CSF somatostatin in Alzheimer's disease and major depression: Relationship to hypothalamic-pituitary-adrenal axis and clinical measures

Patients with Alzheimer's disease (AD) and major depression have been shown to have overlapping clinical symptoms and biological markers, including decreased concentrations of cerebrospinal fluid (CSF) somatostatin-like immunoreactivity (SLI), which may be related to alterations in the hypothalamic-pituitary-adrenal axis activity. As in prior studies, we found that CSF SLI was significantly decreased in a group of AD patients (N = 49) and a group of elderly patients with major depression (N = 18), as compared with 13 age-matched controls (F[2, 77] = 12.9, p r = 0.49, p r = 0.47, p r = -0.51, p < .03). Clinical measures of dementia severity and depression did not consistently correlate with CSF SLI in either patient group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31089/1/0000766.pd

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

β-Amyloid precursor protein (APP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer’s disease. The cytoplasmic domain of APP is important for the metabolism and physiological functions of APP. The cytoplasmic domain contains a GYENPTY motif that interacts with proteins that contain a phosphotyrosine binding (PTB) domain such as X11/Mint, FE65, and the JIP family of proteins. X11 and X11-like proteins are neuronal adaptor proteins involved in presynaptic function and the intracellular trafficking of proteins. Recent studies in X11s knock-out mice confirmed findings from in vitro studies that X11 proteins affect APP metabolism and the generation of β-amyloid peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of APP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with APP to play a role in neuronal cytoskeletal regulation. c-Jun N-terminal kinase (JNK) interacting protein-1 (JIP-1), a scaffolding protein for the JNK kinase cascade, has been suggested to mediate the intracellular trafficking of APP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of APP by APP binding proteins

Effects of anticholinergic drugs on regional brain neurotensin concentrations

Chronic treatment with atropine sulfate (20 mg/kg), atropine methyl bromide (20 mg/kg), or scopolamine (2 mg/kg) did not increase neurotensin concentrations in the nucleus accumbens or caudate nucleus. Chronic co-administration of atropine sulfate did not alter the increases in neurotensin concentrations in the nucleus accumbens and caudate nucleus produced by chronic treatment with haloperidol (1 mg/kg). The anticholinergic properties of antipsychotic drugs apparently do not mediate the increases in neurotensin concentration observed after chronic treatment with antipsychotic drugs

Monoamine metabolites, corticotropin releasing factor and somatostatin as CSF markers in depressed patients

CSF samples from ten healthy volunteers and 22 patients with major depression were collected by lumbar puncture at 9 a.m. and the content of monoamine metabolites, corticotropin releasing factor (CRF) and somatostatin (SRIF) was analyzed. Plasma concentrations of TSH following a TRH challenge test (200 gmg) and plasma cortisol following dexamethasone (1 mg; DST) were also analyzed. No relationships were observed between the CRF or SRIF concentrations and either basal or post-dexamethasone cortisol concentrations. Fourteen of 21 depressed patients were DST nonsuppressors using a plasma cortisol concentration cut off point ≧ 138 nmol/1. If a more conservative cut off point was used (> 290 nmol/1) seven out of 21 patients revealed a severity-related cortisol nonsuppression. No significant difference was observed between healthy volunteers and depressed patients with regard to TSH response to TRH. The CSF content of CRF was elevated and the content of SRIF reduced in the depressed patients. In the healthy volunteers an inverse relationship was observed between CSF concentrations of CRF and MHPG ( r= -0.72; P = 0.019); no relationship was observed between the concentrations of CRF and 5-HIAA or HVA. In the depressed patients positive correlations were found between CSF concentrations of CRF and 5-HIAA ( r = 0.59; P = 0.004) and between CRF and HVA ( r = 0.44; P = 0.042). These data are concordant with the view that norepinephrine and serotonin may be involved in the regulation of CRF secretion. However, these regulatory mechanisms may be altered in patients with major depression, where a normal noradrenergic inhibitory tone is postulated to be replaced by a serotoninergic stimulation of CRF release

Centrally administered neurotensin inhibits pentobarbital metabolism in mice but not in rats

Neurotensin (NT), a tridecapeptide with a widespread and uneven distribution within the central nervous system of mammals, is known to be involved in a variety of physiological, behavioral, endocrine and biochemical functions. Groups of rats and mice were given i.p. injections of pentobarbital followed by intracisternal administration of NT or saline. Following decapitation, the plasma, liver and brain concentrations of pentobarbital were measured with a gas chromatographic/mass fragmentographic method. In the mice, but not in the rats, the NT injection caused a substantial inhibition of the pentobarbital metabolism and a prolongation of the sleeping time. The mechanism(s) behind this inhibition still remains unclear

Effects of excitotoxic amino acids on pituitary hormone secretion in the rat

The acute effects of administration of 4 excitatory amino acids (n-methyl- dl-aspartic acid (NMA), kainic acid (KA), ibotenic acid (IA) and quinolinic acid (QA)) on the serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH) and prolactin (PRL) were studied in the rat. NMA-treated rats exhibited increased serum LH and GH concentrations while KA-treated rats showed increases only in serum GH concentrations. Neither IA nor QA altered adenohypophyseal hormone levels. These endocrine alterations induced by NMA and KA are different from those previously reported after administration of glutamate, another excitatory amino acid. The finding that all of the excitatory amino acids studied did not produce identical effects on anterior pituitary hormone secretion may be due to differential permeability of these substances into the central nervous system or because they act at different subtypes of excitatory amino acid receptors

Acute effects of alprazolam and adinazolam on the concentrations of corticotropin‐releasing factor in the rat brain

Corticotropin‐releasing factor (CRF) is the major physiological regulator of the hypothalamic‐pituitary‐adrenal (HPA) axis. However, considerable evidence indicates that CRF may be responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress as well. In addition, clinical studies indicate that CRF of both hypothalamic and extrahypothalamic origin may be hypersecreted in major depression as well as other psychiatric disorders. These findings, taken together, led to the hypothesis that the efficacy of antidepressant and/or anxiolytic drugs may be related to their actions on CRF‐containing neural pathways in the central nervous system (CNS). Therefore, alterations of CRF concentrations in 18 rat brain regions were studied after acute administration of a tricyclic antidepressant (imipramine) or one of two triazolobenzodiazepines (alprazolam or adinazolam) that possess anxiolytic properties typical of benzodiazepines, as well as purported antidepressant activity unique to these compounds. Treatment with alprazolam or adinazolam increased hypothalamic CRF concentrations, which was associated with lower plasma ACTH concentrations. In contrast, the concentration of CRF was markedly reduced in the locus coeruleus, amygdala, and several cortical regions by either triazalobenzodiazepine. Acute treatment with imipramine was without effect on CRF concentrations in any brain region studied. Of particular interest is the finding that the two triazolobenzodiazepines exert effects on CRF concentrations in the locus coeruleus and hypothalamus that are opposite to CRF changes seen after stress