Corticotropin-releasing factor (CRF) is the primary factor involved in controlling the release of ACTH from the anterior pituitary and also acts as a neurotransmitter in a variety of brain systems. The actions of CRF are mediated by G-protein coupled membrane bound receptors and a high affinity CRF receptor, CRF1, has been previously cloned and functionally characterized. We have recently isolated a cDNA encoding a second member of the CRF receptor family, designated CRF2, which displays approximately 70% homology at the nucleotide level to the CRF1 receptor and exhibits a distinctive pharmacological profile. The present study utilized in situ hybridization histochemistry to localize the distribution of CRF2 receptor mRNA in rat brain and pituitary gland and compared this with the distribution of CRF1, receptor expression. While CRF1 receptor expression was very high in neocortical, cerebellar, and sensory relay structures, CRF2 receptor expression was generally confined to subcortical structures. The highest levels of CRF2 receptor mRNA in brain were evident within the lateral septal nucleus, the ventromedial hypothalamic nucleus and the choroid plexus. Moderate levels of CRF2 receptor expression were evident in the olfactory bulb, amygdaloid nuclei, the paraventricular and suraoptic nuclei of the hypothalamus, the inferior colliculus and 5-HT-associated raphe nuclei of the midbrain. CRF2-expressing cells were also evident in the bed nucleus of the stria terminalis, the hippocampal formation and anterior and lateral hypothalmic areas. In addition, CRF2 receptor mRNA was also found in cerebral arterioles throughout the brain. Within the pituitary gland, CRF2 receptor mRNA was detectable only at very low levels in scattered cells while CRF1 receptor mRNA was readily detectable in anterior and intermediate lobes. This heterogeneous distribution of CRF1 and CRF2 receptor mRNA suggests distinctive functional roles for each receptor in CRF-related systems. The CRF1 receptor may be regarded as the primary neuroendocrine pituitary CRF receptor and important in cortical, cerebellar and sensory roles of CRF. The anatomical distribution of CRF2 receptor mRNA indicates a role for this novel receptor in hypothalamic neuroendocrine, autonomic and general behavioral actions of central CRF.
The psychotropic amphetamine derivatives 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) have been used for recreational and therapeutic purposes in man. In rats, these drugs cause large reductions in brain levels of serotonin (5-HT). This study employs immunocytochemistry to characterize the neurotoxic effects of these compounds upon monoaminergic neurons in the rat brain. Two weeks after systemic administration of MDA or MDMA (20 mg/kg, s.c., twice daily for 4 d), there is profound loss of serotonergic (5-HT) axons throughout the forebrain; catecholamine axons are completely spared. Regional differences in drug toxicity are exemplified by partial sparing of 5-HT axons in hippocampus, lateral hypothalamus, basal forebrain, and in some areas of neocortex. The terminals of 5-HT axons are selectively ablated, while axons of passage and raphe cell bodies are spared. Thickened preterminal fibers exhibit increased staining due to damming-up of neurotransmitter and other axonal constituents. Fine 5-HT axon terminals are extremely vulnerable to these drugs, whereas terminal-like axons with large varicosities survive, raising the possibility that some 5-HT axons may be resistant to the neurotoxic effects. At short survivals, visualization of greatly swollen, fragmented 5-HT axons provides anatomic evidence for degeneration of 5-HT projections. The results establish that MDA and MDMA produce structural damage to 5-HT axon terminals followed by lasting denervation of the forebrain. Both drugs have similar effects, but MDA produces a greater reduction of 5-HT axons than does MDMA at the same dosage. The selective degeneration of 5-HT axons indicates that these drugs may serve as experimental tools to analyze the organization and function of 5-HT projections. Caution should be exercised until further studies determine whether these compounds may be hazardous in man.
