A higher selectivity for sigma1 relative to sigma2 receptors is associated with lower efficacy in achieving a dose-dependent attenuation of cocaine consumption

Title : A higher selectivity for sigma1 relative to sigma2 receptors is associated with lower efficacy in achieving a dose-dependent attenuation of cocaine consumption

Abstract:

Background: There is an epidemic of Psychostimulant Use Disorders (PUD) in the United States. In addition to the dopamine transporter (DAT), cocaine also exerts its effects via the sigma receptors, and sigma receptors may represent a promising pharmacotherapeutic target. However, it is not clear which of the sigma receptors (sigma1 and sigma2) plays the more important role in cocaine’s effects.

Objective: In this study, we compared the efficacy of ligands with different selectivity for sigma1 versus sigma2 receptors to suppress cocaine consumption dose-dependently. Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor. BD1063 and BD1008 are sigma receptor antagonists. BD1063 has a higher selectivity for sigma1:sigma2 than BD1008. Based on 1) the assumption that sigma1 is more important in the mechanism of cocaine consumption and 2) the sigma1 versus sigma2 receptor selectivity of these ligands, we hypothesized that a combination of DAT inhibitor (MPH) and BD1063 should have a higher efficacy than a combination of the same DAT inhibitor and BD1008.

Methods: Rats were trained to self-administer cocaine. We assessed the effects of combinations of MPH (1 mg/kg i.p.) and different doses of (a) BD1063 (sigma1/sigma2 selectivity = 70.9, doses = 0, 3.2, 10 mg/kg i.p.), and (b) BD1008 (sigma1/sigma2 selectivity = 7.8, doses = 0, 3.2, 10 mg/kg i.p.). Behavioral economic analysis of cocaine demand curves were employed to quantify the cocaine consumption at zero price (Q₀). Linear regression analysis was used to assess the dose-dependency of the effects of these ligands on cocaine Q₀.

Results: ??Combinations of MPH and BD1008, but not combinations of MPH and BD1063, exerted dose-dependent suppression of cocaine Q₀. Our results suggest that higher selectivity for sigma1 relative to sigma2 receptor is associated with lower efficacy in exerting a dose-dependent suppression of cocaine Q₀. 

Conclusions: Higher selectivity for sigma1 relative to sigma2 receptor is associated with lower efficacy in exerting a dose-dependent suppression of cocaine Q₀. Sigma 2 may be the more important receptor in the mechanism of cocaine consumption. 

Audience Take Away Notes:

• The information in this presentation will provide researchers with new information on sigma receptors that may help push more research toward the sigma2 receptor
• This research will help normalize and further research in drug targets for cocaine addiction, as there are currently few options for psychostimulant use disorders
• This research can motivate other medical students to participate in addiction medicine research and broaden their skills when working with substance use patients in practice

Biography:

Reshma Paul graduated from New Jersey Institute of Technology in 2021 with a B.S. degree in Biomedical Engineering. While at NJIT, she worked in a biomaterials lab, KumarLab, focusing on identifying potential drug targets for wound healing hydrogels. She then went on to study at Cooper Medical School of Rowan University. She is currently a third year medical student on clerkship rotations. She works with Dr. Martin O. Job in the department of biomedical sciences on Psychostimulant Use research.