Monoamine receptors targeted by methamphetamine differentially modulate basal and fentanyl-depressed respiration in mice

Abstract

Rationale

Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine is a growing concern. Our lab previously demonstrated that racemic methamphetamine could have either respiratory stimulant or depressant effects depending on dose and separately determined by its enantiomers, dextromethamphetamine, and levomethamphetamine, respectively. Enantiomeric separation of methamphetamine's stimulant and depressant effects indicates that differences in their pharmacology might be exploited to develop novel respiratory stimulants. It is presently unknown which of methamphetamine's monoamine receptor mechanisms mediate these respiratory effects. Thus, systematic evaluation of monoamine receptor-selective agents may identify treatment targets for OIRD.

Methods

Six selective agonists at monoamine receptors involved in methamphetamine's activity [phenylephrine (PNE; α₁), clonidine (CLON; α₂), SKF-82958 (SKF; D₁), quinpirole (QPR; D₂-like), 8-OH-DPAT (8-OH; 5HT_1A), and DOI (5HT₂)] were tested in adult male mice to determine their effects on basal and fentanyl-depressed minute volume (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. Agonists were initially tested at three behaviorally active doses for their effects on basal MVb. Agonists that stimulated respiration or did not decrease respiration were then tested in combination with fentanyl.

Results

The α₁ and D₁ agonists PNE and SKF dose-dependently increased basal MVb while the α₂ and D₂-like agonists CLON and QPR depressed basal MVb. Neither serotonin receptor agonist significantly altered basal MVb. Under fentanyl-depressed conditions, SKF produced transient but significant increases in MVb, while PNE more persistently elevated it. Interestingly, DOI transiently elevated depressed MVb, while 8-OH further exacerbated OIRD.

Conclusions

Selective activation of monoamine receptors alters basal respiration and OIRD, with D₁ and α₁ receptors representing potential targets as respiratory stimulants, whereas α₂, D₂-like, and 5HT_1A receptors may mediate the exacerbation of OIRD by methamphetamine.