International Journal of Molecular Sciences
October 2, 2021
Paul J. Fitzgerald
30 citations
Many drugs of abuse, including stimulants, opioids, psychedelics, and alcohol, may be directly converted in the body into catecholamines—dopamine, norepinephrine, and epinephrine—rather than merely modulating these neurotransmitter systems through receptor binding. This hypothesized transformation could explain both the intoxicating effects and the physiological side effects (elevated heart rate, blood pressure, rapid breathing, increased temperature, sweating, and dilated pupils) typically associated with these substances. If correct, this would revise understanding of catecholamine biosynthesis and the neural basis of substance abuse, dependence, and stress-induced relapse. The hypothesis can be tested by administering stable isotope-labeled drugs to rodents or humans and detecting labeled catecholamines in brain, blood, or urine using liquid chromatography-mass spectrometry.
Frontiers in Psychiatry
May 11, 2021
Ridge G. Weston, Paul J. Fitzgerald, Brendon O. Watson
19 citations
The anesthetic drug ketamine has been repurposed as a rapid-acting antidepressant for major depressive disorder (MDD), including treatment-resistant cases, unlike slower monoaminergic antidepressants. Its fast onset suggests a unique mechanism studied in reverse translational rodent models. Most research examines single ketamine doses, but MDD often requires ongoing treatment. This review of rodent studies using repeated ketamine dosing in the forced swim test (FST) found that repeated dosing can paradoxically increase immobility at high doses (50 or 100 mg/kg). However, several studies show repeated dosing more effectively decreases immobility than a single dose, with longer-lasting behavioral effects. The findings indicate repeated ketamine has prominent depression-related effects in rodents, which may help optimize human MDD treatment.
bioRxiv Preprint Server
June 29, 2021
Colin J. Johnston, Paul J. Fitzgerald, Jena S. Gewarges et al.
5 citations
preprint
Ketamine, an antidepressant, interacts with the HPA axis, but its behavioral effects' dependence on this axis is unknown. In male and female mice subjected to chronic unpredictable stress, ketamine (30 mg/kg) or vehicle was given with or without metyrapone to block corticosterone production. No significant drug effects on behavior were observed. Males had higher fecal corticosterone levels and stress-induced increases than females. Ketamine lowered the corticosterone response to a novel stressor only in males. Corticosterone levels correlated with immobility in a behavioral test across all mice, suggesting shared neural circuitry for endocrine and behavioral responses that may be ketamine-responsive only in males.