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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in
Harrison J Elder1, D Matthew Walentiny2, Patrick M Beardsley3
1Now at Behavioral 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 (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into 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 respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography.
Results:
When tested at dose ranges of 1.0-10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg.
Conclusions:
d-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.
Insights
Dextromethamphetamine (d-METH) stimulates respiration, while levomethamphetamine (l-METH) depresses it, explaining racemic methamphetamine
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Fentanyl overdoses are a major public health crisis.
- Co-use of fentanyl and methamphetamine (METH) complicates overdose outcomes.
- Previous research indicated racemic METH has dose-dependent effects on opioid-induced respiratory depression (OIRD).
Purpose of the Study:
- To investigate the distinct respiratory effects of METH enantiomers, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH).
- To elucidate the mechanisms underlying the bidirectional effects of racemic METH on OIRD.
- To identify potential therapeutic targets for OIRD.
Main Methods:
- Adult male mice were used to assess respiratory parameters (frequency, tidal volume, minute ventilation).
- Whole-body plethysmography was employed to measure respiratory function.
- The effects of d-METH and l-METH were evaluated under both basal and fentanyl-depressed conditions.
Main Results:
- d-METH increased minute ventilation at doses of 1.0-10 mg/kg.
- l-METH decreased basal minute ventilation at lower doses (1.0-3.0 mg/kg) but increased it at 30 mg/kg.
- l-METH exacerbated fentanyl-induced respiratory depression at 1.0 and 3.0 mg/kg, while d-METH showed mitigating effects.
Conclusions:
- d-METH and l-METH exert opposing effects on respiratory function.
- d-METH primarily exhibits stimulatory respiratory effects.
- l-METH primarily exhibits depressant respiratory effects, worsening OIRD at specific doses.
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