David L. Margules

Beta-endorphin and endoloxone: Hormones of the autonomic nervous system for the conservation or expenditure of bodily resources and energy in anticipation of famine or feast ☆

The feeding pattern of mammals evolved long before the current era of plentiful food and energy. In those early millenia, species survived which could take advantage of infrequent feasts in order to store enough calories to survive the long intervening periods of famine. As a result, many mammals, including humans, acquired the capacity to eat one half to all of their daily basal calorie requirements in a single 10-minute meal (Owen et al., 1979). If given the opportunity, many people tend toward overeating and gorging themselves. They store the extra nutrient in adipose tissue. This tissue is kept plump so that it can yield back enough calories to provide the ability to survive the inevitable famine. Today in affluent nations obesity is quite common and it represents a preparation for the famine that never comes.

Hibernation: An opioid-dependent state?☆

Hibernation reduces substantially the heart rate of hamsters as well as the respiratory rate, the body temperature and the arousal level. The heart rate is reversed dramatically by the injection of low doses of Naloxone and in some cases the hamster arouses prematurely from hibernation. The effect is not due to the pain of the injection because saline injections do not produce such changes. The effect requires a pre-existing state of hibernation because Naloxone has no cardioacceleratory or arousal effect in non-hibernating hamsters that have had their heart rate and body temperature decreased substantially during hypothermia. These results suggest that endogenous opioids may contribute specifically to the state of hibernation. Moreover, a physiological role may exist for an anti-opioid system in the promotion of arousal from hibernation.

Increased immunoreactive dynorphin and leu-enkephalin in posterior pituitary of obese mice (ob/ob) and super-sensitivity to drugs that act at kappa receptors.

Posterior pituitaries of obese mice (ob/ob) contained significantly more immunoreactive dynorphin (P less than .01) and leu-enkephalin (P less than .01) than their lean littermates. Drinking in obese mice was stimulated by 0.3%, and feeding by 10%, of the dose of ethylketocyclazocine, a kappa receptor agonist, needed to produce extra feeding and drinking in lean mice. Obese mice also showed greater and longer lasting suppression of ingestion after MR-2266, a kappa antagonist, than did lean mice. MR-2266 was much more effective than naloxone in suppressing schedule-induced polydipsia in rats. These results indicate that kappa receptors are involved in feeding and drinking and that obesity is associated with changes in these receptors and their ligands.

Enhancement of conditioned taste aversions by lesions of the midbrain raphe nuclei that deplete serotonin

Electrolytic lesions of the dorsal and median raphe nuclei enhanced the avoidance of a saccharin solution that had been paired with a single injection of the toxic drug, lithium chloride. A chemically specific lesion of the same nuclei by intracerebral infusion of 5,7-dihydroxytryptamine produced the same behavioral effect. Neither lesion group differed from control animals in the consumption of an unpaired novel fluid or of an unpaired familiar fluid. Both lesions caused a significant depletion of telencephalic serotonin. The data suggest that the enhanced suppression of saccharin intake was due to damage to serotonergic neurons. Rats with electrolytic lesions in the median raphe nucleus alone showed a significant enhancement of saccharin avoidance in the taste aversion paradigm. The addition of a dorsal raphe lesion increased serotonin depletion but did not produce a significant increment in saccharin avoidance. Thus, decreased hippocampal or septal serotonin, produced by the median lesions, may be responsible for the facilitation of the learned taste aversion. Furthermore, this facilitation may be due to the development of associations between the injection procedure and nongustatory aspects of the test situation.

Food intake and body weight: Effects of specific and non-specific lesions in the midbrain path of the ascending noradrenergic neurons of the rat

Bilateral injections of 4.8 or 12 microgram of 6-hydroxydopamine hydrobromide were made in the midbrain path of the ascending norepinephrine (NE) fibers. Maximum NE depletion was obtained with the 4 microgram dose. Increasing the dose did not increase NE depletion in either the hypothalamus or the telencephalon. Increases in food intake were observed following the 12 microgram dose only. Electrolytic, copper sulfate, or 5,6-dihydroxytryptamine lesions at the same site caused increases in both food intake and body weight with only moderate (-32 to -58%) decreases in NE levels. Behavioral changes were seen in only those groups in which a large amount of non-specific tissue damage was also observed. Therefore, the behavioral effects were attributed to general tissue damage in the area and not the NE fibers specifically.

