Intermediate lobe activity

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

The POMC protein is processed differendy in the anterior lobe than in the intermediate lobe. The intermediate lobe of the pituitary is mdimentary in adult humans, but it is active in human fetuses and in pregnant women during late gestation and is also active in many animal species. Processing of the POMC protein in the peripheral tissues (gut, placenta, male reproductive tract) resem-... 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

Additional modifications of POMC peptide family There are extensive additional modifications of these peptides. Much of the N-terminal peptides of POMC as well as ACTH are glycosylated in the anterior pituitary. a-MSH is found predominantly in an N-acetylated and carboxy terminal amidated form. /3-Endorphin is rapidly acetylated in the intermediate lobe and made less active. In the hypothalamus /3-endorphin is not acetylated and is presumably active. /8-Endorphin is also trimmed in the intermediate lobe at the C-terminal end to form a- and y-endorphin. The large N-terminal fragment is also extensively cleaved but not much is known about this fragment. 

Many biologically active secreted peptides are also amidated at their carboxyl terminal, and acetylated at their amino-terminal. The consequences of these modifications are (a) to reduce the susceptibility of these peptides to degradative actions of extracellular aminopeptidases and carboxypeptidases after their secretion and (b) to influence the biological activity of the peptides. Corticotropin-releasing factor, gastrin, cholecystokinin and vasopressin require the C-terminal amide for full activity [54—56]. Acetylation of the N-terminus of a-MSH is necessary for activity, whereas acetylation of /3-endorphin inhibits its opioid activity [57], The enzymes responsible for acetylation have been identified from bovine and rat intermediate lobes [57] and enzymes with a-amidation activity have been reported in preparations of pituitary secretory granules [54,55]. 

There have been several studies characterizing the stimulatory effects of neurotensin on PHDA neurons terminating in the intermediate lobe of the posterior pituitary. Central (icv) administration of neurotensin increases the activity of PHDA neurons and this causes a concomitant decrease in concentration of aMSH in plasma (Pan et al., 1992). Neurotensin stimulates DA release in vitro from explants containing PHDA neurons, but not from isolated neurointermediate lobes, which is consistent with a hypothalamic site of action of neurotensin in stimulating the activity of PHDA neurons (Davis and Kilts 1987a,b). Neurotensin causes a sustained excitation of DA release from PHDA neurons with little or no tolerance as compared with short-lived transient responses of mesolimbic DA neurons to neurotensin (Davis and Kilts, 1987b). 

Stressful situations activate mesolimbic and mesocortical DA neurons (see references in Lookingland et al., 1991 Fleckenstein et al., 1994 Le Moal, 1995), but under some circumstances can decrease impulse traffic in TIDA and PHDA neurons. As a consequence of removing DA inhibitory tone provided by the latter neuronal systems, stressful manipulations release prolactin from the anterior lobe and aMSH from the intermediate lobe of the pituitary (Moore, 1987 Lookingland and Moore, 1995). 

Chronwall BM, Hook GR, Millington WR (1988) Dopaminergic regulation of the biosynthetic activity of individual melanotropes in the rat pituitary intermediate lobe a morphometric analysis by light and electron microscopy and in situ hybridization. Endocrinology 725 1992-2002. 

Lindley SE, Gunnet JW, Lookingland KJ, Moore KE (1990a) 3,4-Dihydroxyphenylacetic acid concentrations in the intermediate lobe and neural lobe of the posterior pituitary gland as an index of tuberoinfundibular dopaminergic neuronal activity. Brain Res 506 133-138. 

ACTH is derived from a large polypeptide precursor, proopiomelanocortin (POMC) that also includes in its amino acid sequence both MSH and the related opiate -lipotropin (y3-LPH), the latter giving rise to the biologically active )3-endorphin (Mains and Eipper, 1980). POMC, a 31 kDa polypeptide, is synthesized in the anterior and intermediate lobes of the pituitary gland, which is the most important source of this prohormone. Other notable sources of POMC synthesis in the brain include the amygdala and the arcuate nucleus of the hypothalamus (Watson and Akil, 1980 Civelli et al., 1982). In addition, the structure of the POMC molecule, the POMC gene and the mRNA sequence for POMC have been elucidated (Roberts... 

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