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Effects of zometapine, a structurally novel antidepressant, in an animal model of depression.

Zometapine, a pyrazolodiazepine, bears a close structural resemblance to benzodiazepines. It possesses an unusual pharmacological profile, and is active in some, but not all, tests of antidepressant activity. In clinical tests it appears to be an extremely effective pharmacotherapeutic agent, and may represent a new class of antidepressant. Because the preclinical profile of zometapine is unusual, we examined its effects in a behavioral test of antidepressant potential. Following three weeks of treatment, the drug selectively reversed a behavioral depression following chronic stress. Drug-induced reversal was seen only in rats activated by acute noise exposure, and was dose related. Reversal was confirmed by a second measure, defecation, and partially confirmed by the normalization of an elevated basal corticosterone response.

Animals↗

Effects of propranolol, buspirone, pCPA, reserpine, and chlordiazepoxide on open-field behavior.

The study examined the possibility that propranolol, buspirone, pCPA, and reserpine have antianxiety effects by comparing their effects with those of chlordiazepoxide on an open-field test of emotionality in rats. The effects of intraperitoneal injections of d,l, propranolol (5, 10, 20 mg/kg), buspirone (1.25, 2.5, 5 mg/kg), reserpine (0.5 mg/kg), parachlorophenylalanine (pCPA) (100 mg/kg), and chlordiazepoxide (CDP) (2.5, 5, 10 mg/kg) were compared with performance of rats under saline or water using an open-field test on 5 successive days. Significant effects were found on peripheral movements, rearing, grooming, immobility, and defecation. The patterns of effects of high doses of propranolol and buspirone resembled those of CDP, while pCPA had some of the effects of CDP, and reserpine produced few effects. With propranolol, buspirone, and CDP, there was evidence of dose sensitivity. The effects of repeated testing across 5 days were different from these of CDP or other drugs. The results are consistent with the hypothesis that the effects of propranolol and buspirone on open-field behavior are anxiolytic, and may be mediated by action on the same brain systems.

Animals↗

Cyclosporine A affects open field behavior in DA rats.

Since the introduction of Cyclosporine A (CsA) for immunosuppression in solid-organ transplantation, the rate of allograft rejection has decreased substantially. However, treatment with CsA induces neuropsychological complications in patients, including affective disorders such as anxiety, disorientation, depression, aggression, paranoia, and apathy. These CsA-induced affective side effects cannot be extensively studied in humans. Therefore, this study investigates the effects of intraperitoneal CsA (20 mg/kg) injections on the open-field behavior of male Dark Agouti (DA) rats 1, 6, 12, and 23 h after drug administration on 3 consecutive days. CsA induced an increase in emotionality in DA rats 6 h after injection, reflected by decreased ambulatory activity in the open field and increased defecation. In addition, a decrease in rearing activity was observed 12 h after CsA administration. These behavioral alterations are discussed in the view of changes in cytokine profiles induced by CsA.

Animals↗

Physiology of the lower urinary tract.

This article presents the concepts that give meaning to the pressures observed in the various parts of the body occurring normally and abnormally in various conditions. Normal pressure relationships, holding urine, voiding, incontinence, and flatulence and defecation are discussed.

Defecation↗

Sacral spinal nerve stimulation for faecal incontinence: multicentre study.

BACKGROUND: In patients with faecal incontinence in whom conservative treatment fails, options are limited for those with a functionally deficient but morphologically intact sphincter. We investigated the effect of sacral nerve stimulation on continence and quality of life. METHODS: In this multicentre prospective trial, 37 patients underwent a test stimulation period, followed by implantation of a neurostimulator for chronic stimulation in 34. Effect on continence was assessed by daily bowel-habit diaries over a 3-week period and on quality of life by the disease-specific American Society of Colon and Rectal Surgeons (ASCRS) questionnaire and the standard short form health survey questionnaire (SF-36). Every patient served as his or her own control. FINDINGS: Frequency of incontinent episodes per week fell (mean 16.4 vs 3.1 and 2.0 at 12 and 24 months; p<0.0001) for both urge and passive incontinence during median follow-up of 23.9 months. Mean number of days per week with incontinent episodes also declined (4.5 vs 1.4 and 1.2 at 12 and 24 months, p<0.0001), as did staining (5.6 vs 2.4 at 12 months; p<0.0001) and pad use (5.9 vs 3.7 at 12 months; p<0.0001). Ability to postpone defecation was enhanced (at 12 months, p<0.0001), and ability to completely empty the bowel was slightly raised during follow-up (at 12 months, p=0.4122). Quality of life improved in all four ASCRS scales (p<0.0001) and in seven of eight SF-36 scales, though only social functioning was significantly improved (p=0.0002). INTERPRETATION: Sacral nerve stimulation greatly improves continence and quality of life in selected patients with morphologically intact or repaired sphincter complex offering a treatment for patients in whom treatment options are limited.

