Available online 4 April 2024, 111276

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Oleoyl alanine (OlAla) prevents nicotine-induced conditioned place preference (CPP) in mice

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OlAla attenuates nicotine CPP through a PPARα independent mechanism

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OlAla reduces spontaneous somatic and affective nicotine withdrawal signs

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OlAla shows a similar time course in mouse plasma and brain as oleoyl glycine

AbstractBackground

As nicotine dependence represents a longstanding major public health issue, new nicotine cessation pharmacotherapies are needed. Administration of N-oleoyl glycine (OlGly), an endogenous lipid signaling molecule, prevents nicotine-induced conditioned place preference (CPP) through a peroxisome proliferator-activated receptor-alpha (PPARα) dependent mechanism, and also ameliorated withdrawal signs in nicotine-dependent mice. Pharmacological evidence suggests that the methylated analogue of OlGly, N-oleoyl alanine (OlAla), has an increased duration of action and may offer translational benefit. Accordingly, OlAla was assessed in nicotine CPP and dependence assays as well as its pharmacokinetics compared to OlGly.

Methods

ICR female and male mice were tested in nicotine-induced CPP with and without the PPARα antagonist GW6471. OlAla was also assessed in nicotine-dependent mice following removal of nicotine minipumps: somatic withdrawal signs, thermal hyper-nociception and altered affective behavior (i.e., light/dark box). Finally, plasma and brain were collected after administration of OlGly or OlAla and analyzed by high-performance liquid chromatography tandem mass spectrometry.

Results

OlAla prevented nicotine-induced CPP, but this effect was not blocked by GW6471. OlAla attenuated somatic and affective nicotine withdrawal signs, but not thermal hyper-nociception in nicotine-dependent mice undergoing withdrawal. OlAla and OlGly showed similar time-courses in plasma and brain.

Conclusions

The observation that both molecules showed similar pharmacokinetics argues against the notion that OlAla offers increased metabolic stability. Moreover, while these structurally similar lipids show efficacy in mouse models of reward and dependence, they reduce nicotine reward through distinct mechanisms.

Section snippetsINTRODUCTION

Tobacco use continues to be the leading cause of preventable disease in the United States, and annually results in more than 8 million annual deaths worldwide. The Surgeon General’s report concluded that smoking cessation improves health outcomes by reducing the risk for tobacco-related diseases, such as chronic obstructive pulmonary disease and cancer. The report also indicated that of the 55% of adult smokers (21.5 million) attempting to quit smoking in 2018, only 7.5% (2.9 million)

Subjects

Female and male ICR mice (Envigo, Indianapolis, IN) were housed on a 12 hr/12 hr light/dark cycle in a temperature regulated vivarium (22°C) with standard rodent chow and water available ad libitum. All laboratory animal protocols were approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee and were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals.

Drugs

(-)-Nicotine hydrogen tartrate (Glentham Life Sciences,

OlAla prevents nicotine-induced CPP through a PPARα independent mechanism

As can be seen in Fig. 1, mice administered nicotine alone during conditioning displayed a significant CPP compared to the saline control group (planned comparison). A two-way ANOVA of the OlAla dose-response experiment (Fig. 1A) revealed significant main effects of nicotine and OlAla, but no nicotine by OlAla interaction (Table 1). In addition, planned comparisons showed that saline-nicotine administration elicited a place preference, which was blocked by OlAla (30 mg/kg).

The PPARα antagonist

DISCUSSION

Donvito et al. (2019) demonstrated that exogenously administered OlGly attenuated nicotine-induced CPP and reduced mecamylamine-precipitated affective and somatic withdrawal signs in nicotine-dependent mice. Based on the proposal that the methylated OlGly analogue, OlAla, may possess increased metabolic stability (Ayoub et al., 2020), the present study compared the pharmacokinetics of these compounds in mice, and also evaluated whether OlAla would ameliorate nicotine-induced CPP and spontaneous

CONCLUSIONS

The N-acyl amino acid, OlAla, attenuates nicotine reward and signs of spontaneous nicotine withdrawal in mice. These effects are similar to OlGly, for which OlAla was proposed as a more metabolically stable analogue. While OlAla reduces nicotine-induced CPP similar to OlGly, OlAla appears to exert its effects through a PPARα independent mechanism, unlike OlGly. The distinct mechanism through which OlAla reduces nicotine reward has yet to be elucidated. The similar time-courses of exogenously

Role of Funding Source

This project was funded in part by the National Institutes of Health [grant numbers: P30DA033934, T32DA007027, F31DA056228], start-up funds from the VCU School of Pharmacy, bridge funds from the VCU School of Medicine, and Plantext Ltd with work done under Plantext Ltd patents. None of these sponsors played a role in the study design, collection, analysis and interpretation of data; writing of the report; and decision to submit the article for publication.

Uncited references

(Epstein et al., 2006, U.S, 2020)

CRediT authorship contribution statement

Mohammed Damaj: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing. Aron H. Lichtman: Conceptualization, Formal analysis, Funding acquisition, Supervision, Writing – review & editing. Mohammed Mustafa: Writing – review & editing, Investigation, Methodology. Justin Poklis: Data curation. Joel Schlosburg: Data curation, Writing – review & editing. Linda Parker: Conceptualization, Writing – review & editing. Kimberly Karin: Conceptualization,

Acknowledgements

We thank the Pharmacology and Toxicology Bioanalytical Core funded by P30DA033934 for supporting the high-performance liquid chromatography tandem mass spectrometry analysis and thank Dr. Carl E. Wolf of Virginia Commonwealth University Department of Pathology for allowing us to use the FIRM Laboratory extraction equipment.

Declaration of Competing Interest

Drs. M. Imad Damaj, Aron H. Lichtman, and Linda Parker are inventors on a patent entitled “Fatty acid amides and uses thereof in the treatment of addiction disorder and addiction related conditions” (US 11,324,709 B2)

ACKNOWLEDGEMENTS

This project was funded in part by the National Institutes of Health [grant numbers: P30DA033934, T32DA007027, F31DA056228], start-up funds from the VCU School of Pharmacy, and bridge funds from the VCU School of Medicine, and PlantEXT Ltd. We thank the Pharmacology and Toxicology Bioanalytical Core funded by P30DA033934 for supporting the high-performance liquid chromatography tandem mass spectrometry analysis and thank Dr. Carl E. Wolf of Virginia Commonwealth University Department of

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