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Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526(More)
Gene amplification occurs at high frequency in transformed cells (10(-3)-10(-5)), but is undetectable in normal diploid fibroblasts (less than 10(-9)). This study examines whether alterations of one or both p53 alleles were sufficient to allow gene amplification to occur. Cells retaining one wild-type p53 allele mimicked the behavior of primary diploid(More)
Neurons in the suprachiasmatic nucleus (SCN), the site of the endogenous biological clock in mammals, fire spontaneously, peaking in firing rate near ZT6 or at the midpoint of the light phase in a 12:12 light-dark cycle. In rat hypothalamic slices, tissue incubations with drugs can produce a shift in this daily rhythm, the magnitude of which is dependent(More)
In vivo microdialysis in guinea pig hypothalamus was used to study the effect of serotonin [5-hydroxytryptamine (5-HT)] subtype 1D autoreceptor blockade on the increase in extracellular 5-HT levels produced by a selective 5-HT reuptake inhibitor (SSRI). Administration of the selective 5-HT1D antagonist GR127935 at 0.3 mg/kg had no effect, but 5 mg/kg(More)
Daily variation in an organism's physiology and behaviour is regulated by the synchrony that is achieved between the internal timing mechanisms - the circadian rhythms of the biological clock - and the prevailing environmental cues. Proper synchrony constitutes an adaptive response; improper or lost synchrony may well yield maladaptation and, in the case of(More)
PURPOSE The long-standing confusion regarding the clinical relevance of postimplant biopsies is complicated by the common occurrence of temporary PSA rises between 1 and 2 years after brachytherapy. We report here 4 patients with temporary, self-limited PSA rises and postimplant biopsies, for whom radical prostatectomy was strongly advised but for whom(More)
BACKGROUND The documented ability of serotonin (5-HT) to directly modulate circadian rhythms prompted interest in a similar role for therapeutic agents that readily enhance 5-HT neurotransmission, namely the selective serotonin reuptake inhibitors (SSRIs). METHODS Extracellular recordings of unit firing of suprachiasmatic nucleus (SCN) neurons maintained(More)
BACKGROUND Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT(1A) receptors. 5-HT(1A) receptor agonism may be an important feature in ziprasidone's clinical actions because 5-HT(1A) agonists increase cortical dopamine(More)
INTRODUCTION Circadian rhythms in mammals depend upon the cyclic oscillations of transcriptional/translational feedback loops in pacemaker cells of the suprachiasmatic nucleus. The rise and fall of clock-related proteins is a function of synthesis and degradation, the latter involving phosphorylation by casein kinase Iepsilon and delta. OBJECTIVE Earlier(More)
INTRODUCTION Casein kinase I epsilon/delta phosphorylates certain clock-related proteins as part of a complex arrangement of transcriptional/translational feedback loops that comprise the circadian oscillator in mammals. Pharmacologic inhibition leads to a delay of the oscillations with the magnitude of this effect dependent upon the timing of drug(More)