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\begin{document}

\title{Enantiomeric and Monoaminergic Contributions to Methamphetamine's
Bidirectional Effects on Fentanyl-Depressed Respiration in Mice}



\author[1]{Harrison Elder}%
\author[1]{David Walentiny}%
\author[2]{Patrick Beardsley}%
\affil[1]{Virginia Commonwealth University School of Medicine}%
\affil[2]{Virginia Commonwealth University}%


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  \date{June 11, 2024}


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\begin{abstract}
Rationale: Fentanyl remains the primary cause of fatal overdoses, and
its co-use with methamphetamine (METH) is a growing concern. The optical
isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine
(l-METH), differ substantially in dose expression and thus may
differentially contribute to the racemate's bidirectional effects.
Furthermore, it is unknown which of METH's monoamine (MA) receptor
mechanisms mediate these respiratory effects. Thus, systematic
evaluation of monoamine receptor selective agents may identify treatment
targets for OIRD. Methods: The two optical isomers of METH, d-METH and
l-METH, were tested in adult male mice to determine their effects on
basal and fentanyl-depressed minute volume (MVb; i.e., respiratory
frequency x tidal volum) using whole-body plethysmography. Next, six
selective agonists at MA receptors involved in METH's activity
{[}phenylephrine (PNE; \selectlanguage{greek}α\selectlanguage{english}1), clonidine (CLON; \selectlanguage{greek}α\selectlanguage{english}2), SKF-82958 (SKF; D1),
quinpirole (QPR; D2), 8-OH-DPAT (8-OH; 5HT1A), and DOI (5HT2){]} were
singly tested on basal MVb, and then in combination with fentanyl.
Results: d-METH elevated MVb and l-METH decreased MVb. Under
fentanyl-depressed conditions, the bidirectional effects of racemic METH
were recreated by d-METH while l-METH significantly exacerbated OIRD at
1.0 and 3.0 mg/kg. MVb was dose-dependently increased by PNE and SKF and
decreased by CLON and QPR. Neither 8-OH nor DOI altered basal MVb. Under
fentanyl-depressed conditions, SKF transiently elevated MVb, while PNE
more persistently increased it, while DOI transiently increased MVb, and
8-OH decreased MVb. Conclusions: d-METH and l-METH differentially
contribute to the bidirectional respiratory modulation observed with the
racemate and selective activation of MA receptors altered basal
respiration and OIRD.%
\end{abstract}%



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