Presence of immunoreactive calcitonin in the hypothalamus and pituitary lobes of rats

We have found calcitonin-like immunoreactive material in extracts of hypothalami from six-month old, male rats. The level of this immunoreactivity, 0.21 ng/hypothalamus, is substantial considering out lower limit of detection of 0.006 ng of rat calcitonin. However, the hypothalamus contains less calcitonin-like immunoreactive material than either the anterior lobe (1.16 ng) or neurointermediate lobe (0.81 ng) of the pituitary. Taken together these three sources of calcitonin-like immunoreactive material contain less than one thousandth the immunoreactivity found in the thyroid. The exact nature of the calcitonin-like immunoreactive material found in these extrathyroidal sites and its physiological role, if any, remain to be discovered. The recent report of the occurrence of calcitonin receptors in the hypothalamus and other brain regions in conjunction with our finding of calcitonin-like immunoreactivity in the hypothalamus suggests that calcitonin-like molecules may be active within the brain.

Opiate antagonists overcome the learned helplessness effect but impair competent escape performance.

Rats exposed to inescapable shocks exhibited deficiencies in learning to escape shock in a novel situation 24 hours later (learned helplessness). Opiate antagonists (naloxone or naltrexone) blocked the learned helplessness effect, allowing efficient escape performance on the subsequent test. In contrast, these drugs impaired the performance of rats pretrained with escapable shocks and animals with no previous exposure to shock. Both effects occurred at small doses and increased substantially with higher doses. The results suggest a significant role for endogenous opiates in the induction of learned helplessness as well as in the acquisition of efficient escape behavior.

Elevation of calcitonin immunoreactivity in the pituitary and thyroid glands of genetically obese rats (fa/fa).

This paper contains the first demonstration of quantitative changes in the levels of calcitonin-like immunoreactivity in the pituitary. The concentration of calcitonin-like material in lean Zucker rats (?/+) was 0.42 +/- 0.09 ng/mg wet weight of pituitary. The pituitaries of obese rats (fa/fa) contained significantly greater levels (1.56 +/- 0.56 ng/mg wet weight). This 271% increase represents the first indication that pituitary calcitonin-like material may have a physiological role in genetically obese rats. Thyroidal calcitonin also elevated in the obese (111%). These large elevations in the calcitonin content of the glands of obese rats were not accompanied by significant elevations of calcitonin in the blood. This suggests that obese rats have problems with mechanisms for the release of calcitonin into the blood and might not be able to combat hypercalcemia as effectively as leans. However, this hypothesis remains to be tested.

Shock controllability and opioid substrates of escape performance and nociception: differential effects of peripherally and centrally acting naltrexone.

Rats exposed to inescapable shock exhibited analgesia and a significant impairment of shock-escape learning in a shuttle box situation 24 hr later. In contrast, rats exposed to escapable shock or to no shock displayed neither effect. Naltrexone (10 mg/kg) significantly reduced the analgesia and completely eliminated the escape deficit in inescapably shocked rats but induced hyperalgesia, coupled with a marked deterioration of escape performance, in escapably shocked and nonshocked rats. The same dose of quaternary naltrexone, which has low ability to cross the blood-brain barrier, had no effect on either the antinociception or the escape deficit produced by inescapable shock, although it also induced escape impairment and hyperalgesia in rats preexposed to escapable shock or to no shock. A second experiment demonstrated that both the escape interference and the antinociceptive consequences of prior inescapable shock could be reduced partially by a much lower dose (1 mg/kg) of naltrexone but 50 times this amount of quaternary naltrexone was still without effect. These results imply that the consequences of exposure to inescapable shock are mediated by activation of central opioid processes whereas naltrexone-induced effects in escapably shocked and nonshocked animals may be peripherally mediated. The relevance of these findings to the possible role of nociception in escape performance is discussed.

Genetically obese (OB/OB) mice are hypersensitive to glucocorticoid stimulation of feeding but dramatically resist glucocorticoid-induced weight loss

The genetically obese (ob/ob) mouse is hyperphagic and hypercorticosteronemic; both hyperphagia and excessive weight gain are ameliorated by adrenalectomy. We report here that corticosterone or dexamethasone stimulate feeding in obese mice at one-fifth the dose needed to increase feeding in lean littermates. Metabolic weight loss, a measure of carbon dioxide and water lost due to respiration, is stimulated by glucocorticoids. Yet we find that obese mice are only one-seventh as sensitive as lean mice to the enhancement of metabolic weight loss following corticosterone. Therefore, hypersensitivity to glucocorticoid-induced feeding and hyposensitivity to glucocorticoid-stimulated weight loss may act in tandem to produce the ob/obs exaggerated weight gain.