p-Chlorophenylalanine-induced chemical manifestations of phenylketonuria in rats.

p-Chlorophenylalanine, a potent inhibitor of phenylalanine hydroxylase in vivo, has been used to simulate phenylketonuria in rats. This inhibitor, when administered with phenylalanine, produces marked elevation of blood and tissue phenylalanine without an increase in tyrosine. Disproportionate ratios of phenylalanine to tyrosine are characteristic of phenylketonuria in humans. The use of p-chlorophenylalanine permits the production of this characteristics amino acid imbalance in experimental animals.

Cholecystokinin inhibits tail pinch-induced eating in rats.

Peripheral administration of the COOH-terminal octapeptide of cholecystokinin in doses from 1 to 100 micrograms per kilogram of body weight (0.25 to 25.0 micrograms per rat) significantly antagonized tail pinch-induced eating in rats, an animal model for stress-induced human hyperphagia. Centrally administered cholecystokinin was effective only in high doses (3 micrograms into the cerebral ventricle). The finding that the minimal effective dose of cholecystokinin in suppressing stress-induced appetitive behavior is smaller after peripheral than central administration suggests that the peptide is acting on peripheral, as opposed to central nervous system, substrates.

Intravenous injection in man of 9 -tetrahydrocannabinol and 11-OH- 9 -tetrahydrocannabinol.

A microsuspension of Delta(9)-tetrahydrocannabinol and of its metabolic derivative 11-OH-Delta(9)-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.

Erythrosine (Red No. 3) and its nonspecific biochemical actions: what relation to behavioral changes?

Biochemical studies have shown that the ability of erythrosine to inhibit dopamine uptake into brain synaptosomal preparations is dependent on the concentration of tissue present in the assay mixture. Thus, the finding that erythrosine inhibits dopamine uptake (which, if true, would provide a plausible explanation of the Feingold hypothesis of childhood hyperactivity) may simply be an artifact that results from nonspecific interactions with brain membranes. In addition, although erythrosine given parenterally (50 milligrams per kilogram) did not alter locomotor activity of control of 6-hydroxydopamine-treated rats, erythrosine (50 to 300 milligrams per kilogram) attenuated the effect of punishment in a "conflict" paradigm.

Thyrotropin-releasing hormone-like bioactivity in placenta: evidence for the existence of substances other than Pyroglu-His-Pro-NH2 (TRH) capable of stimulating pituitary thyrotropin release.

The purpose of this study was to investigate the chemical nature of the TRH-like bioactivity and immunoreactivity in extracts of human placenta. Methanolic extracts of human placenta contained nearly 36 ng TRH-like bioactivity/g dried tissue. The immunoreactivity of this extract was only 3 ng/g dried tissue. Two molar acetic acid extracts of human placenta yielded 9 ng TRH-like bioactivity/g dried tissue. The immunoreactivity of these acetic acid extracts, however, was 5.5 ng/g dried tissue. When these placental extracts were subjected to gel filtration chromatography, the bioactivity was found to reside in two fractions which were distinct from synthetic TRH. Furthermore, the immunoreactivity present in these placental extracts was also chromatographically distinct from that of synthetic TRH. In conclusion, these experiments confirm the presence of substantial quantities of materials in placenta which possess TRH-like immunoreactivity and bioactivity. These results also argue that the immunoreactive fractions are not bioactive and provide firm evidence that neither the TSH-releasing substances nor the TRH-like immunoreactivity found in human placenta are identical to pyroglu-His-Pro-NH2.

Motivational factors in abortion patients.

PIP: From June 1970 through January 1971, a psychological comparison between 99 single white pregnant women seeking abortion and a control group of 79 single nonpregnant women of similar background showed that, as a group, the women seeking abortion were no more neurotic than nonpregnant women of the same ages. Both groups (comprised mainly of college students) were equally informed about contraceptives. 77% of the abortion group used no contraceptives prior to the pregnancy. 82% of the sexually active members of the control group consistently used contraceptives. Conscious motivational factors, such as guilt over use of contraception, reactions to loss, or severe acting-out character disorders, may have influenced the occurrence of the pregnancy in 40% of the abortion group. Psychological testing showed that the pregnant group stated themselves as more impulsive and as tending to externalize aggression.^ieng

Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders.

Six women and 6 men who were treated in double-blind fashion major depressive illness did not respond to imipramine or amitriptyline, 150-300 mg/day, during periods of 26-112 days. After the addition of 25 micrograms/day (10 patients) or 50 micrograms/day (2 patients) of L-triiodothyronine (T3), 9 patients showed statistically significant improvement in depression scores; in 8 patients the response was marked. Improvement generally began within 1-3 days and was noted in all aspects of the depressive syndrome; side effects were minimal. T3 did not change plasma levels of imipramine or desipramine or their ratio but did suppress serum thyroxine.

