Title : Sigma-2 receptors appear to be more relevant than Sigma-1 receptors in the mechanism of cocaine consumption
Abstract:
The health problems associated with psychostimulant abuse have become an epidemic with huge socioeconomic impacts. Currently, there are no FDA approved drugs for the management of psychostimulant use disorders, and therefore it is important to identify the mechanisms governing psychostimulant use to advance knowledge related to the development of pharmacotherapies.
There is evidence that drugs with dual affinity at the dopamine transporter (DAT) and the sigma-receptors (sigma-R) or combinations of DAT inhibitors (DATi) and sigma-R ligands suppress the consumption and reinforcing effects of psychostimulants such as cocaine. There are two identified subtypes of sigma-R, namely sigma-1 and sigma-2 receptors (sigma-1R and sigma-2R) which are thought to play a role in psychostimulant effects, but it is not clear what comparative roles these receptors may play in the consumption and reinforcing mechanisms of psychostimulants. The consensus in the field is that sigma-1R is more important than sigma-2R in cocaine’s mechanism.
However, based on prior research, we hypothesized that the sigma-2R may play a greater role in suppressing cocaine reinforcement than the sigma-1R.
First, a comprehensive review of the literature was conducted to understand the comparative roles these two receptors in cocaine consumption and reinforcement. Next, male Sprague Dawley rats were treated with either (a) rimcazole, (b) methylphenidate + BD 1063 (affinity for sigma-1R > sigma-2R), or (c) methylphenidate + BD 1008 (affinity for sigma-2R > sigma-1R), and the effects on consumption of cocaine when cocaine is freely available was measured.
Based on demand curves and models, this research shows that drugs with high affinity for DAT and greater selectivity for sigma-2R relative to sigma-1R were more effective in suppressing cocaine reinforcement. The implication for the field is that sigma-2R may be more relevant than sigma-1R in the mechanism of cocaine reinforcement.
Audience Take Away Notes:
- The current consensus in the field is that sigma-1R are more important in the mechanism of cocaine consumption, but hopefully this research can demonstrate the importance of sigma-2R and help drive research in that direction.
- Psychostimulant abuse has become an epidemic, and members of healthcare are constantly faced with the challenge of how to best manage the disease. Learning more about the mechanism in which cocaine exerts its actions on the brain can also help the audience guide management practices.
- This research is something that other faculty can use and build upon by allowing them to research a whole new set of substrates that target sigma-2R while developing more effective therapeutics for cocaine addiction.
