The sigma-1 receptor as key common factor in cocaine and food seeking behaviors

Addiction and eating disorders involve brain reward circuits. A previous history of binge eating predisposes to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward activities, including intake of tasty foods. Cocaine use is associated with a decrease in food intake, with reversal after the drug use is stopped. Exciting new findings show that receptors for the 'hunger' hormone, ghrelin, directly interact with the sigma-1 receptors (1R), which is a target of cocaine. 1R are key players in regulating dopaminergic neurotransmission and ghrelin-mediated actions. This review focuses on the 1 receptor as general neuroendocrine regulator by directly interacting with neuronal G-protein-coupled receptors. This review also covers the early mechanisms by which cocaine binding to 1 blocks the food-seeking behavior triggered by ghrelin. Such new findings appear as fundamental to understand common mechanisms in drug addiction and eating disorders

Adenosine A2A receptor antagonists affects NMDA glutamate receptor function. Potential to address neurodegeneration in Alzheimer's disease

(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer's disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A2A receptor (A2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APPSw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APPSw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A2AR. However, the activation of the A2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A2AR antagonists such as istradefylline, which is already approved for Parkinson's disease (Nouriast® in Japan and Nourianz® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i.e., via both neurons and microglia

Differential effect of amphetamine over the corticotropin-releasing factor CRF2 receptor, the orexin OX1 receptor and the CRF2-OX1 heteroreceptor complex

Stress is one of the factors underlying drug seeking behavior that often goes in parallel with loss of appetite. We here demonstrate that orexin 1 receptors (OX1R) may form complexes with the corticotropin releasing factor CRF2 receptor. Two specific features of the heteromer were a cross-antagonism and a blockade by CRF2 of OX1R signaling. In cells expressing one of the receptors, agonist-mediated signal transduction mechanisms were potentiated by amphetamine. Sigma 1 (σ1) and 2 (σ2) receptors are targets of drugs of abuse and, despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is not known. We here show that σ1 receptors interact with CRF2 receptors and that σ2 receptors interact with OX1R. Moreover, we show that amphetamine effect on CRF2 receptors was mediated by σ1R whereas the effect on OX1 receptors was mediated by σ2R. Amphetamine did potentiate the negative cross-talk occurring within the CRF2-OX1 receptor heteromer context, likely by a macromolecular complex involving the two sigma receptors and the two GPCRs. Finally, in vivo microdialysis experiments showed that amphetamine potentiated orexin A-induced dopamine and glutamate release in the ventral tegmental area (VTA). Remarkably, the in vivo orexin A effects were blocked by a selective CRF2R antagonist. These results show that amphetamine impacts on the OX1R-, CRF2R- and OX1R/CRF2R-mediated signaling and that cross-antagonism is instrumental for in vivo detection of GPCR heteromers

Complejos del receptor sigma y de heterómeros de receptores acoplados a proteínas G en adicción y control de apetito

