Dopaminergic modulation of rat pup ultrasonic vocalizations.

The dopamine D(1) receptor agonist, R(+)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297), the dopamine D(2)/D(3) receptor agonist, trans-(-)-4aR-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo[3, 4-g]quinoline hydrochloride (quinpirole), and the dopamine D(3) receptor agonist, (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) all reduced the frequency of isolation-induced infant rat ultrasonic vocalizations and lowered body temperature when compared to saline-injected controls. Ultrasonic vocalization rate was not affected by either the dopamine D(1) receptor antagonist, R(+)-2,3,4, 5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) or the dopamine D(2)/D(3) receptor antagonist, S(-)-raclopride-L-tartrate (raclopride) when given alone, nor did these antagonists block the ultrasonic vocalization reductions caused by the dopamine D(1) receptor agonist or the dopamine D(2)/D(3) receptor agonist. The dopamine D(2)/D(3) receptor antagonist but not the dopamine D(1) receptor antagonist blocked the dopamine D(3) receptor agonist's ultrasonic vocalization reduction. SKF 81297 reduced general activity while quinpirole and 7-OH-DPAT increased activity. Raclopride reversed quinpirole's reduction in body temperature, as well as 7-OH-DPAT's effects on body temperature, ultrasonic vocalizations, and activity. These results indicate that dopamine D(1), D(2)/D(3), and D(3) receptor agonists all reduce ultrasonic vocalizations by as yet undetermined mechanisms.     

Pharmacological evaluation of a modified conflict procedure: punished drinking in non-water-deprived rats

Rationale: Conflict procedures used to detect anxiolytic-like activity of drugs often rely on maintaining strict schedules of water or food availability. It is ethically and practically desirable to reduce such states of deprivation in animal testing. Objective: The purpose of the present experiment was to develop and pharmacologically characterize a conflict drinking procedure that did not require the use of water-deprived animals. Methods: Rats were tested during daily sessions with alternating unpunished drinking (no tone: lick=sucrose solution) and signaled punished drinking (tone: lick=sucrose+shock) components, and developed individual steady baselines over a brief training period (approximately 3–4 weeks). The drugs tested i.p. were the positive allosteric modulators of γ-amino butyric acid_A (GABA)_A receptors, diazepam (0.03–30 mg/kg), chlordiazepoxide (0.03–30 mg/kg), lorazepam (0.03–10 mg/kg), zolpidem (0.3–10 mg/kg), pentobarbital (1–30 mg/kg), pregnanolone (1–30 mg/kg), and bretazenil (0.03– 10 mg/kg); the 5-hydroxy tryptamine_1A (HT)_1A-mediated anxiolytics, buspirone (1–10 mg/kg) and ipsapirone (1–17 mg/kg); and the negative controls d-amphetamine (0.3–3 mg/kg), haloperidol (0.01–0.3 mg/kg), morphine (0.3–17 mg/kg), and imipramine (0.3–30 mg/kg). Results: The experimental procedure was sensitive to increases in punished drinking by the GABA_A-positive modulators, consistent with their known or putative anxiolytic activity. Further, the 5-HT_1A-mediated anxiolytics increased punished drinking, although to a lesser extent and over a more narrow dose range than did the GABAergic drugs. In contrast, d-amphetamine, haloperidol, morphine, and imipramine failed to increase punished drinking up to doses that decreased unpunished drinking. Conclusions: The present results indicate that water deprivation is not a necessary condition to engender drinking conflict behavior or to obtain pharmacological effects similar to those obtained with other classical conflict procedures. Received: 23 November 1998 / Final version: 15 March 1999     

Pharmacokinetics and Safety of a Selegiline Transdermal System Relative to Single-Dose Oral Administration in the Elderly

This open-label, two-phase cross-over study compared the safety and pharmacokinetics of transdermally administered selegiline and orally administered selegiline hydrochloride in elderly men and women (n = 6/gender). Single oral doses of 10 mg selegiline hydrochloride and single 1/2 and 1 selegiline transdermal system (STS) (delivering similar3.4 and 6.3 mg over 24 h) administered topically were safe and well tolerated in all subjects. Plasma concentrations of selegiline (SEL) and its N-desmethylselegiline (DMS), L-amphetamine (AMP), and L-methamphetamine (MET) metabolites were measured using an HPLC/MS/MS method with lower quantitation limits of 10, 50, 200, and 200 pg/mL, respectively. No significant gender-related differences were observed following single 10-mg oral doses of selegiline hydrochloride or single 24-h applications of 1/2 and 1 STS to elderly males and females. The low level of dermal irritation as assessed by erythema and edema rating scales suggests that the STS was similar to Band-Aid (Johnson & Johnson, Skillman, NJ) controls. The transdermal administration of SEL bypasses the first-pass metabolism, that is significant after oral administration (first-pass extraction >90%). Peak plasma levels of 1.19, 23.22, 4.78, and 14.08 ng/mL were observed for SEL, DMS, AMP, and MET after a single 10-mg oral dose to the elderly. By contrast, peak plasma levels of 2.10, 0.85, 1.06, and 2.71 ng/mL were observed for SEL, DMS, AMP, and MET after a single 24-h application of 1 STS. Comparison of dose-corrected areas under the curve (AUCs) (made under the assumption of linear pharmacokinetics) indicate the SEL exposure after transdermal application was more than 50-fold greater than that obtained orally. This increase in systemic SEL exposure at the expense of metabolite formation that is reduced to <70% of that obtained orally for N-DMS, L-AMP, and L-MET is hypothesized to be of therapeutic value in patients with a variety of neurodegenerative and psychiatric disorders.     

