neurons. It is of high interest also that in the NAc shell of 3-months alcohol-drinking (of intermittent-access to 20% ethanol (IA20E)) compared to alcohol-naïve rats the number of D2R homoreceptor complexes was decreased, whereas the number of A2R-D2R heteroreceptor complexes was increased. The results show the relevance of the balance or dynamic changes between the homo and heteroreceptor complexes in presence of cocaine or alcohol. Overall, a novel understanding of the molecular basis of alcohol intake and cocaine use disorder is given together with new strategies for their treatment by targeting heteroreceptor complexes based on a new pharmacology with combined treatment, multi-targeted drugs and heterobivalent drugs.

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