DOI
https://doi.org/10.25772/SMJX-RK09
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Aron Lichtman
Second Advisor
Phillip Gerk
Third Advisor
M. Imad Damaj
Fourth Advisor
Michelle Peace
Fifth Advisor
Joseph Ritter
Abstract
A growing body of research is exploring the efficacy of N-acyl amino acids (N-oleoyl glycine; OlGly and N-oleoyl alanine; OlAla) in rodent models of drug reward and dependence. In particular, OlGly attenuated the reinforcing effects of nicotine in the mouse nicotine-induced conditioned place preference (CPP) paradigm and reduced somatic and affective signs of mecamylamine-precipitated withdrawal in nicotine-dependent mice. Based on the addition of a methyl group on the head group, OlAla was proposed to have increased metabolic stability compared to OlGly. While OlAla has been assessed in assays of reward and withdrawal of opioids, cocaine, and alcohol, OlAla has yet to be assessed in rodent models of nicotine reward and dependence. Nicotine and tobacco use continues to be a worldwide health problem, for which current nicotine cessation treatments lack efficacy in promoting long-term cessation. As such, this dissertation investigates the effects of these N-acyl amino acids in rodent models of nicotine reward and seeking behavior.
Since OlAla has not previously been assessed in rodent models of nicotine reward and dependence, OlAla was first evaluated in mouse assays of nicotine-induced CPP and nicotine withdrawal. Similar to OlGly, OlAla prevented nicotine-induced CPP in mice and decreased somatic and affective signs of nicotine withdrawal. Unlike OlGly, a PPARα antagonist failed to block the effects of OlAla in nicotine-induced CPP, suggesting the effects of OlAla are dependent on another mechanism.
OlGly and OlAla were evaluated in the CPP paradigm, in which nicotine administration is delivered by the experimenter independent of the animal’s behavior. Following the observation that both OlGly and OlAla reduced nicotine reward, these ligands were evaluated for effects on active nicotine seeking in the self-administration and cue/prime-induced reinstatement rat assays. In self-administration, nicotine administration is contingent on the animal achieving the learned operant response requirement, such as lever responding. OlGly and OlAla decreased nicotine seeking in self-administration and reinstatement to a similar extent, but through distinct mechanisms. In concordance with the nicotine-induced CPP data, OlGly reduced nicotine self-administration by a PPARα-dependent mechanism, while OlAla reduced nicotine self-administration through mechanisms independent of PPARα, PPARγ, and cannabinoid receptor 1.
In addition to the antagonist studies in nicotine-induced CPP and self-administration, OlGly and OlAla were assessed for direct effects on nicotinic acetylcholine receptors (nAChRs) implicated in nicotine reward. While OlGly did not directly affect agonist-induced function of the following nAChRs implicated in nicotine reward: α3β4-, α4β2-, and α6/3β2β3-, OlAla produced minimal suppression of α6/3β2β3-nAChR, which may partly contribute to its pharmacological effects.
Finally, plasma and brain levels of OlGly and OlAla in mice and rats were measured following their exogenous administration to determine if OlAla possesses enhanced metabolic stability over OlGly. In both mice and rats, OlGly and OlAla displayed similar time-courses to one another in plasma and brain, suggesting the methylated analogue did not have increased metabolic stability.
The studies suggest both OlGly and OlAla attenuate nicotine reward, albeit through distinct mechanisms. OlAla, similar to OlGly, also reduces somatic and affective signs of nicotine withdrawal. More generally, these studies add to the previous literature suggesting that OlGly and now the analogue, OlAla, could serve as lead compounds for new nicotine cessation treatments.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
10-29-2023