2-µm Ho emitter-based coherent DIAL for CO(2) profiling in the atmosphere.

We report on the use of a thulium-fiber-pumped holmium-based emitter in a coherent differential absorption lidar (CDIAL) experiment for high time and space resolution of CO(2) absorption field in the atmosphere. The 2-µm high-power dual-wavelength single-mode Q-switched Ho:YLF oscillator delivers 10-mJ pulses with a duration of 40 ns at 2 kHz. Both short pulse duration and high repetition rate were chosen to increase the DIAL precision and time and space resolution in coherent detection. The CDIAL provides 150-m range and 15-min time-resolved CO(2) absorption coefficient with a calculated instrumental error of 0.5% at 500 m and less than 2% at 1 km. Dry-air CO(2) mixing ratio estimates from the DIAL system are compared with simultaneous in situ gas analyzer measurements during a 20-h-long experiment.

Correlated ion-(ion/neutral) time of flight mass spectrometer.

The fragmentation of molecular systems into ions and neutral species is ubiquitous in fundamental and applied science. While the ion fragments are relatively easily detected by mass spectrometry technique, the information on the neutral product that is formed in correlation is challenging. In this contribution, we present a detailed description of the correlated ion-(ion/neutral) time of flight mass spectrometer, which is dedicated to the study of molecular dissociation induced by electrons at low energies (<20 eV). This new mass spectrometer uptakes the challenge to provide the correlation of ion/neural species produced in low energy electron-molecule collision processes.

Renin biosynthesis by human tumoral juxtaglomerular cells. Evidences for a renin precursor.

Renin biosynthesis was studied in a juxtaglomerular cell tumor. The tumoral tissue had a high renin content (180 Goldblatt Units/g of tissue), was heavily stained by immunofluorescence using human renin antiserum, and exhibited numerous characteristic secretory granules by electron microscopy. In one series of experiments, renin biosynthesis was studied in tissue slices, by following the incorporation of radiolabeled amino acids into specific immunoprecipitable renin. Time course studies showed that renin was first synthesized in a high molecular weight form, 55,000 mol wt, i.e., 10,000 mol wt higher than that of active renin, and was then converted into a 44,000-mol wt form. In a second series of experiments renin tumoral cells were cultured. Small, round, birefringent cells obtained after collagenase digestion produced renin in both primary culture and subculture media. After 5 d most of the renin found in the culture medium was inactive, but could be activated by trypsin treatment. The tumoral tissue exhibited a strong renin immunofluorescence and numerous secretory granules were observed by electron microscopy. In contrast, the renin-producing cells isolated from this tumor and grown in culture showed little renin immunofluorescence and no secretory granule could be observed. The renin-producing cells in primary culture and subculture were pulsed with radiolabeled amino acids, and immunoprecipitable radiolabeled renin was found in the culture media, thus demonstrating the actual biosynthesis of the enzyme. This renin was not stored inside cultured cells but was rapidly released into the medium and had a molecular weight of 55,000. No conversion of this inactive high molecular weight renin into the active, 44,000 mol wt form of renin was observed. We postulate the existence of two pathways for the processing, packaging, and secretion of renin in the tumoral cells: in juxtaglomerular cells of tumoral tissue renin is synthesized as a preprorenin and rapidly converted into prorenin (55,000 mol wt), which is in turn packaged in secretory granules where it is processed into active renin (44,000 mol wt) and finally secreted; in the cultured tumoral cells renin is still biosynthesized as a preprorenin molecule and then converted into prorenin, but is neither stored as granules nor processed into active renin. In this case the renin is released in an inactive form.

Cubilin is an albumin binding protein important for renal tubular albumin reabsorption.

Using affinity chromatography and surface plasmon resonance analysis, we have identified cubilin, a 460-kDa receptor heavily expressed in kidney proximal tubule epithelial cells, as an albumin binding protein. Dogs with a functional defect in cubilin excrete large amounts of albumin in combination with virtually abolished proximal tubule reabsorption, showing the critical role for cubilin in the uptake of albumin by the proximal tubule. Also, by immunoblotting and immunocytochemistry we show that previously identified low-molecular-weight renal albumin binding proteins are fragments of cubilin. In addition, we find that mice lacking the endocytic receptor megalin show altered urinary excretion, and reduced tubular reabsorption, of albumin. Because cubilin has been shown to colocalize and interact with megalin, we propose a mechanism of albumin reabsorption mediated by both of these proteins. This process may prove important for understanding interstitial renal inflammation and fibrosis caused by proximal tubule uptake of an increased load of filtered albumin.

