Evaluation of the agonist PET radioligand [¹¹C]GR103545 to image kappa opioid receptor in humans: kinetic model selection, test-retest reproducibility and receptor occupancy by the antagonist PF-04455242.

Introduction: Kappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone.

Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical research unit.

Objective: This study sought to compare devices that use actigraphy for measuring sleep endpoints in the clinical research unit (CRU) and home environment. The abilities of polysomnography (PSG) and actigraphy monitors to detect drug effects in a CRU were also investigated.

Methods: Eleven healthy subjects were recruited and monitored with PSG for four consecutive nights in a CRU after receiving no treatment (night 1, N1), and then placebo or 5 mg day(-1) or 10 mg day(-1) zolpidem in a randomised, cross-over design.

Quantitative PK-PD model-based translational pharmacology of a novel kappa opioid receptor antagonist between rats and humans.

Pharmacokinetic-pharmacodynamic (PK-PD) modeling greatly enables quantitative implementation of the "learn and confirm" paradigm across different stages of drug discovery and development. This work describes the successful prospective application of this concept in the discovery and early development of a novel κ-opioid receptor (KOR) antagonist, PF-04455242, where PK-PD understanding from preclinical biomarker responses enabled successful prediction of the clinical response in a proof of mechanism study. Preclinical data obtained in rats included time course measures of the KOR antagonist (PF-04455242), a KOR agonist (spiradoline), and a KOR-mediated biomarker response (prolactin secretion) in plasma.

Comparison of the stress response in rats to repeated isoflurane or CO2:O2 anesthesia used for restraint during serial blood collection via the jugular vein.

The primary objective of this study was to compare the effect of 2 commonly used anesthetics, isoflurane and CO2, on the physiologic stress hormone, corticosterone, in rats during serial blood collections. Circulating corticosterone concentrations were monitored during serial jugular blood sampling in rats exposed to either isoflurane or CO2 anesthesia. Blood was drawn under anesthesia at 6 time points (initial sampling and 0.

Noradrenergic regulation of prolactin secretion at the level of the paraventricular nucleus of the hypothalamus: functional significance of the alpha-1b and beta-adrenergic receptor subtypes.

Previous research has demonstrated that in the Siberian hamster, both photoperiod and estrous cyclicity alter the profile of noradrenergic activity with the paraventricular nucleus of the hypothalamus (PVN), and that noradrenergic activity is correlated with changes in circulating levels of prolactin. Work from our laboratory has demonstrated an inhibitory role for norepinephrine (NE) acting at the alpha-2 receptor subtype within the PVN on serum prolactin levels; however, the functional significance of other adrenergic receptor subtypes on this system is unknown. The purpose of this study was to investigate the functional significance of the alpha-1b and beta-adrenergic receptor subtypes at the level of the PVN on circulating levels of prolactin.

Male-induced estrus synchronization in the female Siberian hamster (Phodopus sungorus sungorus).

Olfactory cues play an integral role in the organization of events that mediate reproductive success. In a variety of species, priming pheromones, in particular, are important for ensuring reproductive fitness. To date, very little research has focused on how male-emitted priming pheromones, such as those that regulate the onset of puberty and estrus synchronization in females, affect the reproductive physiology of the female Siberian hamster (Phodopus sungorus sungorus).

5HT and 5HIAA dialysate levels within the arcuate nucleus of the hypothalamus: relationship with photoperiod-driven differences in serum prolactin and luteinizing hormone in the Siberian hamster.

This study examined the relationship between dialysate levels of serotonin (5HT), and its major metabolite 5HIIAA within the arcuate nucleus of the hypothalamus (ARC) and serum gonadotropin levels under two different in vivo paradigms. Experiment 1 evaluated the relationship between dialysate levels of 5HT and 5HIAA within the ARC and circulating prolactin (PRL) and lutenizing hormone (LH) levels under long- and short-day photoperiod conditions. In experiment 2, the profile of 5HT and 5HIAA dialysate levels within the ARC on the afternoon of proestrous was investigated to determine if changes in serotonergic neurotransmission are correlated with preovulatory surges in LH and PRL.

Infusion of alpha-2-adrenergic agents into the paraventricular and arcuate nuclei of the hypothalamus in the Siberian hamster: opposing effects on basal prolactin.

Although the alpha(2)-adrenergic receptor subtype has been shown to have a significant influence on circulating levels of prolactin (PRL), its exact role remains unclear. A multitude of studies have demonstrated that blockade of the alpha(2)-receptor can either elevate or decrease circulating levels of PRL. Alpha(2)-receptor-mediated control of both stimulatory and inhibitory arms of the PRL regulatory system may explain this discrepancy.