Blood pressure response to bolus administration of vasoactive drugs in the rat.

The time course of systemic blood pressure response in normotensive anaesthetized rats was studied after a bolus administration of standard doses (0.4 microgram/kg) of noradrenaline, adrenaline, isoprenaline, acetylcholine, serotonin, bradykinin, and histamine. The single stimulus of a vasoactive agent elicits a blood pressure deviation with typical phasing. The time dimension of the individual wave is less variable and less dose dependent than their amplitude. Under the given experimental conditions the blood pressure response is predominantly determined by the peripheral vasomotor reactions; the cardiac component is of minor importance. Though the overall responses to the individual drugs are quite characteristic, they seem to comprise several common components. Thus the peripheral vascular system is supposed to consist of different regulatory subsystems which take part in the systemic blood pressure control by typically timed responses. The pattern of the reaction is then given by their unequal combination and various intensity.     

Endocrine effects of chronic administration of psychoactive drugs to prepubertal male rats. II. LSD.

The endocrine effects of chronic D-lysergic acid diethylamide (LSD) administration to prepubertal animals were studied by injecting intraperitoneally three times a week for a month either 100 mug or 500 mug of the psychoactive drug per kilogram or the vehicle to groups of Sprague-Dawley male rats starting at 21 days of age. Animals injected with either dosage of LSD had smaller body weights than controls and tail length was significantly reduced in the high dosage group, plasma levels of growth hormone (GH) were decreased in the high dosage group, and pituitary levels in the low dosage group. Plasma levels and pituitary concentrations of luteinizing hormone and follicle stimulating hormone were not significantly modified by the drug. The low dosage of LSD decreased the brain levels of noradrenaline and increased those of dopamine, while the high dosage decreased those of 5-hydroxyindoleacetic acid. These data suggest that LSD, when administered chronically to developing animals, can inhibit body growth probably by altering the secretion of GH through modifications of its neuroendocrine control.     

A simple method for the intragastric administration of drugs to fully conscious guineapigs.

The design and use of a simple system for the intragastric administration of miniature capsules or fluids to fully conscious guineapigs is described. The system is suitable for repeated drug administration. It causes minimal discomfort to the animals.     

Conditioned taste aversion elicited by intracerebral administration of drugs

Conditioned taste aversion (CTA) is a vital adaptive reaction governed by highly reliable but poorly understood central mechanisms. In an attempt to elucidate the site of action of various CTA eliciting drugs, equipotent dosages were applied by the systemic (i.p.) and intracerebral (i.c.) route. Rats were offered water on days 1 and 2. On day 3 they received 0.1% sodium saccharin (CS) followed by pentobarbital anaesthesia and i.p. or i.c. injection of the drug (US). After water on day 4, the rats were allowed to choose between water and saccharin on day 5. The putative central action of amphetamine was not confirmed by this experimental arrangement, since CTA was evoked by only moderately (about 10 times) lower i.c. than i.p. dosages. Similar ratio of the i.c. to i.p. effective dosages was obtained with carbachol. On the other hand, CTA of clearly central origin was caused by harmaline and by other monoamine oxidase inhibitors, pargyline and clorgyline, which elicited comparable aversion using 500, 400 and 250 times lower i.c. than i.p. dosages, respectively. The intracerebral gradient of the effect pointed to the lower medulla (inferior olive, raphe nuclei) as the critical brain region and to serotonin as the transmitter participating in the aversive labeling of the gustatory stimulus. The CTA-forming mechanism can also be studied by analysing the action of drugs, e.g. convulsants, which do not produce CTA even when applied at highly toxic dosages (LD 50) eliciting long lasting convulsions (picrotoxin, 5 mg/kg; bicuculline, 5 mg/kg). It is concluded that comparison of brain events elicited by drugs which can or cannot serve as unconditioned stimuli in the CTA paradigm may substantially contribute to the exploration of the underlying neural mechanisms.     

Non-transferrin-bound iron in plasma following administration of oral iron drugs

Non-transferrin-bound iron (NTBI) was detected in serum samples from volunteers with normal iron stores or from patients with iron deficiency anaemia after oral application of pharmaceutical iron preparations. Following a 100 mg ferrous iron dosage, NTBI values up to 9 μM were found within the time period of 1–4 h after administration whereas transferrin saturation was clearly below 100%. Smaller iron dosages (10 and 30 mg) gave lower but still measurable NTBI values. The physiological relevance of this finding for patients under iron medication has to be elucidated.     

The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs.

The substituted glucopyranose ring structure 2-hydroxypropyl-beta-cyclodextrin (CDEX) increases the solubility of molecules by inclusion of the agent in the lipophilic interior of the ring. This property is of particular use for the administration of molecules by the intracerebral (ICV) or intrathecal (IT) routes. In concentrations up to 40% w/v (isotonic), this agent (10 microliters) effect upon nociceptive or motor function after IT injection or on EEG and general behavior after ICV injection in rats. Using 20% CDEX, there is no change in the ED50 as compared to saline on the hot plate (HP) after IT injection of morphine, D-Ala2-D-Leu5 enkephalin or Tyr-Aib-Gly-gPhe-mAib-NH2, (Aib: alpha-aminoisobutyric acid) although there is an increase in their respective durations of effect. Cyclic peptide opioids: Tyr-c[D-A2bu-Gly-D-beta Nal(1)-D-Leu] (A2bu: alpha, gamma-diaminobutyric acid; beta-Nal(1): beta-naphthylalanine(1)) or Tyr-c[DA2bu-Gly-beta Nal(1)-D-Leu] are insoluble in saline but are readily dissolved in CDEX, and display a naloxone-sensitive antinociception following spinal administration. In other studies, saline insoluble capsaicin is administered in 25% dimethylsulfoxide (DMSO) or 20% CDEX (15 microliters; 5 mg/ml) which result in a significant reduction in the spinal levels of substance P and calcitonin gene related peptide and an increase in the HP latency. DMSO alone, but not CDEX alone, reduces the levels of the two peptides. These data emphasize the utility of complexation with CDEX for intracerebral drug delivery and compatibility with brain and spinal tissue.