Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity

  Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to ”isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isolation deprives animals of mild daily stressors that are inherent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, repeated stressors may abolish the effects of isolation. Objectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abolish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the elevated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxiolytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk assessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of ”isolation stress”. However, isolation was anxiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation. Received: 23 May 1998 / Final version: 3 December 1998     

The effect of lithium on amphetamine-induced locomotor stimulation

Rats were treated chronically with -methyl-p-tyrosine methyl-ester HCl (-MT) twice daily for 0–14 days. At 1 h after the (last) -MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of -MT markedly reduced the activity response after amphetamine. After 1–3 days of -MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7–14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the -MT tolerant rats with an early (at 0–1 h) and a late (2–4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of -MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of -MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.     

Interphase cell death as related to the cell cycle of melphalan-treated human myeloma cells

The effect of melphalan on cell loss, cell growth and cell-cycle traverse was studied on the human myeloma cell line RPMI 8226. Melphalan treatment resulted in arrest of cells in late S- and G₂-phases in a population of unsynchronized cells. At high concentrations of melphalan (e.g. 40 μm), cell loss was noticed duringthe first cell cycle after melphalan treatment in addition to the aforementioned arrest of cells in late S and G₂. The cell loss after melphalan treatment was further analysed in cells enriched for G₁-phase. Cell death in this population of cells occurred between 24 and 48 hr after treatment as the cells were in S and moving over to G₂.     

Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine

Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.     

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 g/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 g/l, DMI: 24–659 g/l and IP+DMI: 58–809 g/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.     

The active phase-related increase in corticosterone and aggression are linked

Recently we demonstrated that corticosterone exerts an acute facilitatory effect on aggression in male rats. Corticosterone production reaches a maximum at the onset of the dark period, while male rats are more aggressive in the dark. Here we present evidence demonstrating that the corticosterone increase at the beginning of the dark period is causally linked to the increase in aggressiveness. We measured plasma corticosterone and quantified aggressive behaviour of male territorial rats at various time points of the day-night transition. Low aggression levels were observed in the full light period when plasma concentrations of corticosterone were low. An increase in plasma corticosterone occurred just prior to the dark phase, when aggressive responding was the highest. Aggressive behaviour remained high in the early dark period when corticosterone was still high. We found that blocking the high affinity mineralocorticoid receptor (MR) with spironolactone (5 or 10 mg/kg) during the early dark period dramatically and specifically reduced territorial aggression.     

Bipartite parietal bone: A rare cause of plagiocephaly

A case of an infant with an asymmetrical head is presented. On clinical assessment the patient displayed features of deformational plagiocephaly. With the aid of three‐dimensional CT imaging of the skull, a bipartite parietal bone was diagnosed. The prevalence and possible aetiology of a bipartite parietal bone is discussed as well as a brief overview of the common causes of plagiocephaly.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.