Use of dopamine-beta-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs.

Norepinephrine (NE) is thought to play an important role in the pathophysiology of depression, and in the mechanism of action of antidepressant compounds. Previously, we created mice that are unable to synthesize NE and epinephrine due to targeted disruption of the dopamine-beta-hydroxylase gene (Dbh). To specifically test the role of NE in mediating behavioral changes elicited by antidepressants, these mice were examined in the forced swim test. There was no difference in baseline immobility scores in the forced swim test between Dbh(+/-) mice, which have normal levels of NE, and Dbh(-/-) mice. However, the Dbh(-/-) mice failed to demonstrate antidepressant-like behavioral effects following the administration of several classes of antidepressants. These included the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion. In addition, desipramine significantly reduced immobility in the Dbh(-/-) mice following pretreatment with the synthetic NE precursor L-threo-3,4-dihydroxyphenylserine, but not saline. Biochemical studies showed that there was no significant difference in the regional brain levels of NE transporter immunoreactivity or monoamine oxidase activity, the primary targets for most of the compounds examined. Taken together, these data show that the use of mice that lack endogenous NE may be an important strategy for unraveling the role of NE in tests sensitive to the effects of various psychotherapeutic agents.

Defective epinephrine and growth hormone responses in type I diabetes are stimulus specific.

The counterregulatory hormone responses to hypoglycemia and a non-glucose stimulus, exercise, were evaluated in 18 subjects with type I diabetes and in 9 normal controls. Subjects with diabetes had no overt neuropathy, with R-R variations and postural plasma norepinephrine increments that were similar to those of controls. The diabetic subjects exhibited normal increments in plasma growth hormone (GH), norepinephrine, and cortisol but blunted or absent responses in plasma epinephrine and glucagon when hypoglycemia was severe (less than 40 mg/dl). During a 60-min clamped reduction in plasma glucose at approximately 65 mg/dl, plasma GH and epinephrine increased 6- to 15-fold in controls but 2- to 4-fold in diabetics (P less than .05). However, when subjects were exercised at this plasma glucose level (50 W for 10 min), plasma epinephrine and GH in diabetics rose markedly by 150-400% to attain the peaks reached by the controls. Plasma norepinephrine and cortisol increased to similar levels in both groups, and plasma glucagon was not significantly changed. We conclude that epinephrine and GH secretion in response to hypoglycemia are reduced in type I diabetes but that these defects are stimulus specific because the responses to exercise are not reduced.

Comparison of pituitary-thyroid function in patients with endstage renal disease and in age- and sex-matched controls.

The response to i.v. bolus thyrotropin-releasing hormone (TRH) of 14 dialysis patients with end-stage renal disease (ESRD) was compared to the response of 14 age- and sex-matched renal clinic patients (controls) with normal renal function (serum creatinine concentrations less than 1.2 mg/dl). The mean basal serum levels of thyrotropin (TSH) were similar in the two groups. There was no difference between the two groups in the mean maximal increase in TSH after TRH (6.3 microU/ml and 7.2 microU/ml in ESRD and control groups, respectively); The rate of fall in TSH from 60 to 90 min after TRH was slower in the ESRD group than in the controls. The mean increase in serum triiodothyronine (T3) concentration after TRH was similar in both groups (25.4 ng/dl, ESRD; 18.4 ng/dl, controls). As previously reported, basal serum T3 content was subnormal in the ESRD patients. Serum thyroxine (T4) concentrations were comparable in control and ESRD groups and did not change significantly during the 90-min TRH test in either group. We conclude that ESRD patients, clinically stable on dialysis, have normal pituitary TRH responsiveness and normal thyroidal response to endogenous TSH secretion, as compared with an age- and sex-matched group of patients with normal renal function. The results of this study support the contention that ESRD patients are eumetabolic.

Synthesis of secretory component by colonic neoplasms.

The secretory component (SC) polypeptide chain of secretory immunoglobulin A can be considered as a differentiation marker in that it is normally synthesized in the non-mucus-containing columnar epithelial cells, but not goblet cells, of the large intestine. With this in mind, we have studied the expression of SC in 36 colonic adenocarcinomas and 15 polyps (adenomatous and villous) by the fluorescent antibody technique. As in the normal mucosa, the synthesis of SC in tumors found in non-mucus-containing columnar cells and was absent from goblet cells. However, in several well-differentiated carcinomas it appeared that columnar cells contained both SC and mucin; these cells could be analogous to the normal mucosal precursor of both cell types. SC was synthesized throughout all adenomatous polyps and villous adenomas with the exception of some atypical nonmucinous areas of adenomatous polyps. Secretory component synthesis by carcinomas was associated with mucus production, although goblet cells did not contain SC. The presence of SC also correlated with the degree of differentiation. Secretory component was absent from half of the carcinomas as well as from atypical nonmucinous areas of polyps, and this could represent one of the earliest changes associated with the development of malignancy.