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The ovulation-inducing and gonadotropin-releasing activities of [d-Leu-6, des-Gly NH2-10, Pro-ethylamide-9]-GnRH (II), were evaluated in rats, rabbits, and sheep. A sc dose of 3.4 ng/100 g body wt of the analog was equal to 160 ng/100 g body wt of GnRH in causing ovulation in the diestrous rat. At these dose levels, the integrated LH release was 1.9 times greater for the analog. Both the time of increase and maximum serum concentrations of LH were delayed after injection of the analog. Oral administration of II and GnRH to the proestrous rat resulted in an ED50 for ovulation of 0.92 and 54 mug/100 g body wt,respectively. Serum levels of LH and FSH were highly variable for the various treatment groups when both releasing substances were administered orally. The intense ovulating activity of II was also evident in the estrous rabbit as indicated by an activity 31 times greater than that of GnRH. Additionally, the analog was at least 50 times more active than GnRH in releasing LH in both the mid-luteal and anestrous ewe. From our experiments with the cycling rat it appears that the intense ovulation-inducing activity of II can be accounted for by the intrinsic LH-releasing activity of the nonapeptide, rather than by a prolonged release stimulus.

Drugs may interact with oral contraceptives by influencing their absorption, stimulating or inhibiting their metabolism, or acting through the same or physiologically opposing receptor mechanisms. Breakthrough bleeding and spotting are the warning signs that should encourage enquiry about additional drug taking. The use of powerful enzyme-inducing drugs like phenobarbitone or rifampicin, effectively rules out the use of oral contraception as a reliable method of fertility control. The problem of drug interaction with oral contraceptives should be kept in perspective; the number of reports is still very low.

1. The effects of strychnine on the degree of depression of neuronal firing induced by glycine, gamma-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT) have been examined quantitatively. All drugs were applied by iontophoresis to spontaneously active cerebral cortical neurones in the anaesthetized cat. The application of these drugs was continued until a plateau or equilibrium depression was reached. The time taken to reach this steady state was noted. Dose-response curves were then constructed for those currents giving less than complete depression.2. Glycine was less potent than GABA and about 7-fold larger currents were needed to achieve comparable depression. 5-HT was also a weak depressant compared with GABA and had 0.6 the potency of glycine on a current basis.3. Strychnine in currents up to 25 nA shifted the dose-response curve of glycine to the right at a time when equilibrium depression in the same cells induced by the control agonists GABA or 5-HT was unaffected. These currents of strychnine did, however, prolong the time-course of onset of GABA and 5-HT depression.4. In larger currents strychnine reduced GABA equilibrium depression, but the dose-response curve was not shifted in a parallel fashion.5. It is concluded that strychnine can specifically and competitively antagonize the effect of glycine on cortical neurones.

1. Noradrenaline, isoprenaline, 5-hydroxytryptamine and acetylcholine have been applied into the environment of single neurones in the cat cerebral cortex by micro-iontophoresis. The influence of anaesthesia on the neuronal responses to these drugs was studied.2. In general, excitation of neurones by noradrenaline occurred commonly in both unanaesthetized encéphale isolé (48%) and N(2)O-halothane anaesthetized preparations (57%) while depressions were less frequent (24 and 20% respectively). The picture differed markedly in barbiturate anaesthetized animals where excitation was uncommon (12%) and the majority of cells (59%) was depressed by noradrenaline. Although fewer cells were studied, similar differences were obtained with isoprenaline and 5-hydroxytryptamine for the three types of preparation. In sharp contrast, the vast majority of cells was excited by acetylcholine in each of the preparations: encéphale isolé 84%; N(2)O-halothane 92%; barbiturate anaesthetized preparations 85%.3. The differing neuronal responses observed in these experimental situations were not the result of variations in the depth of anaesthesia.4. Although the depths at which neurones were encountered within the cortex did not differ in N(2)O-halothane and encéphale isolé preparations, significantly more cells were found in deeper layers of cortex in barbiturate preparations. The proportion of cells excited or depressed by noradrenaline was generally similar at each depth in the three preparations used.5. The distribution of rates of cell firing was strikingly similar in each preparation, and most of the cells studied had frequencies below 10/sec.6. The direction in which a cell responds to noradrenaline is mainly determined by the type of anaesthetic used, and not by the depth of anaesthesia, the rate of cell firing, or cell depth within the cortex. This suggests important differences in the central pharmacology of halothane and barbiturates.