Changes in anterior pituitary hormone levels after serotonin 1A receptor stimulation.

Although the role of serotonin (5HT) in the regulation of anterior pituitary hormone secretion is well documented, the involvement of specific 5HT receptor subtypes in this action is not yet fully elucidated. In the present work we attempted to determine the neuroendocrine role of the 5HT1A receptor subtype. This was chosen mainly because highly selective pharmacological tools are available for that subtype. 8-Hydroxy-2-(di-n-propylamino)tetralin (8OHDPAT) and ipsapirone were injected iv in conscious, freely moving male rats cannulated in the jugular vein. For the sake of comparison, a 5HT receptor agonist with preference for the 5HT1B and 5HT1C receptor subtypes 1-(m-trifluoromethyl-phenyl)piperazine (TFMPP) was also administered. Plasma PRL, ACTH, and beta-endorphin levels increased in a dose-dependent manner after 8-OHDPAT (0.01-1 mg/kg) or ipsapirone (0.5-7.5 mg/kg) injection. Maximal effects were obtained between 7-15 min. Only the highest dose of 1-(m-trifluoromethyl-phenyl)piperazine (5 mg/kg) resulted in the same response. In contrast, none of the drugs used affected plasma GH, TSH, or LH levels at any dose tested. The results indicate that 5HT1A receptors are involved in the regulation of PRL as well as ACTH and beta-endorphin secretion. 8OHDPAT was almost 40 times more potent than ipsapirone. The maximal effects of the two drugs on PRL release were comparable. In contrast, ipsapirone behaved as a partial agonist only on ACTH and beta-endorphin secretion, thus suggesting that different neuronal targets are involved in the stimulation of the three hormones by 5HT.

Intrahypothalamic growth hormone feedback: from dwarfism to acromegaly in the rat.

Two different dwarf rat models with primary (dw/dw, DW) or secondary (transgenic growth retarded, WF/Tgr) GH deficiency and contrasting hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) expression were implanted sc with GC cells. These form encapsulated rat GH-secreting tumors that maintain high plasma rat GH levels for several weeks. In both strains, GC cell tumors stimulated growth and raised GHBP levels, without affecting pituitary GH content. In DW rats, GC cell implants increased SRIH expression in the periventricular nucleus (PeV), but not in the arcuate nucleus (ARC), whereas their high GHRH expression in ARC was decreased by GC cells. In contrast, GC cell implants in WF/Tgr rats had little effect on the already high SRIH expression in PeV or low GHRH expression in ARC, although they reduced SRIH expression in ARC. GC cell implants also reduced GH receptor expression in both ARC and PeV in the WF/Tgr dwarves. Thus, chronic GH overexposure stimulates rapid growth in both dwarf strains, but has differential hypothalamic effects in these models. This experimental approach now makes it possible to study the effects of pathophysiological concentrations of GH ranging from dwarfism to acromegaly in the same animal model.

Involvement of dopamine D1 receptors in the control of growth hormone secretion in the rat.

The effects of dopamine on GH release were investigated both in vivo in freely moving intact rats and in rats with a mediobasal hypothalamic lesion, and in vitro in a perifusion system using dispersed male rat pituitary cells kept in primary culture. In vivo, dopamine (5 mg/kg body weight) induced a rapid and very transient increase in plasma GH levels in lesioned but not in intact rats. This increase was markedly inhibited by a prior injection of the D1 antagonist SCH 23390 (0.5 mg/kg) but not of the D2 antagonist domperidone (0.5 mg/kg). The D1 agonist SKF 38393 induced a dose-dependent stimulation of GH release in lesioned rats, and the effect obtained with a dose of 5 mg/kg was abolished by pretreatment with SCH 23390 (0.5 mg/kg). In vitro, dopamine (0.1 mumol/l) and SKF 38393 (0.1 mumol/l) provoked a rapid and reversible release of GH from superfused rat pituitary cells; this effect was markedly inhibited by simultaneous superfusion of SCH 23390 (1 mumol/l). These findings indicate that dopamine can stimulate basal GH release at the pituitary level and that this stimulation is mediated by D1 but not by D2 receptors. They also support the hypothesis that unidentified hypothalamic neurohormones may modulate this effect.

Monoaminergic regulation of growth hormone in the rat.

The administration of gamma-hydroxybutyrate (GHB) induced a consistent secretory episode of growth hormone (GH) in the morning followed by basal levels of secretion of GH for several hours. The measurement of endogenous noradrenaline, dopamine and serotonin (5-HT) following infusion of GHB showed that dopamine concentrations were significantly increased in the striatum; at the level of the hypothalamus, however, no significant differences were observed between control and GHB-treated animals. The data reported in this study are consistent with the interpretation that the neurotransmitter regulation of GH release and the modulation of hypothalamic glucoreceptor systems are not fundamentally different in rodents and primates. Clonidine, and alpha-adrenergic agonist, enhanced the peak of GH observed in the morning and caused a rapid increment of GH during the period when it was normally at basal levels. Under the same experimental conditions, dopamine agonists, apomorphine and levodopa, had no effect on GH secretion. The inhibition of catecholamine synthesis by alpha-methyl-p-tyrosine blocked the secretory episode of GH following administration of GHB and after insulin hypoglycaemia whereas the GH rise induced by clonidine was unchanged. The inhibition of 5-HT synthesis by p-chlorophenylalanine also suppressed the secretory episode of GH seen in the morning and the release of GH induced by hypoglycaemia; both being partly restored in animals pretreated with 5-hydroxytryptamine.

Continuous intracerebroventricular administration of a corticotropin releasing hormone antagonist amplifies spontaneous growth hormone pulses in the rat.

Involvement of endogenous corticotropin releasing hormone (CRH) in the regulation of spontaneous growth hormone (GH) secretion was investigated. A CRH antagonist, alpha helical CRH 9-41, was intracerebroventricularly infused for 36 h at a rate of 1 microgram/0.5 microliter/h to freely moving, cannulated adult male rats. Serial blood samples were drawn every 20 min for the last 8 hours of alpha helical CRH 9-41 infusion. The treatment induced a marked increase in GH peak amplitude without affecting either trough levels or numbers of peaks. In parallel, levels of growth hormone releasing hormone (GHRH) mRNA in the arcuate nucleus, but not of somatotropin release inhibiting hormone (SRIH) mRNA in the periventricular and arcuate nuclei, were increased. These data suggest that, in addition to its action in the stress-induced inhibition of GH secretion through regulation of periventricular SRIH neurons, CRH can also act as a modulator of endogenous GH secretion through regulation of arcuate GHRH neurons. Whether the modulatory effects of CRH on GHRH neurons are direct or indirect remains to be established.

Interaction of beta-adrenergic agonists and antagonists with the stimulation of growth hormone release induced by clonidine or by morphine in the rat.

The beta-adrenergic agonist, isoprenaline, and antagonist, propranolol, had no effect on the delayed basal secretion of GH consistently observed in rats treated with the narco-analgesic gamma-hydroxybutyrate. Under the same experimental conditions, GH release was distinctly stimulated by infusion of the alpha-adrenergic agonist, clonidine, and by morphine; both responses were dose-dependent. The effects of beta-adrenergic agonists and antagonists on these GH responses were as follows: in rats pretreated with isoprenaline -the GH release induced by clonidine and morphine was abolished whereas it was enhanced in rats pretreated with propranolol. These data confirmed and extended previous reports from this laboratory on the inhibitory role of beta-adrenergic receptors on GH regulation.

A second endogenous molecular form of mammalian hypothalamic luteinizing hormone-releasing hormone (LHRH), (hydroxyproline9)LHRH, releases luteinizing hormone and follicle-stimulating hormone in vitro and in vivo.

In vitro and in vivo release of pituitary hormones were studied in the presence of (hydroxyproline9)LHRH ((Hyp)LHRH), a newly characterized endogenous molecular form of LHRH. Results were compared to those obtained with LHRH itself. (Hyp)LHRH, as LHRH, stimulated both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in a homothetic manner. The hydroxylated compound was, however, 24 times (in vitro) and 5 times (in vivo) less potent than LHRH. The lower activity of (Hyp)LHRH than of LHRH in the in vitro assay correlated well with a 28-fold lesser potency in a binding test using pituitary membrane preparations. The higher relative potency and the prolonged effect of (Hyp)LHRH in the in vivo test were related to a lesser susceptibility of the hydroxylated form to proteolytic degradation. Effects of LHRH and of (Hyp)LHRH were not additive, both peptides were equally able to desensitize gonadotrophs to a subsequent challenge by the other. Taken together, these observations suggest that both forms of LHRH act at the same receptor site. The lesser affinity of the hydroxylated compound is compensated to a certain extent by its higher resistance to enzymatic degradation. It is concluded that in spite of its lesser potency, (Hyp)LHRH may participate in the regulation of gonadotropins.

Temperature and protein kinase C modulation of gonadotropin-releasing hormone receptors in pituitary cells from intact or castrated male rats.

Abstract Binding constants of [(125) I]Des-Gly(10)-(D-Ala(6))-gonadotropin-releasing hormone-ethylamide (GnRHa) to dispersed pituitary cells were evaluated in a 4-day culture. Cells were sampled either from intact or from castrated male rats and binding was measured at various temperatures before or after treatment with phorbol-12-myristate-13-acetate (PMA) or 1-5-(isoquinolinyl-sulfoxyl) 2-methylpiperazine (H7), which activate or inhibit, respectively, protein kinase C (PKC). In cells from intact rats incubated with increasing concentrations of ligand at 21 degrees C for 25 min, the Scatchard plot was not linear and calculation of the Hill coefficient (N(H)) was indicative of positive cooperativity (N(H)= 1.26 +/- 0.02). Such non-linearity was not observed when cells were incubated at 0.5 degrees C for 3 h. In that condition the maximal number of binding sites measured at equilibrium (B(max)) increased (15.1 +/- 0.05 versus 9.3 +/- 0.5 fmoles x mg(-1) proteins at 21 degrees C). Two control experiments permitted us to rule out the possibility that lower B(max) at 21 degrees C might reflect internalization: 1) Cells were first incubated with the ligand at 21 degrees C for 25 min and subsequently for 3 additional hours at 0.5 degrees C. Preincubation did not affect the B(max) obtained at 0.5 degrees C; 2) when the radioligand bound to the cell surface was washed out with an acidic buffer, only 13% of the specific radioactivity was retained irrespective of the ligand concentration applied, a much lower value than the 40% binding difference observed between 0.5 degrees C and 21 degrees C. When the cells were incubated with PMA, the Scatchard plot was linearized and the B(max) recorded at 21 degrees C increased by 50% over control cells (13 +/- 0.7 fmoles x mg(-1) proteins). Conversely, inhibition of PKC by H7, a preferential PKC inhibitor, was ineffective. In contrast, cells sampled from castrates exhibited linear and comparable Scatchard plots at either 0.5 degrees or 21 degrees C, with B(max) values of 14.4 +/- 0.3 and 15 +/- 0.34 fmoles x mg(-1) proteins, respectively. PKC activation did not affect binding in that model, but H7 decreased the number of sites (B(max)= 10.7 +/- 0.9) and induced appearance of positive cooperativity (N(H)= 1.36 +/- 0.07). Taken together, these experiments reveal a pool of GnRH receptors in the pituitary of intact rats that recognizes the ligand in a phosphorylation-dependent manner. These binding sites also became evident when biological properties of the membrane were modified by temperature or cell homogenization. After castration, PKC activation was no longer a prerequisite for recruitment of the total population of receptors whereas protein kinase inhibition resulted in a reduction of maximal binding. Finally, our observations demonstrate that GnRH binding can exhibit positive cooperativity, either on normal cells or on cells from castrates after protein kinase inhibition, suggesting that such a cooperativity is not related to a GnRH-dependent phosphorylation.

Differential response of lactotrophs and somatotrophs to a joint application of vasoactive intestinal Peptide and thyrotrophin-releasing hormone in the rat.

Abstract We have studied the responses of growth hormone, prolactin and thyrotrophin to vasoactive intestinal peptide and thyrotrophin-releasing hormone added either together or separately under various in vivo (free-moving, intact animals or rats bearing hypothalamic lesions) or in vitro (perifused anterior pituitary fragments) conditions. Thyrotrophin-releasing hormone or vasoactive intestinal peptide stimulated prolactin release in all cases and the individual effects of both peptides were additive when administered together. Vasoactive intestinal peptide, but not thyrotrophin-releasing hormone, induced a growth hormone response in intact rats. In contrast, both peptides stimulated growth hormone release in lesioned rats as well as in perifused anterior pituitary fragments. In that case, the effect of vasoactive intestinal peptide on growth hormone release was not additive with that of thyrotrophin-releasing hormone, either in vivo or in vitro. Thyrotrophin release was slightly stimulated by vasoactive intestinal peptide, whereas it responded markedly to thyrotrophin-releasing hormone. The effect of thyrotrophin releasing-hormone was not further affected by simultaneous vasoactive intestinal peptide administration. These data suggest that additivity of the effect of second messengers generated as a response to thyrotrophin-releasing hormone and vasoactive intestinal peptide are specific of the target cell type.

Activation of locus coeruleus somatostatin receptors induces an increase of growth hormone release in male rats.

Noradrenergic neurons of the locus coeruleus (LC) negatively regulate the endogenous rhythmicity of growth hormone (GH) secretion. These neurons express high concentrations of receptors for somatostatin (SRIH) and galanin (GAL), two neuropeptides which can affect electrical activity of LC neurons and also centrally modulate plasma GH levels. We thus investigated whether somatostatin and galanin receptors located in the LC are involved in GH regulation. Pulsatile patterns of endogenous GH secretion were monitored after unilateral infusion of the peptides into the lateral ventricle (ICV) or into the LC, after lesion of contralateral LC neurons by 6 hydroxydopamine. Neither unilateral LC lesions nor administration of saline affected GH release. When administered ICV, both SRIH (5 micrograms/microliter/15 min) and GAL (1 microgram/microliter/15 min) resulted in a marked increase in GH secretion. Infusion of SRIH into the LC induced a significant but weaker stimulation of plasma GH as compared to ICV injections. In contrast, infusion of GAL into the LC was ineffective. These results indicate that somatostatin can exhibit direct effects on noradrenergic neurons of the LC involved in GH regulation, whereas central effects of galanin on the hormone are mediated by distinct structures.

6-hydroxydopamine lesions of the locus coeruleus induce a paradoxical increase in growth hormone secretion in male rats.

While the pharmacology of noradrenaline effects on growth hormone (GH) secretion has been extensively studied, the precise localization of noradrenergic neurons involved remains unclear. In the present work, we investigated whether A6 noradrenergic neurons located in the locus coeruleus can play a role in the rhythmic pattern of GH secretion or in the sensitivity of the hormone response to different external challenges. Three weeks after bilateral 6-hydroxydopamine injections (8µg/3µl) into the locus coeruleus, hypothalamic noradrenaline concentrations were reduced by 60%. Pulsatile GH secretory patterns were observed in unanaesthetized, freely moving control, sham-operated or locus coeruleus-lesioned male rats. The amplitude of the pulses and the area under the curves during the 6- or 12-h sampling period were twice as high in locus coeruleus-lesioned than in control and sham-operated rats. In contrast, trough levels of GH and intervals between GH peaks were similar in all groups. Prolactin, adrenocorticotrophin, thyroid-stimulating hormone and luteinizing hormone plasma levels were not affected by the lesion. GH responses to two centrally acting drugs i.e. clonidine (2.5, 5 and 10µg/100g body wt) and morphine (200µg/100g body wt) were also highly amplified in locus coeruleus-lesioned rats. In contrast, GH responses to two peptides directly acting on somatotrophs i.e. GH-releasing factor (0.05 and 1.25µg/100g body wt) and vasoactive intestinal peptide (1.5µg/100g body wt) were the same in sham-operated and lesioned animals. These data suggest that noradrenergic inputs from the locus coeruleus exert a selective inhibitory influence on GH secretion through centrally mediated mechanisms.

Neuropeptide-E-I antagonizes the action of melanin-concentrating hormone on stress-induced release of adrenocorticotropin in the rat.

The physiological role of melanin-concentrating hormone (MCH) in mammals is still very elusive, but this peptide might participate in the central control of the hypothalamopituitary adrenal (HPA) axis during adaptation to stress. Cloning and sequencing of the rat MCH (rMCH) cDNA revealed the existence of additional peptides encoded into the MCH precursor. Among these peptides, neuropeptide (N) glutamic acid (E) isoleucine (I) amide (NEI) is co-processed and secreted with MCH in rat hypothalamus. In the present work we examined: (1) The pattern of rMCH mRNA expression during the light and dark conditions in the rat hypothalamus and (2) The effect of intracerebroventricular (ICV) injections of rMCH and NEI in the control of basal or ether stress-modified release of corticotropin (ACTH), prolactin (PRL) and growth hormone (GH) secretion in vivo in light-on and light-off conditions. Our data indicate that rMCH mRNA levels do not change during the light-on period, but increase after the onset of darkness. Either alone or co-administered, rMCH and NEI do not modify basal secretion of GH and PRL at any time tested nor do they alter ether stress-induced changes in these two hormonal secretions. At the end of the light on period corresponding to the peak of the circadian rhythm in ACTH, administration of rMCH but not NEI leads to a decrease in ACTH levels while MCH is not effective during the light off period of the cycle (i.e. when basal ACTH levels are already low). Using a moderate ether induced stress, ACTH levels are only stimulated during the dark phase of the cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic octreotide treatment on GH secretory dynamics and tumor growth in rats bearing an ectopic somatotroph (GC) tumor.

