| First Author | Moreno E | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 10 | Pages | 3545-58 |
| PubMed ID | 24599455 | Mgi Jnum | J:209622 |
| Mgi Id | MGI:5568191 | Doi | 10.1523/JNEUROSCI.4147-13.2014 |
| Citation | Moreno E, et al. (2014) Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: sigma1-D1-H3 receptor complexes as key targets for reducing cocaine's effects. J Neurosci 34(10):3545-58 |
| abstractText | The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the sigma1 receptor and occurs upon cocaine binding to sigma1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits beta-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of sigma1 receptor, we show that blockade of sigma1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of sigma1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine. |