TRH-like immunoreactivity in urine, serum and extrahypothalamic brain: non-identity with synthetic pyroglu-hist-pro-NH2 (TRH).

TRH-like immunoreactive substances obtained from several areas of rat brain and from human serum and urine were chromatographically separated by TLC and the resulting immunoreactive 'elution profiles' compared with that obtained for pyroglu-hist-pro-NH2 (TRH). For hypothalamus and septal-preoptic samples TRH was present, but represented less than 100% of the immunoreactive substances. For cortex, amygdala, brain stem, serum and urine, no TRH was detectable in the immunoreactive substances from those samples. The implications of these findings in relation to 'TRH' distribution studies and validation of small peptide RIAs are discussed.

Neurotensin: central nervous system effects of a hypothalamic peptide.

The central administration of neurotensin, an endogenous hypothalamic tridecapeptide, produces a marked dose-related decrease in body temperature of mice and rats at an ambient temperature of 25 degrees C. This effect is even more pronounced when mice are placed at 4 degrees C to increase the rate of decline of body temperature. Other sequelae observed after central administration of neurotensin are decreases in locomotor activity in rats and a marked dose-related enhancement in pentobarbital-induced mortality, sedation and hypothermia. This latter effect was shown to be due to a significant reduction in the metabolic degradation of the barbiturate. None of the above-mentioned effects are observed after peripheral neurotensin administration, suggesting that this peptide does not readily cross the blood-brain barrier. Neurotensin appears to be one of a growing list of neuropeptides that can affect CNS function.

Naltrexone prevents footshock-induced performance deficit in rats.

Three experiments demonstrate that inescapable footshock delivered to unrestrained rats produces analgesia as well as performance deficits in subsequent one-way shuttle acquisition. Both the performance and the antinociceptive effects are prevented by pretreatment with as little as 0.1 mg/kg i.p. of the opiate antagonist, naltrexone. These studies suggest that both effects are mediated through opiate receptors with similar underlying naltrexone pharmaco-dynamics.

Diet and hyperkinesis--an update.

Ten years ago, Dr. Feingold proposed that hyperactivity and learning disabilities in children are commonly caused by the ingestion of food additives and claimed that elimination of foods with additives from the diet resulted in major improvements in three-quarters of hyperactive children. In the last five years, controlled double-blind studies have been conducted by many investigators to test this hypothesis. The results, which are mainly negative, are summarized. The authors conclude that 2% (contrasted with Feingold's claims of 75%) of hyperactive children respond adversely to dye additives. Even the 2% are questionable. There is no need for high-priority research or for changes in public policy regarding the use and labeling of foods containing additives. Hyperkinesis has multiple etiologies, which require other types of biological and psychological research.

Comparison of the analeptic potency of TRH, ACTH 4-10, LHRH, and related peptides.

Various peptide hormones appear to exert behavioral and pharmacologic effects apart from their classical endocrine actions. Thytrotopin-releasing hormone (TRH), for example, antagonizes the sedation and hypothermia produced by barbiturate and other depressant drugs and de Wied has shown that ACTH 4-10, TRH, LHRH and certain related substances show some activity in inhibition of extinction of a pole-jumping avoidance response in the rat. These data provided the impetus for screening ACTH 4-10, LHRH, and related peptides for analeptic activity. ACTH 4-10 and ACTH 4-7 were inactive in antagonizing pentobarbital whether administered peripherally or centrally. ACTH 4-7 amide and 4-Met(O2), 8-D-Lys,9-Phe-ACTH 4-9 were active regardless of route of administration LHRH and two tripeptide fragments (pGlu-His-Trp-NH, and pGlu-His-Phe-NH2) showed analeptic activity only after intracisternal administration. Thus, some peptide fragments related to ACTH 4-10 and LHRH were shown to share to some degree the analeptic properties previously demonstrated for TRH.

Lack of effect of chronically administered thyrotropin-releasing hormone (TRH) on regional rat brain tyrosine hydroxylase activity.

Chronic treatment of adult male rats with TRH (1 or 10 mg/kg IP) for 5 or 9 days failed to alter the activity of tyrosine hydroxylase (TH), the enzyme regulating the rate-limiting step in catecholamine biosynthesis. In contrast, as previously described, chronic reserpine administration (0.5 mg/kg IP: 9 days) resulted in a significant rise in TH activity in midbrain, hypothalamus, pons-medulla and forebrain. These results suggest that the enhanced brain norepinephrine turnover reported to occur after treatment with TRH is not due to synthesis of new TH enzyme protein.