Search

The recognition that the 7 alpha-hydroxylation of 27-hydroxycholesterol is catalyzed by an enzyme that is different from cholesterol 7 alpha-hydroxylase raises the question as to the number of similar enzymes that may be present in liver and subserve bile acid synthesis. Thus, both 3 beta-hydroxy-5-cholestenoic acid and 3 beta-hydroxy-5-cholenoic acid, further oxidation products derived from 27-hydroxycholesterol, are also 7 alpha-hydroxylated during their metabolism to chenodeoxycholic acid. Using a microsomal fraction of hamster liver and competition plot analysis, we found that the 7 alpha-hydroxylase activity for the acid substrates was approximately one-tenth that found for 27-hydroxycholesterol. Mixtures of the different substrates did not depress the total rate of 7 alpha-hydroxylation. The evidence supports the view that these substrates share the same catalytic site on a single enzyme.

A variety of stimuli can act through the central nervous system to alter gastric acid secretion. Lesioning and stimulation experiments have established roles for the lateral and ventromedial hypothalamus and the limbic system in the central regulation of gastric acid secretion. Recently a number of neuropeptides have been demonstrated to alter gastric acid secretion after central administration. Thyrotropin-releasing hormone (TRH) and gastrin both increase gastric acid secretion, whereas bombesin, calcitonin, the endogenous opioid peptides and neurotensin decrease gastric acid secretion. With the exception of bombesin, all the other neuropeptides appear to produce their effects through a vagally mediated mechanism. In addition, a number of these neuropeptides, when centrally administered, have been demonstrated to exert a potent cytoprotective effect against stress ulcer development. This review develops a peptidergic hypothesis of gastric acid secretion, suggesting that the final integration of the cephalic phase of gastric acid secretion is brought about by maintaining a delicate balance in the concentration of a number of interacting peptides and monoamines.

The hypothesis that a quantity of noradrenaline released contingently on every response made to obtain brain stimulation mediates the reward produced by the stimulation was tested. An alternative hypothesis is that reward is mediated by a different system, but that a steady activation of post-synaptic receptors by noradrenaline is necessary for normal behavior. The synthesis of noradrenaline was inhibited by disulfiran, and when lateral hypothalamic self-stimulation in the rat had ceased, alpha-adrenergic stimulants were injected intraventricularly (IC) or intraperitoneally (IP). The directly acting receptor stimulants oxymetazoline (0.9-250 mug IC), naphazoline (20-250 mug IC), and clonidine (0.75-3 mug IC, 0.037-3 mg/kg IP) did not restore self-stimulation, but the indirectly acting stimulants amphetamine (2 mg/kg IP), methylphenidate (3 mg/kg IP) and phenylephrine (15 mug IC) did not restore self-stimulation. In Experiments 2 and 3, in which either the functional noradrenaline pool was depleted with disulfiram and amphetamine, or the reserve noradrenaline pool was depleted with reserpine, the action of phenylephrine in restoring self-stimulation was shown to be indirect, probably by mobilizing a reserve pool of noradrenaline. Because only indirectly acting noradrenergic stimulants which facilitate the release of noradrenaline restores self-stimulation, it is concluded that noradrenaline must be released contingent on every response for self-stimulation to occur. Whether this released noradrenaline mediates the reward or has some other function associated with bar-pressing behavior remains to be shown.

3H-Octopamine binds reversibly and with high affinity to sites on adult firefly light organ membranes. The binding is characterized by multiple affinities. Scatchard analysis supported a two site binding model with a tentative Kd value of about 1 nM for the high affinity component. The more abundant lower affinity site had a Kd value of about 60 nM. Guanyl nucleotides (Gpp(NH)p and GTP) greatly reduced the apparent number of octopamine binding sites. Competition studies with known octopaminergic agonists including the formamidine pesticides chlordimeform (CDM) and N-demethyl chlordimeform (DCDM) showed the following rank order of potencies in displacing octopamine: DCDM greater than octopamine = synephrine greater than naphazoline greater than clonidine greater than CDM. It was also observed that phentolamine was much more active than propranolol in antagonizing OA-binding. These relative activities are similar to the abilities of the same compounds to alter adenylate cyclase activity in light organ homogenates. Together with the effect of GTP on binding, these results suggest that the binding sites are functional octopamine receptors of the light organ.

Tonic immobility in chickens was influenced by a variety of drugs that act on the adrenergic neurochemical system of the body. Alpha 1 agonists such as methoxamine and phenylephrine produced decreases in the duration of immobility, although the former compound also caused a significant increase in the immobility response at high dosages. Alpha 2 agonists such as clonidine, naphazoline, and guanfacine enhanced the duration of immobility, but clonidine also produced an apparent reversal of this effect at high dosages. Subsequent experiments examined more fully the biphasic effects by methoxamine and clonidine on tonic immobility through interactions with alpha antagonists. Yohimbine, an alpha 2 blocker, attenuated the duration of immobility, either alone or in conjunction with various dosages of methoxamine. Prazosin, an alpha 1 blocker, had no direct effect on tonic immobility, but potentiated the duration of the response when given in conjunction with various dosages of methoxamine. When these antagonists were given in conjunction with clonidine, yohimbine reduced immobility durations, while prazosin had no apparent effect on this response. These results are discussed in terms of the relative contributions of the alpha 1 and alpha 2 adrenoceptors to the duration of the immobility response.