The cytokine interleukin-1 (IL-l) has a number of biologic activities, including pronounced effects on the nervous and neuroendocrine systems. In this study, in situ histochemical techniques were used to investigate the distribution of cells expressing type I IL-1 receptor mRNA in the CNS, pituitary, and adrenal gland of the mouse. Hybridization of %-labeled antisense cRNA probes derived from a murine T-cell IL-1 receptor cDNA revealed a distinct regional distribution of the type I IL-1 receptor, both in brain and in the pituitary gland. In the brain, an intense signal was observed over the granule cell layer of the dentate gyrus, over the entire midline raphe system, over the choroid plexus, and over endothelial cells of postcapillary venules throughout the neuraxis. A weak to moderate signal was observed over the pyramidal ceil layer of the hilus and CA3 region of the hippocampus, over the anterodorsal thalamic nucleus, over Purkinje cells of the cerebellar cortex, and in scattered clusters over the externalmost layer of the median eminence.In the pituitary gland, a dense and homogeneously distributed signal was observed over the entire anterior lobe. No autoradiographic signal above background was observed over the posterior and intermediate lobes of the pituitary, or over the adrenal gland. This study therefore provides evidence for discrete receptor substrates subserving the central effects of IL-l, thus supporting the notion that IL-1 acts as a neurotransmitter/neuromodulator in brain. It also supports studies suggesting that IL-1 -mediated activation of the hypothalamic-pituitary-adrenal axis occurs primarily at the level of the brain and/or pituitary gland.Interleukin-1 (IL-l) is one of a growing number of cytokines that mediate important regulatory interactions between lymphocytes and many other cell types (see Dinarello, 1989). IL-l has also been identified as a key mediator in the acute-phase
A stable, iodine-125-labeled analog of rat/human corticotropin- releasing factor (CRF) was used to define the characteristics of CRF receptors in a crude mitochondrial/synaptosomal membrane preparation of rat olfactory bulb, and to study the distribution of CRF binding sites in discrete regions of the rat CNS. The binding of 125I-Tyro rat/human CRF (125I-rCRF) was time- and temperature-dependent, was sensitive to the pH, ionic strength, and cationic composition of the incubation buffer, and was linear over a broad range of membrane protein concentrations. 125I-rCRF binding to olfactory bulb membrane was saturable, reversible, and, on Scatchard analysis, revealed a high- affinity component with an apparent equilibrium dissociation constant (Kd) of 0.2 nM and a low-affinity binding site with Kd of approximately 20 nM. Data from pharmacological studies indicated that the ability of a variety of CRF fragments and analogs to inhibit 125I-rCRF to olfactory bulb membranes correlates well with their reported relative potencies in stimulating pituitary adrenocorticotropic hormone secretion in vitro. Consistent with a coupling of CRF receptors to adenylate cyclase, the binding of 125I-rCRF was decreased by guanine nucleotides and increased by magnesium ions. A heterogeneous distribution of 125I-rCRF binding sites was found in the rat CNS, with highest densities present in olfactory bulb, cerebellum, cerebral cortex and striatum, and progressively lower but significant levels of binding were detected in cervical spinal cord, hypothalamus, medulla, midbrain, thalamus, pons, and hippocampus. These data, using a rat CRF ligand homologous to the endogenous peptide, are consistent with those from previous studies demonstrating the presence of specific binding sites for ovine CRF in rat brain, and provide further support for the suggestion that endogenous CRF may function as a neurotransmitter in the CNS.
Corticotropin-releasing factor (CRF) receptors were identified in rat forebrain by autoradiography with an iodine-125-labeled analog of ovine CRF substituted with norleucine and tyrosine at amino acid residues 21 and 32, respectively. High-affinity receptors for CRF were found in discrete areas of rat forebrain, including laminae I and IV of the neocortex, the external layer of the medium eminence, the lateral nucleus of the amygdala, and the striatum. These results are consistent with earlier findings on the immunohistochemical distribution of CRF and suggest that endogenous CRF has a physiological role in regulating activity of the central nervous system.
This study reports the ontogeny of corticotropin-releasing factor (CRF) receptor binding sites in rat brain, using both membrane binding assays and in vitro receptor autoradiography. CRF binding sites are evident by prenatal day 17, increase to 312% of their adult density by postnatal day 8, then decrease to reach adult values by day 21. Not only the density, but the distribution of CRF binding undergoes major modifications in development. CRF binding sites are most numerous in striatum prenatally, but postnatally, binding is more dense in the cortex, reaching the adult laminar distribution by postnatal day 14. Brain CRF receptors are linked to adenylate cyclase early in postnatal life. This contrasts with the later appearance of most of the guanine nucleotide stimulatory protein and catalytic subunit sites in the rat brain and suggests that CRF receptors may become functional earlier than several other brain receptors that are linked to adenylate cyclase.
DHEA did not significantly improve cognitive performance or overall ratings of change in severity in this small-scale pilot study. A transient effect on cognitive performance may have been seen at month 3, but narrowly missed significance.
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