Date of Award

12-2014

Degree Name

Doctor of Philosophy

Department

Psychology

First Advisor

Dr. Lisa E. Baker

Second Advisor

Dr. Bradley Huitema

Third Advisor

Dr. C. Richard Spates

Fourth Advisor

Dr. Stephen W. Frantz

Keywords

Kappa agonists, locomotor activity, amphetamine, kappa opioid, Sprague-Dawley, d-amphetamine

Abstract

Stimulant abuse is a widespread problem that often leads to detrimental health and social consequences. Currently, there are no FDA-approved pharmacotherapies available as a treatment option for stimulant abuse or the prevention of relapse. Drugs targeting kappa opioid receptors (KOR) are under investigation as a potential pharmacotherapy. KOR agonists have been shown to modulate dopamine levels within brain reward pathways, thereby producing anti-addictive effects. Traditional KOR agonists unfortunately tend to produce untoward side effects, including sedation, limiting their therapeutic utility. Structurally different from traditional KOR agonists, salvinorin A (salvA) may produce less sedating effects while still exerting anti-addictive properties. SalvA and synthetic derivatives of salvA, PR-37 and EOM, were screened in three preclinical experiments evaluating several indices of locomotor activity. In Experiment 1, male rats were administered acute doses of salvA or PR-37, and locomotor activity was evaluated for signs of sedation. Effects of salvA were rapid, short-acting, and limited to decreases in select indices of locomotor activity. PR-37 produced no significant changes in activity levels. In Experiment 2, male rats were administered acute doses of damphetamine (AMPH) in combination with salvA, PR-37, or EOM. SalvA and EOM produced partial to full attenuation of the hyperlocomotor effects of AMPH, whereas PR-37 was ineffective in counteracting AMPH-stimulated activity. In Experiment 3, both male and female rats were administered 10 intermittent doses of AMPH or saline over a period of five weeks. Following a two-week wash out period, rats were administered a challenge dose of AMPH with and without the addition of salvA or EOM. SalvA and EOM attenuated the hyperlocomotor effects of AMPH in male rats with and without a history of AMPH exposure. In contrast, these substances demonstrated little to no effect in female rats. Considered together, these findings suggest that KOR agonists may hold some promise in reducing the dopamine-mediated reward properties of AMPH as indicated by their ability to decrease the locomotor stimulatory effects of AMPH. However, further studies are warranted to determine the mechanisms underlying sex differences in the effects of KOR agonists in combination with AMPH.

Access Setting

Dissertation-Campus Only

Restricted to Campus until

12-15-2024

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