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Neurons that synthesize melanin-concentrating hormone (MCH) colocalize GABA, regulate energy homeostasis, modulate water intake, and influence anxiety, stress, and social interaction. Similarly, vasopressin and oxytocin can influence the same behaviors and states, suggesting that these neuropeptides may exert part of their effect by modulating MCH neurons. Using whole cell recording in MCH-green fluorescent protein (GFP) transgenic mouse hypothalamic brain slices, we found that both vasopressin and oxytocin evoked a substantial excitatory effect. Both peptides reversibly increased spike frequency and depolarized the membrane potential in a concentration-dependent and tetrodotoxin-resistant manner, indicating a direct effect. Substitution of lithium for extracellular sodium, Na(+)/Ca(2+) exchanger blockers KB-R7943 and SN-6, and intracellular calcium chelator BAPTA, all substantially reduced the vasopressin-mediated depolarization, suggesting activation of the Na(+)/Ca(2+) exchanger. Vasopressin reduced input resistance, and the vasopressin-mediated depolarization was attenuated by SKF-96265, suggesting a second mechanism based on opening nonselective cation channels. Neither vasopressin nor oxytocin showed substantial excitatory actions on lateral hypothalamic inhibitory neurons identified in a glutamate decarboxylase 67 (GAD67)-GFP mouse. The primary vasopressin receptor was vasopressin receptor 1a (V1aR), as suggested by the excitation by V1aR agonist [Arg(8)]vasotocin, the selective V1aR agonist [Phe(2)]OVT and by the presence of V1aR mRNA in MCH cells, but not in other nearby GABA cells, as detected with single-cell RT-PCR. Oxytocin receptor mRNA was also detected in MCH neurons. Together, these data suggest that vasopressin or oxytocin exert a minimal effect on most GABA neurons in the lateral hypothalamus but exert a robust excitatory effect on presumptive GABA cells that contain MCH. Thus, some of the central actions of vasopressin and oxytocin may be mediated through MCH cells.

Hepatic alcohol dehydrogenase (ADH) activity is higher in female than in male rats. Although sex steroids, thyroid, and growth hormone (GH) have been shown to regulate hepatic ADH, the mechanism(s) for sexual dimorphic expression is unclear. We tested the possibility that the GH secretory pattern determined differential expression of ADH. Gonadectomized and hypophysectomized male and female rats were examined. Hepatic ADH activity was 2.1-fold greater in females. Because protein and mRNA content were also 1.7- and 2.4-fold greater, results indicated that activity differences were due to pretranslational mechanisms. Estradiol increased ADH selectively in males, and testosterone selectively decreased activity and mRNA levels in females. Effect of sex steroids on ADH was lost after hypophysectomy; infusion of GH in males increased ADH to basal female levels, supporting a role of the pituitary-liver axis. However, GH and L-thyroxine (T4) replacements alone in hypophysectomized rats did not restore dimorphic differences for either ADH activity or mRNA levels. On the other hand, T4 in combination with intermittent administration of GH reduced ADH activity and mRNA to basal male values, whereas T4 plus GH infusion replicated female levels. These results indicate that the intermittent male pattern of GH secretion combined with T4 is the principal determinant of low ADH activity in male liver.

Melanin-concentrating hormone (MCH) and alpha-melanocyte-stimulating hormone (alpha-MSH) demonstrate opposite actions on skin coloration in teleost fish. Both peptides are present in the mammalian brain, although their specific physiological roles remain largely unknown. In this study, we examined the interactions between MCH and alpha-MSH after intracerebroventricular administration in rats. MCH increased food intake in a dose-dependent manner and lowered plasma glucocorticoid levels through a mechanism involving ACTH. In contrast, alpha-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of alpha-MSH. alpha-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block alpha-MSH binding or the ability of alpha-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain alpha-MSH receptor subtypes. These data suggest that MCH and alpha-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.

The data reviewed establish the presence and important role in body fluid homeostasis of brain atrial natriuretic peptide (ANP) in all vertebrate-species examined. The peptide is localized in neurons in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation, and its receptors are located in regions that contain the peptide. Most, if not all, of the actions of ANP are mediated by activation of particulate guanylyl cyclase with generation of guanosine 3',5'-cyclic monophosphate, which mediates its actions in brain as in the periphery. Although atrial stretch releases ANP from cardiac myocytes, the experiments indicate that the response to acute blood volume expansion is markedly reduced after elimination of neural control. Volume expansion distends baroreceptors in the right atria, carotid-aortic sinuses, and kidney, altering afferent input to the brain stem and hence the hypothalamus, resulting in stimulation via ANPergic neurons in the hypothalamus of oxytocin release from the neurohypophysis that circulates to the right atrium to stimulate ANP release. The ANP circulates to the kidney and induces natriuresis. Atrial natriuretic peptide also induces vasodilation compensating rapidly for increased blood volume by increased vascular capacity. Atrial natriuretic peptide released into hypophysial portal blood vessels inhibits release of adrenocorticotropic hormone (ACTH), thereby decreasing aldosterone release and enhancing natriuresis. Furthermore, the ANP neurons inhibit AVP release leading to diuresis and decreased ACTH release. Activation of hypothalamic ANPergic neurons via volume expansion also inhibits water and salt intake. These inhibitory actions may be partially mediated via ANP neurons in the olfactory system altering salt taste. Atrial natriuretic peptide neurons probably also alter fluid movement in the choroid plexus and in other brain vascular beds. Therefore, brain ANP neurons play an important role in modulating not only intake of body fluids, but their excretion to maintain body fluid homeostasis.

This in vitro study examined the ontogeny of arginine vasopressin (AVP) and arginine vasotocin (AVT) compared with norepinephrine (NE)-mediated contraction in rat thoracic aortas. Aortas from three age groups (2-3 days, 6-7 days, and 12 wk) of Sprague-Dawley rats were used. Ring segment resting length was adjusted to optimize tension developed to a dose that produces half-maximal tension of NE in Krebs solution (pH 7.4, 37 degrees C) and gassed with 95% O2-5% CO2. Cumulative dose-response curves were generated for KCl (5-100 mM), NE (10(-10)-10(-5) M), AVP, and AVT (both 10(-10)-10(-6) M) in the presence and absence of a selective V1 vasopressinergic inhibitor, [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin ([d(CH2)5Tyr(Me)]AVP). A progressive increase in sensitivity among all age groups was found for KCl and NE. There was a slight decrease in sensitivity to both AVP and AVT in the 1st wk. Maximum contractile response to NE increased between 2-3 and 6-7 days, whereas no change was observed for KCl, AVP, or AVT. AVP- and AVT-mediated contractions were selectively inhibited by [d(CH2)5Tyr(Me)]-AVP. These results suggest 1) receptor-mediated contractility is present from 2 days of age for NE, AVP, and AVT; 2) sensitivity to KCl and NE increases progressively during postnatal development, whereas sensitivity to AVP and AVT slightly decreases in the 1st wk with no progressive age-related increase by 12 wk; 3) AVP and AVT mediate contraction via a similar V1-like receptor.

The hypothesis that pituitary hormones are required for increased fibrinogen synthesis after inflammation or endotoxin was tested by measuring plasma fibrinogen concentrations after inflammation or endotoxin in normal and hypophysectomized rats. Animals were divide into groups receiving no exogenous adrenal steroids, low-dose adrenal steroids, or high-dose adrenal steroids. Hypophysectomy failed to prevent fibrinogen levels from rising after intramuscular turpentine (mean 240 mg/100 ml prior to and 556 mg/100 ml 24 h after turpentine). Steroids did not suppress this rise. Endotoxin, 5 mug/100 g, caused a marked rise in fibrinogen in normal rats at 24 h (mean 296 mg/100 ml before endotoxin and 554 mg/100 ml after endotoxin). This dose of endotoxin killed hypophysectomized rats within 12 h. Hoevr, if hypophysectomized rats were protected with high-dose adrenal steroids, then 5 mug of endotoxin per 100 g caused the same fibrinogen rise as in normal rats (mean 299 mg/100 ml before endotoxin and 587 mg/100 ml after endotoxin). Aparently, pituitary hormones are not necessay for increased fibrinogen synthesis after either inflammation or endotoxin in the rat.