[spa] Actualmente, entre el 30-40% de los medicamentos comercializados tienen como diana a un receptor acoplado a proteína G (GPCR). Además, la capacidad que tienen estos receptores para interaccionar físicamente entre ellos y formar nuevas unidades funcionales con propiedades farmacológicas distintas a las que tienen sus componentes individuales, permite generar nuevas dianas terapéuticas para combatir distintas enfermedades como la adicción a sustancias de abuso. Aunque millones de personas sufren de adicción en todo el mundo, actualmente no existe ninguna cura. Entre otros efectos adversos, el consumo de psicoestimulantes provoca un estado de euforia debido a una sobreestimulación del sistema de recompensa, inhibición del apetito, sensibilidad a situaciones de estrés y, a largo plazo, neurodegeneración. Se ha demostrado que determinadas sustancias de abuso, como la cocaína o las anfetaminas, son capaces de ejercer parte de sus efectos a través de su interacción con los receptores sigma (V1R y V2R), que, a su vez, son capaces de interaccionar y modular la señalización de otras proteínas, como los GPCR. Así, el principal objetivo de esta Tesis Doctoral ha sido estudiar la posible formación de complejos entre GPCR y receptores sigma implicados en la adicción a psicoestimulantes y en la inhibición del apetito. Durante la realización de esta Tesis Doctoral se han usado técnicas de transferencia de energía y de complementación biomolecular, además del ensayo de ligación por proximidad, para demostrar la formación de oligómeros entre GPCR y receptores sigma. Además, se ha estudiado la huella de estos heterómeros analizando la acumulación de AMPc en el citosol, la liberación de calcio desde el retículo endoplásmico, la activación de la vía de las MAPK, el reclutamiento de E-arrestinas y la redistribución dinámica de masas. Los resultados de esta Tesis Doctoral ponen de manifiesto un papel muy importante de la heteromerización de los GPCR en el mecanismo molecular que regulan los procesos de adicción a psicoestimulantes y la inhibición del apetito. En primer lugar, se han propuesto dos mecanismos moleculares mediante los cuales la cocaína, a través de su unión a V1R, puede mediar su acción anorexigénica. En concreto, la cocaína es capaz de bloquear completamente la señalización inducida por la hormona orexigénica grelina y de alterar la funcionalidad del complejo tetramérico formado por un homodímero de receptores de dopamina D1 y un homodímero de receptores de grelina 1a capaz de señalizar a través de una Gs y una Gq. En segundo lugar, se ha demostrado que el receptor de orexina 1 y el receptor del factor liberador de corticotropina 2 son capaces de heteromerizar y podrían tener un papel muy importante en el estrés y la recaída en el consumo de anfetamina. Finalmente, se ha observado que la metanfetamina, a través de su unión a V1R, altera la funcionalidad del heterómero formado por el receptor de adenosina A2A y el receptor cannabinoide CB1, siendo ambos receptores objeto de estudio en la neuroprotección. Así, el heterómero A2AR-CB1R podría ser una buena diana terapéutica para combatir la neurodegeneración asociada a un consumo crónico de metanfetamina.[eng] G protein-coupled receptors (GPCR), which comprise the largest superfamily of plasma membrane proteins in mammals, have had a strong interest in biomedical research. Indeed, between 30-40% of the current drugs marketed target a GPCR. In addition, these receptors are able to physically interact between them creating new functional units with significantly different pharmacological properties than those of their individual components. In this way, heteromerization among GPCR is a novel strategy to look for new therapeutic targets to combat a large variety of diseases, such as drug addiction. Even though millions of individuals suffer from addiction, currently there is no cure available. Among many effects, the use of psychostimulants causes euphoria due to an overstimulation of the reward system, inhibition of appetite, sensitivity to stress, and, in the long term, neurodegeneration. Research in this area revealed that some substances of abuse, including cocaine and amphetamines, are able to exert part of their effects through their interaction with sigma receptors (V1R and V2R). Several authors have published that sigma receptors are able to interact and modulate the signalling of other proteins, such as GPCR. Thus, the main objective of this Thesis has been to study the possible formation of complexes between GPCR and sigma receptors involved in psychostimulant addiction and appetite suppression. During the development of this Thesis, resonance energy transfer and bimolecular complementation techniques, and proximity ligation assays have been used to demonstrate the formation of GPCR and sigma receptors oligomers. Moreover, the fingerprint of these heteromers has been studied by analysing the signalling pathways through measurement of cAMP accumulation in the cytosol, calcium release from the endoplasmic reticulum, MAPK pathway activation, E-arrestin recruitment and dynamic mass redistribution. The results of this Thesis reveal a very important role of GPCR heteromerization in the molecular mechanisms that regulate both drug addiction and appetite suppression. Firstly, it has been proposed two molecular mechanisms by which cocaine, binding to V1R, may mediate its anorexigenic action. Deep inside, cocaine completely blocks the signalling induced by the orexigenic hormone ghrelin and affects functionality of the tetrameric complex consisting of one homodimer of dopamine D1 receptor and one homodimer of ghrelin 1a receptor capable of signalling through a Gs and a Gq. Secondly, it has been observed that the orexin receptor type 1 and the corticotropin-releasing factor receptor type 2 are able to heteromerize and could play a key role in stress and relapse of amphetamine use. Finally, it has been shown that methamphetamine, via interacting with V1R, alters the correct functionality of the heteromer formed by the adenosine A2A receptor and the cannabinoid CB1 receptor, both of them targets for neuroprotection. Therefore, the A2AR-CB1R complexes appear as new therapeutic target to combat neurodegeneration associated with chronic methamphetamine use

Cocaine blocks effects of hunger hormone, ghrelin, via interaction with neuronal sigma-1 receptors.

Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g., binge eating, anorexia, bulimia) share a central control involving reward circuits. However, we here show that the sigma-1 receptor (σ1R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ1R and GHS-R1a at the cell surface. Moreover, in transfected HEK-293T and neuroblastoma SH-SY5Y cells, and in primary neuronal cultures, pretreatment with cocaine or a σ1R agonist inhibited ghrelin-mediated signaling, in a similar manner as the GHS-R1a antagonist YIL-781. Results were similar in G protein-dependent (cAMP accumulation and calcium release) and in partly dependent or independent (ERK1/2 phosphorylation and label-free) assays. We provide solid evidence for direct interaction between receptors and the functional consequences, as well as a reliable structural model of the macromolecular σ1R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors