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The distribution of specifically labeled neurotensin (NT) binding sites was examined by light and electron microscopic radioautography in the ventral tegmental area (VTA) and nucleus interfascicularis of the rat following incubation of lightly prefixed midbrain slices with the monoiodinated ligand, 125I-(Tyr3)-NT. Film radioautograms of whole 125I-NT-incubated slices exhibited intense NT displaceable binding throughout the VTA and interfascicular nucleus. In light microscopic radioautographs from 1-microns-thick sections taken from the surface of the slices, the label was found to be present both inside and outside neuronal perikarya. Probability circle analysis of silver grain distribution in electron microscopic radioautographs confirmed that a significant proportion (greater than 20%) of the specifically labeled binding sites was intraneuronal. The frequent association of these sites with profiles of rough endoplasmic reticulum or Golgi apparatus suggested that they corresponded in part to receptors undergoing synthesis and/or glycosylation. The remainder was associated with neuronal and/or glial plasma membranes, as attested by comparing the distribution of grains overlying apposed cellular elements with the distribution of hypothetical grains originating from randomly distributed membrane bound radioactive sources. Although the resolution of the technique did not make it possible to ascribe labeled membrane-bound receptors to either one of the apposed plasma membranes, their frequent association with interfaces involving the plasmalemma of perikarya and dendrites, together with the occurrence of silver grain alignments along the membrane of certain somata and dendrites suggested that a proportion of them was associated with the perikarya and dendrites of a subpopulation of ventral tegmental neurons. Interestingly, these perikaryal and dendritic receptors were not exclusively present on, or even concentrated opposite, abutting axon terminals but instead were more or less evenly distributed along the plasma membrane. Only an exceedingly small proportion was found to be associated with synaptic junctions. Such a low incidence makes it unlikely that only the synapse-linked binding sites correspond to functional receptors. On the contrary, the dispersion of labeled receptors seen here along the plasma membrane of presumptive dopamine neurons suggests that NT acts mainly in a paracrine or parasynaptic fashion in the ventral midbrain tegmentum.

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Pliocene changes in the vertical water mass structure of the western South Atlantic are inferred from changes in benthic foraminiferal assemblages and stable isotopes from DSDP Holes 516A, 517, and 518. Factor analysis of 34 samples from Site 518 reveals three distinct benthic foraminiferal assemblages that have been associated with specific subsurface water masses in the modern ocean. These include a Nuttalides umbonifera assemblage (Factor 1) associated with Antarctic Bottom Water (AABW), a Globocassidulina subglobosa-Uvigerina peregrina assemblage (Factor 2) associated with Circumpolar Deep Water (CPDW), and an Oridorsalis umbonatus-Epistominella exigua assemblage associated with North Atlantic Deep Water (NADW). Bathymetric gradients in Δ 13 C between Holes 516A (1313 m), 517 (2963 m), and 518 (3944 m) are calculated whenever possible to monitor the degree of similarity and/or difference in the apparent oxygen utilization (AOU) of water masses located at these depths during the Pliocene. Changes in bathymetric Δ 13 C gradients coupled with benthic foraminiferal assemblages record fundamental changes in the vertical water mass structure of the Vema Channel during the Pliocene from 4.1 to 2.7 Ma.At Site 518, the interval from 4.1 to 3.6 Ma is dominated by the N. umbonifera (Factor 1) and O. umbonatus-E. exigua (Factor 3) assemblages. The Δ 13 C gradient between Holes 518 (3944 m) and 516A (1313 m) undergoes rapid oscillations during this interval though no permanent increase in the gradient is observed. However, δ13 C values at Site 518 are clearly lighter during this interval. These conditions may be related to increased bottom water activity associated with the re-establishment of the West Antarctic Ice Sheet in the late Gilbert Chron (-4.2 to 3.6 Ma) (Osborn et al., 1982).The interval from 3.6 to 3.2 Ma is marked by a dominance of the G. subglobosa-U. peregrina (Factor 2) assemblage and lack of a strong Δ 13 C gradient between Holes 518 (3944 m) and 516A (1313 m). We suggest that shallow circumpolar waters expanded to depths of a least 3944 m (Site 518) during this time.The most profound faunal and isotopic change occurs at 3.2 Ma, and is marked by dominance of the N. umbonifera (Factor 1) and O. umbonatus-E. exigua (Factor 3) assemblages, a l.l‰ enrichment in δ 18 θ, and a large negative increase in the Δ 13 C gradient between Holes 518 and 516A. These changes at Site 518 record the vertical displacement of circumpolar waters by AABW and NADW. This change in vertical water mass structure at 3.2 Ma was probably related to a global cooling event and/or final closure of the Central American seaway. A comparison of the present-day δ 13 C structure of the Vema Channel with a reconstruction between 3.2 and 2.7 Ma indicates that circulation patterns during this late Pliocene interval were similar to those of the modern western South Atlantic.

Stable isotopic analyses (18 O/ 16 O, 13 C/ 12 C) of both benthic and planktonic foraminifers from DSDP Holes 516A and 517 appear to reflect changing paleoclimatic and paleoceanographic conditions in the South Atlantic Ocean during the Pliocene. The δ 18 θ records of Cibicides wuellerstorfi and Globigerinoides sacculifer do not vary in phase with one another, indicating that the δ 18 θ of C. wuellerstorfi is reflecting changing glacial ice volumes, but the δ 18 θ of G. sacculifer is being influenced more by other factors, such as variable sea-surface temperatures and salinities.A net depletion in 18 O and a series of very low-amplitude fluctuations characterize the late Pliocene planktonic δ 18 θ record. The stability of this section may be related to increasing surface-water temperatures in middle southern latitudes during northern hemisphere glacial ice buildup caused by differences in the phasing of the orbital precessional cycle between the northern and southern hemispheres.Hole 516A is presently located in an area of strong δ 13 C gradients in the water column, and a similar situation probably prevailed during the Pliocene. A record of the difference between the δ 13 C of C. wuellerstorfi and G. sacculifer (Δ 13 C) reflects times of increased or decreased similarity in δ 13 C between Circumpolar Water and subtropical surface waters throughout the Pliocene. Periods of increased or decreased Δ 13 C may reflect: 1) changes in water mass boundaries because of expansion or contraction of a particular water mass, or 2) changes in the partitioning of 13 C within the various components of the global carbon reservoir. These changes may be associated with glacial/interglacial climatic changes, such as the initiation of northern hemisphere glaciation.

The distribution of mu opioid receptors was examined by light and electron microscopic autoradiography in the locus coeruleus of the rat following in vitro labelling with the iodinated agonist [125I]FK-33824. At the light microscopic level, specific mu opioid binding sites were concentrated over the perikarya and dendrites of neurons that were tyrosine hydroxylase-immunopositive in adjacent sections. Accordingly, both the number of tyrosine hydroxylase-immunoreactive neurons and the density of labelled mu receptors decreased markedly throughout the rostrocaudal extent of the nucleus following treatment with the catecholaminergic neurotoxin 6-hydroxydopamine. By electron microscopy, specifically labelled receptors were detected both inside and on the surface of locus coeruleus neurons. Intracellular sites were found by resolution circle analysis to be highly concentrated within the endoplasmic reticulum and Golgi apparatus, suggesting that the ligand recognizes both glycosylated and preglycosylated forms of receptor. The remainder were found mainly over the cytoplasmic matrix or intracytoplasmic vesicles, and were attributed to newly synthesized or recycled receptors in transit. Cell surface receptors were present over both dendritic and perikaryal membranes of noradrenergic cells. These were most highly concentrated opposite abutting axon terminals, suggesting the existence of receptor 'hot spots' at sites of putative endogenous ligand release. However, only a small proportion of these sites was associated with synaptic specializations. Furthermore, an important contingent was detected opposite non-axonal elements, such as dendrites and glial cells, suggesting that mu opioid ligands act mainly parasynaptically on locus coeruleus neurons. Finally, approximately 5% of labelled receptors were associated with axoglial interfaces, indicating that a minor action of mu opioids in the locus may be presynaptic and/or glial.

Studies were performed to substantiate the hypothesis that a physiological change, apart from the rise in blood pressure, occurs in two-kidney hypertensive rats. Both the slow development of hypertension following renal arterial constriction versus its rapid reversal following removal of the constriction and the early increase in plasma renin activity which subsides in the chronic hypertensive phase suggest such a progressive change. We studied the development of hypertension following initial renal arterial constriction (clipping) and after reclipping in rats that had been relieved of two-kidney hypertension by unclipping for 2 or 21 days. Full hypertensive blood pressure levels were established within 1-2 hours after reclipping in 2-day undipped rats, but similar levels were not reached in either of the other two groups for at least 1 week. These changes in response to renal arterial constriction were paralleled by differences in responsiveness to hog renin and angiotensin infusions. Plasma renin activity 1 hour after clipping or reclipping was adequate to account for the observed blood pressure increases in all groups. These data suggest that (1) a physiological change resulting in increased vasoresponsiveness to renin and angiotensin occurs concomitantly with the development of two-kidney hypertension and (2) this type of hypertension is dependent on both renin and increased sensitivity to angiotensin. Moreover, we suggest that study of recently undipped, normotensive rats may help to uncover the causes for the angiotensin sensitivity change. KEY WORDS removal of constriction vasopressor sensitivity renal arterial constriction blood pressure reconstriction plasma renin activity• In rats made hypertensive by unilateral renal arterial constriction without contralateral nephrectomy (two-kidney hypertension) (1), the development of hypertension has been attributed to the renal secretion of renin (2, 3). Plasma renin activity in such rats increases maximally soon after clipping and then declines (3), although the onset of hypertension is often very gradual (1). These observations suggest that (1) the maintenance of hypertension is not attributable to renin or (2) a physiological change occurs over time which allows lesser concentrations of renin to maintain the full level of hypertension. We suspect that renin or some other renal factor is responsible for the maintenance of the hypertension, since removal of the arterial clip or ablation of the clipped kidney causes a prompt return of blood pressure to normal (4, 5). In this paper, we attempted to substantiate the existence of an altered physiological state. For convenience, the terms clipping, unclipping, and reclipping are used throughout this paper to refer to producing, removing, and reintroducing a constriction of a renal artery with a silver clip. The terms clipped, undipped, and reclipped rats are likewise used to refer to the condition of the artery supplying the left kidney in each rat. MethodsGeneral.-The rats used for these studies were Sprague...