gamma-Hydroxybutyrate (GHB) is a potent sedative/hypnotic and drug of abuse. Tolerance develops to GHB's sedative/hypnotic effects. It is hypothesized that GHB tolerance may be mediated by alterations in central nervous system pharmacokinetics or neurotransmitter response. Rats were dosed daily with GHB (548 mg/kg s.c. q.d. for 5 days), and sleep time was measured as an index of behavioral tolerance. Plasma and brain GHB pharmacokinetics on days 1 and 5 were monitored using blood and microdialysis sampling. Extracellular (ECF) striatal dopamine levels were measured by microdialysis as a pharmacodynamic endpoint of tolerance. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling was performed to describe the plasma and brain disposition using an indirect response model with inhibition of dopamine synthesis rate to describe the pharmacodynamic response. GHB plasma and brain ECF concentration versus time profiles following acute or chronic exposure were not significantly different. GHB sedative/hypnotic tolerance was observed by day 5. Acute GHB administration resulted in a decrease in striatal ECF dopamine (DA) levels compared with baseline levels. GHB tolerance was reflected by a 60% decrease in dopamine area under the curve (effect and baseline): acute, 10.1 +/- 15.3% basal DA/min/10(-3) versus chronic, 4.73 +/- 1.49% basal DA/min/10(-3) (p < 0.05, n = 5; unpaired Student's t test). The PK/PD model revealed an increase in the IC50 following chronic exposure indicating decreased dopaminergic sensitivity toward the inhibitory effects of GHB. Our findings indicate that GHB pharmacokinetics do not contribute to behavioral tolerance; however, changes in neurotransmitter responsiveness may suggest specific neurochemical pathways involved in the development and expression of tolerance.
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http://dx.doi.org/10.1124/jpet.106.113886 | DOI Listing |
Langmuir
January 2025
Department of Physics and Astronomy, The University of Tennessee, Knoxville, Tennessee 37996, United States.
Biological memory is the ability to develop, retain, and retrieve information over time. Currently, it is widely accepted that memories are stored in synapses (i.e.
View Article and Find Full Text PDFCancer Cell Int
January 2025
Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea.
Background: The prognosis of a plasma cell neoplasm (PCN) varies depending on the presence of genetic abnormalities. However, detecting sensitive genetic mutations poses challenges due to the heterogeneous nature of the cell population in bone marrow aspiration. The established gold standard for cell sorting is fluorescence-activated cell sorting (FACS), which is associated with lengthy processing times, substantial cell quantities, and expensive equipment.
View Article and Find Full Text PDFSci Rep
January 2025
INSERM, Bergonié Institute, BPH, U1219, CIC-P 1401, University of Bordeaux, Bordeaux, France.
In vitro and animal studies have suggested that inoculation with herpes simplex virus 1 (HSV-1) can lead to amyloid deposits, hyperphosphorylation of tau, and/or neuronal loss. Here, we studied the association between HSV-1 and Alzheimer's disease biomarkers in humans. Our sample included 182 participants at risk of cognitive decline from the Multidomain Alzheimer Preventive Trial who had HSV-1 plasma serology and an amyloid PET scan.
View Article and Find Full Text PDFJ Hepatol
January 2025
Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida, United States of America. Electronic address:
Background & Aims: Lanifibranor is a pan-PPAR agonist that improves glucose/lipid metabolism and reverses steatohepatitis and fibrosis in adults with MASH. We tested its effect on insulin resistance at the level of different target tissues in relationship to change in intrahepatic triglyceride (IHTG) content.
Methods: This phase 2, single center, study randomized (1:1) 38 patients with T2D and MASLD to receive lanifibranor 800 mg or placebo for 24 weeks.
Brain Res
January 2025
The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 15000, China. Electronic address:
Objectives: Exercise as a non-pharmacological intervention can exert beneficial effects directly through exosomes crossing the blood-brain barrier and reduce apoptosis after cerebral ischaemia/reperfusion injury (CI/RI). miRNA-124 (miR-124) is present in exosomes and plays an important role in regulating cerebral neurological activity; however, the mechanism of the relationship between exercise and the activity of exosomes and apoptosis after CI/RI remains unclear. Therefore, the present study investigated the effects of exercise preconditioning on cerebral ischemia/reperfusion injury from the perspective of exosomal miR-124 and apoptosis.
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