1. Indoramin is a competitive alpha-adrenoceptor blocking agent on the guinea-pig isolated vas deferens and aortic strip; the pA(2) value on the aorta is 7.4.2. Indoramin is devoid of beta-adrenoceptor blocking activity on the guinea-pig isolated trachea (10(-4)M) and the Langendorff preparation of the rabbit heart (10(-6)M). It also has no adrenergic neurone blocking action on the Finkleman preparation of the rabbit small intestine (10(-5)M).3. On the Langendorff preparation of the rabbit isolated heart, indoramin (above 10(-6)M) has cardio-inhibitory properties similar to those of propranolol.4. On the guinea-pig isolated ileum (10(-5)M) and trachea (10(-6)M), indoramin is devoid of anticholinergic activity, but has a potent antihistamine action which satisfies the criteria for competitive antagonism; the pA(2) value for this antagonism on the ileum is 8.2.5. Indoramin antagonizes 5-hydroxytryptamine on the rat isolated fundus and ileum; the pA(2) value for the antagonism on the ileum is 6.0.

Dose/response measurements were made on the guinea-pig isolated ileum with six agonists, acetylcholine, 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium, choline phenyl ether and histamine. The dose effects were repeated in the presence of each of twelve antagonists and one anticholinesterase. Acetylcholine and histamine were chosen because of their direct mode of action on smooth muscle, nicotine, dimethylphenylpiperazinium and choline phenyl ether were used as examples of drugs that act at the ganglionic acetylcholine receptor. 5-Hydroxytryptamine was the drug investigated. Hyoscine blocked the contractions caused by acetylcholine, 5-hydroxytryptamine and the ganglion-stimulants but left the responses to histamine unchanged. The anticholinesterase N,N'-diisopropylphosphorodiamidic fluoride (mipafox) potentiated all the agonists except histamine. The strength of potentiation decreased in the order 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether, and acetylcholine. The local anaesthetic procaine inhibited to the same extent contractions elicited by 5-hydroxytryptamine, nicotine, dimethylphenylpiperazinium and choline phenyl ether. These results showed that 5-hydroxytryptamine, like nicotine, choline phenyl ether and dimethylphenylpiperazinium, mediated its response through the nervous plexus. Of those tested 5-hydroxytryptamine was the only specific antagonist to 5-hydroxytryptamine; lysergic acid derivatives produced spasm and prolonged changes in tone; phenoxybenzamine caused non-specific block. The diverse modes of action of a number of ganglion-blocking agents were selectively used. Thus hexamethonium, pentolinium, and nicotine in its competitive phase, blocked contractions due to nicotine, dimethylphenylpiperazinium and choline phenyl ether and left those due to 5-hydroxytryptamine, acetylcholine and histamine unchanged. The depolarizing ganglion-blocking agents, dimethylphenylpiperazinium and nicotine, inhibited the responses to all the indirectly acting drugs. Furthermore, mecamylamine, a drug with a less well-defined mode of action, partially inhibited contractions due to 5-hydroxytryptamine in a concentration that blocked those due to nicotine, dimethylphenylpiperazinium and choline phenyl ether. Pempidine, known to act like mecamylamine, did not antagonize 5-hydroxytryptamine. It is concluded that 5-hydroxytryptamine activates specific receptors sited at the intramural parasympathetic ganglion cells.

When the guinea-pig isolated ileum had been previously treated with the anticholinesterase, NN-diisopropylphosphodiamidic fluoride (mipafox), and attached to an isotonic lever loaded with 0.5 g, it released acetylcholine into Krebs solution gassed with a mixture of 95% oxygen and 5% carbon dioxide. The amount of acetylcholine spontaneously released depended on the duration of the rest period. Cocaine, procaine or cooling the preparation to 25 degrees C greatly reduced this spontaneous output of acetylcholine, thus providing evidence in support of nervous origin of the ester. Reduction of the calcium ion content of the Krebs solution to one-twentieth of its usual value or increase in the magnesium ion content four-fold, changes which inhibit the release of acetylcholine from somatic motor nerve-endings, inhibited the output of acetylcholine from the ileum. When all the calcium of Krebs solution had been replaced by strontium one-third of the control output of acetylcholine was obtained, but the smooth muscle of the guinea-pig ileum would not respond to drugs under these conditions. Strontium could thus partially substitute for calcium in nerves but not in muscle. Hemicholinium-3 (100 mug/ml.) inhibited the spontaneous release of acetylcholine and 400 mug/ml. of choline was required to reverse the inhibition. It is concluded that cocaine, procaine, cooling, reduction of calcium ion and increase of magnesium ion concentrations all reduce the spontaneous output of acetylcholine, which has its origin in the parasympathetic nerve-endings of the intramural nerve plexuses. Further, the hemicholinium experiments seem to justify the conclusion that the release of acetylcholine is reduced because synthesis is reduced.

The article refers to the Economic Opportunity Act of 1967 in the United States, anti-poverty programs, and collaboration between the public and private sectors. The JOBS program provides training and job opportunities for hard-core unemployed workers and the cost of training is subsidized by the government. The Model Cities Program involves the private citizen in government-funded, social improvement programs based on Housing and Urban Development criteria for model neighborhoods. The characteristics of unskilled trainees, National Alliance of Businessmen, and Housing and Urban Development Act of 1968 are mentioned, as well as the expected demand for transportation services, inflationary trend, and executive interchange plan.