Functional roles of membrane glycoprotein CD36

Cell-cell and cell-extracellular matrix interactions are mediated by a number of membrane glycoproteins. On the basis of structural homologies, several families of cell adhesion molecules (integrins, selectins, immunoglobulins, cadherins, leucine-rich glycoproteins) have been established. Since 1991, a new family of CD36-like proteins has been identified. CD36 is a cell surface glycoprotein that interacts with a large variety of ligands. CD36 has been implicated in thrombosis, vascular biology, lipid metabolism and atherogenesis. In this review, we aim to summarize our present knowledge on this important, multifunctional glycoprotein.     

Effect of fibrin sealant on perianastomotic tumor growth in an experimental model of colorectal cancer surgery

Viable intraluminal tumor cells can penetrate a clinically intact rodent colonic anastomosis and give rise to perianastomotic tumor growth. The aim of this study was to determine whether transanastomotic cell migration can be prevented by fibrin-based tissue sealant. Following distal colonic transection and reanastomosis with 5/0 silk sutures, Fischer F344 rats were randomly allocated to three experimental groups. In Group A, a circumferential ring of tissue sealant was placed around the serosal surface of the anastomosis; in Group B, sealant was limited to 50 percent of the anastomotic circumference; and, in Group C, no sealant was applied. All rats then had 10 ⁵ Mtln ₃ carcinoma cells injected into the proximal colonic lumen via a rectal catheter. The incidence of perianastomotic tumor at 21 days was significantly lower in Group A (3 of 14 animals) than in Group B (11 of 16 rats) (P =0.012; Fisher's exact test) or Group C (10 of 14 rats;P=0.011). A further experiment demonstrated that sealant did not protect the anastomosis when tumor cells were instilled directly into the peritoneal cavity. A topical carcinocidal action therefore appears unlikely, but our results suggest that a circumferential anastomotic ring of fibrin sealant forms an effective mechanical barrier preventing intraluminal tumor cells from reaching the peritoneal cavity.     

Kinds and locations of mutations arising spontaneously in the coding region of theHPRT gene of finite-life-span diploid human fibroblasts

Spontaneous thioguanine-resistant mutants were derived from populations of finite-life-span, diploid human fibroblasts by means of a fluctuation analysis. cDNA was prepared from mutantHPRT mRNA and amplified by the polymerase chain reaction, and the sequence of the product was analyzed. Exon deletions, which very likely arose from mutations in the intron splice site consensus sequences, were found in 10 of the 37 mutants examined (27% of the total). Among the 28 mutations in the coding sequence, base pair substitutions predominated (89%). With the exception of one base pair involved in a tandem mutation, all base pair substitutions resulted in alterations in the predicted amino acid sequence of the protein. In addition there were three frameshift mutations, consisting of the deletion of one or two base pairs. Although mutations occurred throughout the coding sequence, 50% (14/28) were found in the 5 portion of exon 3.     

Disodium D-6-[alpha-(1,2,4-triazine-3,5-dione-6-carboxamido)-4-hydroxyphenylacetamido]penicillanate, BL-P1908.

The synthesis of a new penicillin, disodium D-6-[alpha-(1,2,4-triazine-3,5-dione-6-carboxyamido)-4-hydroxyphenylacetamido]penicillanate (BL-P1908), is described. The compound shows superior in vitro activity against Pseudomonas aeruginosa compared to carbenicillin and ticarcillin and produces higher intramuscular serum levels in mice than does carbenicillin.     

Chronic prenatal exposure to carbon monoxide results in a reduction in tyrosine hydroxylase-immunoreactivity and an increase in choline acetyltransferase-immunoreactivity in the fetal medulla: implications for Sudden Infant Death Syndrome

Maternal cigarette smoking during pregnancy is associated with a significantly increased risk of Sudden Infant Death Syndrome (SIDS). This study investigated the effects of prenatal exposure to carbon monoxide (CO), a major component of cigarette smoke, on the neuroglial and neurochemical development of the medulla in the fetal guinea pig. Pregnant guinea pigs were exposed to 200 p.p.m CO for 10 h per day from day 23-25 of gestation (term = 68 days) until day 61-63, at which time fetuses were removed and brains collected for analysis. Using immunohistochemistry and quantitative image analysis, examination of the medulla of CO-exposed fetuses revealed a significant decrease in tyrosine hydroxylase-immunoreactivity (TH-IR) in the nucleus tractus solitarius, dorsal motor nucleus of the vagus (DMV), area postrema, intermediate reticular nucleus, and the ventrolateral medulla (VLM), and a significant increase in choline acetyltransferase-immunoreactivity (ChAT-IR) in the DMV and hypoglossal nucleus compared with controls. There was no difference between groups in immunoreactivity for the m2 muscarinic acetylcholine receptor, substance P- or met-enkephalin in any of the medullary nuclei examined, nor was there evidence of reactive astrogliosis. The results show that prenatal exposure to CO affects cholinergic and catecholaminergic pathways in the medulla of the guinea pig fetus, particularly in cardiorespiratory centers, regions thought to be compromised in SIDS.