The effects of octreotide, a long-acting somatostatin agonist selective of the sstr2/sstr3/sstr5 receptor subtypes, on ectopic GH secretion and tumor growth were investigated in Wistar-Furth female rats implanted with GH secreting (GC) cells which express mostly somatostatin receptors of the sstr1 and sstr2 subtypes. Octreotide dose dependently inhibited thymidine incorporation (-57%) and GH secretion (-41%) from GC cells in culture. In vivo, 6 weeks after GC cell implantation, plasma GH, IGF-1 and insulin levels were highly elevated. Cluster analysis of GH secretory dynamics revealed that GH secretion was less pulsatile in GC-implanted than in control animals. Furthermore, in GC-implanted animals, passive immunization either with SRIH or GHRH antisera, did not affect GH plasma levels. Three weeks after GC cell implantation, when tumors became palpable, octreotide (1 micrograms/h/kg BW) or saline was infused constantly for three weeks by osmotic minipumps. In octreotide treated rats, GH, IGF-1 and insulin levels were not different from sham-implanted animals and tumors weight were reduced by 80%. High affinity somatostatin binding sites were found in equivalent amounts on tumors from octreotide-treated or saline-treated animals. These findings indicate that GH secretion in GC-rats is mainly derived from the tumors and independent of hypothalamic control and that octreotide reduces both GH secretion and tumor growth. We conclude that the GC-implanted rat represents a good animal model to test the antisecretory and antitrophic properties of somatostatin analogs in vivo.

Vasoactive intestinal peptide induces a transient release of growth hormone in the rat.

Effects of vasoactive intestinal peptide (VIP) on growth hormone (GH) secretion were investigated both in vivo on freely moving, intact or mediobasal hypothalamic lesioned rats, and in vitro in incubation or superfusion systems of anterior pituitary tissue. In vivo, IV injection of VIP induced a rapid but transient increase in plasma GH levels in all animals and in vitro, VIP stimulated GH release from incubated or superfused rat pituitaries in a concentration dependent manner. This increase was potentiated by forskolin, a potent activator of adenylate cyclase. These findings indicate that VIP exerts a direct stimulating action on somatotrophs and that the effect seems to imply a coupling of VIP receptors with cAMP production.

125I-[Tyr0,D-Trp8]somatostatin-14 binding sites in the locus coeruleus of the rat are located on both ascending and descending projecting noradrenergic cells.

Radioautographic determinations of 125I-[Tyr0,D-Trp8]somatostatin-14 (125I-SRIF) binding sites were performed on frozen serial sections of the locus coeruleus (LC) of control rats and of rats subjected to either bilateral microinjections of 6 hydroxydopamine (6-OHDA) into the LC or unilateral microinjection into the ascending noradrenergic bundles. These experiments were performed in order to determine whether 125I-SRIF binding was localized to noradrenergic-containing cells and in which regions the cells which contain the binding sites are projecting. The extent of the lesions was assessed by measuring norepinephrine (NE) levels in the hippocampus (88% decrease as compared to sham-operated animals) for bilateral LC lesions and in the frontal cortex (87% reduction vs. contralateral side) for unilateral bundle lesions. In control rats, 125I-SRIF binding sites were restricted to the boundaries of the LC and followed closely the distribution of tyrosine hydroxylase-labeled cells. Three weeks after bilateral injections of 6-OHDA, 125I-SRIF binding decreased by 79% in all regions of the LC. In contrast, unilateral destruction of the ascending noradrenergic bundles resulted in a moderate decrease only in the middle part of the LC with a more important effect in the dorsal (55%) than in the ventral (24%) portion of the nucleus. These data demonstrate that: 1) most SRIF receptors in the LC are located in the vicinity of NE-containing cell bodies and 2) NE-containing cells bearing SRIF receptors project to the forebrain as well as to other terminal areas located more caudally in the brain. These data suggest a general role for SRIF in the control of the multiple functions of the LC.