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Updated: Jul 24, 2026
Single Cell Measurement of Dopamine Release with Simultaneous Voltage-clamp and Amperometry
Published on: November 21, 2012
Monoamine receptors targeted by methamphetamine differentially modulate basal and fentanyl-depressed respiration in
Harrison J Elder1, D Matthew Walentiny2, Patrick M Beardsley3
1Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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; 5HT1A), 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 5HT1A receptors may mediate the exacerbation of OIRD by methamphetamine.
Insights
Selective activation of dopamine D1 and alpha-1 receptors may treat opioid-induced respiratory depression (OIRD). Methamphetamine
Area of Science:
- Neuropharmacology
- Respiratory Physiology
- Toxicology
Background:
- Fentanyl overdoses are a major public health crisis.
- Methamphetamine co-use complicates overdose risk.
- Methamphetamine's enantiomers have differential effects on respiration.
Purpose of the Study:
- To identify monoamine receptor mechanisms underlying methamphetamine's respiratory effects.
- To explore potential therapeutic targets for opioid-induced respiratory depression (OIRD).
Main Methods:
- Tested selective agonists at alpha1, alpha2, D1, D2-like, 5HT1A, and 5HT2 receptors in mice.
- Assessed effects on basal minute volume (MVb) and fentanyl-depressed MVb using whole-body plethysmography.
Main Results:
- Dopamine D1 and alpha-1 agonists increased basal MVb.
- Alpha-2 and D2-like agonists decreased basal MVb.
- D1 and alpha-1 agonists partially reversed fentanyl-induced respiratory depression.
Conclusions:
- Dopamine D1 and alpha-1 receptors are potential targets for treating OIRD.
- Alpha-2, D2-like, and 5HT1A receptors may contribute to methamphetamine's exacerbation of OIRD.
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