Differential localization of type I and type II benzodiazepine binding sites in substantia nigra

A number of studies have suggested the existence of multiple benzodiazepine binding sites in the brain. We have recently reported the physical separation of two apparent benzodiazepine binding site subtypes, the pharmacological properties, and distribution in tissue sections of which correspond to the putative type I and type II sites. Benzodiazepine and gamma-aminobutyric acid (GABA) receptors have been shown to interact, and lesions of the GABAergic striatonigral pathway, which lead to GABA supersensitivity, both increase the numbers of GABA binding sites and enhance GABA-stimulated benzodiazepine binding. We demonstrate here that degeneration of striatonigral fibres increases the density of putative type I benzodiazepine binding sites in the substantia nigra and decreases the density of the putative type II sites. This suggests that type I sites that increase after denervation are postsynaptic, whereas the type II sites reduced by the lesion may be localized to axons or terminals of the striatonigral pathways.     

Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease

Alzheimer's disease is a progressive degenerative disease of the nervous system characterized neuropathologically by the presence of senile plaques and neurofibrillary tangles in amygdala, hippocampus and neocortex. Dysfunction and death of basal forebrain cholinergic neurones projecting to forebrain targets are associated with marked decreases in cholinergic markers, including the activity of choline acetyltransferase (ChAT). Although cortical levels of somatostatin and somatostatin receptors are reduced in Alzheimer's, no consistent changes have been reported in other neuropeptide systems. We have now examined in control and Alzheimer's brain tissues pre- and postsynaptic markers of corticotropin-releasing factor (CRF), a hypothalamic peptide regulating pituitary-adrenocortical secretion which also seems to act as a neurotransmitter in the central nervous system (CNS). We have found that in Alzheimer's, the concentrations of CRF-like immunoreactivity (CRF-IR) are reduced and that there are reciprocal increases in CRF receptor binding in affected cortical areas. These changes are significantly correlated with decrements in ChAT activity. Our results strongly support a neurotransmitter role for CRF in brain and demonstrate, for the first time, a modulation of CNS CRF receptors associated with altered CRF content. These observations further suggest a possible role for CRF in the pathophysiology of the dementia. Future therapies directed at increasing CRF levels in brain may prove useful for treatment.