Non-NMDA glutamate receptors are present throughout the primate hypothalamus.

To determine the distributions of glutamate receptors throughout the macaque hypothalamus, we utilized highly specific antipeptide antibodies to visualize alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunits (GluR1, GluR2 and GluR3 [designated as GluR2/3], and GluR4); kainate receptor subunits (GluR6 and GluR7, [designated as GluR6/7]), and a metabotropic receptor (mGluR1 alpha). The results indicate that these glutamate receptors are distributed differentially throughout the monkey hypothalamus. alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors are the dominant non-N-methyl-D-aspartate glutamate receptors within the monkey hypothalamus, and the GluR2 subunit is most abundant. GluR1-immunoreactive neurons and neuropil are observed predominantly in the tuberal and mammillary nuclei. GluR2/3-immunoreactive neurons and neuropil have a broader distribution within preoptic, anterior, tuberal, and caudal regions. Separate (but partially overlapping) distributions of GluR1- and GluR2/3-immunoreactive neurons were found, suggesting that the GluR1, GluR2, and/or GluR3 subunits may be coexpressed in subsets of hypothalamic neurons. In contrast, GluR4 immunoreactivity was expressed minimally within monkey hypothalamus. GluR6/7 immunoreactivity was enriched selectively within the suprachiasmatic nucleus. mGluR1 alpha immunoreactivity was present in the mammillary complex. The localization of non-N-methyl-D-aspartate glutamate receptor subunits to neurons throughout the macaque hypothalamus provides further evidence for the glutamatergic regulation of neuroendocrine, autonomic, and limbic circuits. Differential distributions of glutamate receptor subunits may increase the dynamic range of the effects of presynaptic glutamate, allowing for the regulation of several distinct functions subserved by hypothalamic neurons.

Quantitative analysis of tuberoinfundibular tyrosine hydroxylase- and corticotropin-releasing factor-immunoreactive neurons in monkeys raised with differential rearing conditions.

A major goal in assessing biological determinants of behavior lies in studying the effect(s) of rearing on the development of the central nervous system. Specifically, a series of neuroanatomic analyses have been undertaken to identify potential neuropathological changes seen in monkeys exposed to early social deprivation, which leads to profound psychopathology and inappropriate responses to stress. The animals used in this study were either raised with their mother and peers (socially reared) or raised without maternal/peer contact (socially deprived). Within this context, the distribution of tuberoinfundibular dopaminergic neurons in the hypothalamic paraventricular nucleus and arcuate nucleus of rhesus monkeys was determined by immunohistochemistry using an antibody against the enzyme tyrosine hydroxylase, a marker for dopamine-containing systems. Additionally, the distribution of corticotropin-releasing factor-containing neurons in the paraventricular nucleus was assessed immunohistochemically. The majority (97.5%) of dopaminergic neurons in the paraventricular nucleus were parvicellular, with a small (2.5%), but consistently observed population of magnocellular neurons immunoreactive for tyrosine hydroxylase. Within the arcuate nucleus, tyrosine hydroxylase-immunoreactive neurons were similar in morphology to the parvicellular neurons of the paraventricular nucleus. Qualitative assessment of corticotropin-releasing factor-immunoreactive neurons in the paraventricular nucleus revealed a parvicellular population of neurons located in medial aspects of the nucleus, similar to what has been observed in the rat. Quantitative analysis revealed no differences in the number of tyrosine hydroxylase- and corticotropin-releasing factor-immunoreactive neurons between rearing conditions, suggesting that these neurons were not affected, in terms of overall cell counts, by the early environmental insult of social deprivation.

Noradrenergic innervation of the hypothalamus of rhesus monkeys: distribution of dopamine-beta-hydroxylase immunoreactive fibers and quantitative analysis of varicosities in the paraventricular nucleus.

The distribution of noradrenergic processes within the hypothalamus of rhesus monkeys (Macaca mulatta) was examined by immunohistochemistry with an antibody against dopamine-beta-hydroxylase. The results revealed that the pattern of dopamine-beta-hydroxylase immunoreactivity varied systematically throughout the rhesus monkey hypothalamus. Extremely high densities of dopamine-beta-hydroxylase-immunoreactive processes were observed in the paraventricular and supraoptic nuclei, while relatively lower levels were found in the arcuate and dorsomedial nuclei and in the medial preoptic, perifornical, and suprachiasmatic areas. Moderate levels of dopamine-beta-hydroxylase immunoreactivity were found throughout the lateral hypothalamic area and in the internal lamina of the median eminence. Very few immunoreactive processes were found in the ventromedial nucleus or in the mammillary complex. Other midline diencephalic structures were found to have high densities of dopamine-beta-hydroxylase immunoreactivity, including the paraventricular nucleus of the thalamus and a discrete subregion of nucleus reuniens, the magnocellular subfascicular nucleus. A moderate density of dopamine-beta-hydroxylase immunoreactive processes were found in the rhomboid nucleus and zona incerta whereas little dopamine-beta-hydroxylase immunoreactivity was found in the fields of Forel, nucleus reuniens, or subthalamic nucleus. The differential distribution of dopamine-beta-hydroxylase-immunoreactive processes may reflect a potential role of norepinephrine as a regulator of a variety of functions associated with the nuclei that are most heavily innervated, e.g., neuroendocrine release from the paraventricular and supraoptic nuclei, and gonadotropin release from the medial preoptic area and mediobasal hypothalamus. Additionally, quantitative analysis of dopamine-beta-hydroxylase-immunoreactive varicosities was performed on a laser scanning microscope in both magnocellular and parvicellular regions of the paraventricular nucleus of the hypothalamus. The methodology employed in this study allowed for the high resolution of immunoreactive profiles through the volume of tissue being analyzed, and was more accurate than conventional light microscopy in terms of varicosity quantification. Quantitatively, a significant difference in the density of dopamine-beta-hydroxylase-immunoreactive varicosities was found between magnocellular and parvicellular regions, suggesting that parvicellular neurons received a denser noradrenergic input. These differential patterns may reflect an important functional role for norepinephrine in the regulation of anterior pituitary secretion through the hypothalamic-pituitary-adrenal stress axis.

Responses to chemotherapy or chemohormonal therapy in advanced breast cancer patients treated previously with adjuvant chemotherapy. A subset analysis of CALGB Study 8081.

The Cancer and Leukemia Group B (CALGB) evaluated the response to subsequent chemotherapy or chemohormonal therapy in 46 patients with advanced breast cancer treated previously with adjuvant chemotherapy that had been completed 6 months or more before protocol entry. The results were compared with 379 patients in the same study who had not received prior adjuvant chemotherapy. The patients were treated with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF), with or without tamoxifen. There was no difference in response rate, response duration, time to treatment failure, or survival between patients who had received prior adjuvant chemotherapy and those who had not. The addition of tamoxifen to CAF failed to enhance response rates or response durations in all subgroups. Women who relapsed 6 months or more after completion of adjuvant chemotherapy did not have inherently drug-resistant tumors. They responded to standard CAF chemotherapy with the same response rate and survival as patients untreated previously with chemotherapy.

Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.

In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.

Chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil compared to chemotherapy plus hormonal therapy with tamoxifen in the treatment of advanced breast cancer: an interim analysis.

Between February 1980 and August 1982, the Cancer and Leukemia Group B (CALGB) performed a randomized study aimed to compare chemotherapy with CAF (Cyclophosphamide, Adriamycin, 5-Fluorouracil) versus the same chemotherapeutic regimen plus tamoxifen (T-CAF) in stage IV breast cancer patients. Patients were stratified on the basis of menopausal status, estrogen receptors (ER) status, dominant site of metastasis and prior adjuvant treatment. Overall 474 patients were entered into the study of whom 433 were assessable for response. 314 patients were postmenopausal, 85 premenopausal and 34 patients were unknown as far menopausal status was concerned. No difference was evident among postmenopausal patients in overall response rate and duration of responses between T-CAF and CAF (52% vs 50% respectively). Similarly no difference was shown among premenopausal patients, response rates being 63% with T-CAF and 60% with CAF. Lack of benefit from adding T to chemotherapy was seen also according to the different strata, including patients with ER positive tumors. The failure for this combination to be synergistic might reflect an effect of T on tumor kinetics interfering with the activity of chemotherapy.

Test of an orienting-reaction-recovery account of short-interval autonomic conditioning.

The electrodermal and plethysmographic components of the orienting reaction in 24 subjects were examined in a conditioning-analog arrangement (tones and lights patterned analogously to CS and UCS presentations in classical conditioning) in order to test the orienting-reaction-recovery (ORR) account according to which apparent short-interval autonomic conditioning (SIAC) can be completely accounted for by an ORR effect. The form of the test was to see whether ORR following change from a repeatedly presented forward ('CS-UCS') analog would exceed that to change from a backward ('UCS-CS') analog, as is the case in SIAC with CS-alone test trials following repeated CS-UCS versus UCS-CS pairings. The results did not support the ORR account, although they were shown to be consistent with the relevant experimental literature, when critically examined, and to provide internal evidence for the adequacy of the present test of this particular formulation of the ORR account of SIAC.