Exploring the side effect profile of 16-Ethynyl Salvinorin A

Introduction: Drug addiction is a chronic and relapsing disorder that has widespread socioeconomic and health consequences. Globally, there are over 29.5 million people who are drug dependent, and New Zealand has one of the highest rates of drug use rates in the developed world. Currently, there are no Food and Drug Administration (FDA) approved pharmacotherapies that target psychostimulant addiction. Kappa opioid receptor (KOPr) agonists are being studied as a potential pharmacotherapy as it utilizes the brain’s own mechanism for controlling reward, however, KOPr agonists have unwanted side effects such as dysphoria and sedation. This thesis explores the KOPr agonists Salvinorin A (Sal A), a naturally-occurring, highly potent and short-acting non-nitrogenous KOPr agonist and a structural analogue, 16-Ethynyl Salvinorin A (16-Ethy). KOPr agonists, such as Sal A have known preclinical anti-addictive and anti-reward effects, therefore, this thesis focuses on evaluating Sal A and 16-Ethy in preclinical tests of reward and side effects.

Methods: Male Sprague-Dawley rats were used in preclinical tests to evaluate common KOPr-mediated side-effects including anxiety (elevated plus maze), depression (forced swim test) sedation (locomotor activity) and aversion (conditioned place aversion). The anti-cocaine effects were also examined using self-administration, dose-response and drug-behavioural sensitisation tests. 16-Ethy was tested at 2 mg/kg in all experiments.

Results: Acute pre-treatment of 16-Ethy induced sedative effects in non-habituated locomotor activity but when rats were habituated prior to administration, no sedation was observed. In contrast, Sal A (2 mg/kg) had sedative effects in habituated, but not in non-habituated locomotor activity (p = 0.0037). Compared to vehicle-treated rats, 16-Ethy and Sal A did not display pro-depressive effects in the forced swim test, show anxiogenic or aversive properties or modulate behavioural sensitisation to cocaine. Cocaine self-administration and dose-response tests were not successfully completed.

Conclusion: At 2 mg/kg, 16-Ethy was found to display sedative effects in non-habituated locomotor activity but not in a habituated paradigm. Compared to vehicle-treated rats, 16-Ethy did not display pro-depressive effects in the forced swim test, or display anxiogenic or aversive properties and did not show significant cocaine sensitisation. Cocaine self-administration and dose-response tests were not successfully completed and will need to be repeated to ascertain the effects of 16-Ethy on them. However, 16-Ethy has shown glimpses of promise as a potential pharmacotherapy against addiction.