Adult↗

The effects of beta-adrenoceptor antagonists on a rat model of neuroleptic-induced akathisia.

Neuroleptic-induced defecation in rats in a well-habituated environment has been proposed as a model of the subjective component of akathisia. In this study, we examined the effects of two lipophilic beta-adrenoceptor antagonists - the non-selective drug propranolol and the relatively beta1-selective metoprolol - and one non-selective hydrophilic drug nadolol in this model. Young male Wistar rats were randomly assigned to one of eight groups (n = 12 in each group) and treated with haloperidol or vehicle, with or without one of the beta-antagonists. Haloperidol-treated rats had higher bolus counts than vehicle-treated rats, and this increase was significantly reversed by the lipophilic but not the hydrophilic beta-antagonists. This finding is consistent with the reported anti-akathisia effects of these drugs in humans, suggesting that this effect is central in origin and achievable with relatively selective beta1-antagonism. The B-antagonist drugs significantly reduced the cataleptic effect of haloperidol and this effect warrants further examination.

Adrenergic beta-Antagonists↗

Behavioural and intestinal responses to novelty in rats selected for diverging reactivity in the open field test.

There are indications that the severity of functional gastrointestinal disturbances in humans is linked to individual coping styles. In rodents, the open field test can be used to assess individual differences in behavioural responsivity to novel challenges. Two groups of Wistar rats were selected for high (HA) and low (LA) locomotor activity in a novel open field and fitted with electrodes on the proximal colon. During subsequent exposure to a novel box, a smaller locomotor activation in LA was accompanied by a greater increase in colonic spike burst activity compared to HA rats, even though this novel stressful challenge did not result in a clear defecation response in either group. In contrast, no marked behavioural differences between HA and LA were seen in the shock prod paradigm. Although detection of divergent behavioural responsivity in HA and LA rats may depend on stimulus quality or intensity, combined use of behavioural selection and intestinal motility recording in freely moving rats may offer a model to study individual vulnerability to stress-related disturbances of intestinal function.

Action Potentials↗

Differential effects of communal rearing and preweaning handling on open-field behavior and hot-plate latencies in mice.

On day 2 after delivery, dams of the DBA/1 mouse inbred strain (n = 20/group) with their litter were allocated to one of the following groups: NH21, nonhandling, housed 1 litter/cage, weaned on postnatal day (PND) 21;H21, handling, housed 1 litter/cage, weaned on PND 21; NH30, nonhandling, group-housed (5 litters/cage), weaned on PND 30; H30, handling, group-housed (5 litters/cage), weaned on PND 30. Two male pups of each litter were color marked on PND 2. From PND 8-21 they were removed from their cage, gently held in the experimenter's hand for 5 min/day. The two marked males of each litter were housed together after weaning, and tested in the open-field on PNDs 51-53, and one of each of these siblings was tested for hot-plate latencies on PND 54. Being raised in group-housing and weaned on PND 30 resulted in offspring exhibiting shorter latencies to initiate behavior and higher percentages of centerfield entries in the open field, hot-plate latencies, however, remained unaffected. Preweaning handling increased hot-plate latencies and the number of grooming episodes in the open field, and it decreased defecation, percent centerfield entries and open-field activity in general. It is concluded that the two forms of early experience have different effects on neurobehavioral endpoints 8 weeks after birth.

Animals↗

Discriminative fear conditioning to context expressed by multiple measures of fear in the rat.

There has been a renewed interest in the neural basis of fear conditioning to context. These current approaches are accompanied by some limitations including the use of short testing windows, non-discriminative paradigms, and unitary fear response assessment. In an attempt to circumvent these limitations, a discriminative context procedure assessing multiple response measures of fear was used in the present study. Conditioning consisted of three training sessions and each session consisted of 2 days. On day one, the animals were placed in the paired context and received three foot shocks. On the other day, they were placed in the unpaired chamber in the absence of any aversive event. Animals were tested after each training session and the response measures of fear recorded included: preference, freezing, heart rate, ultrasonic vocalizations, defecation, body temperature, urination and locomotion. The results suggest that behavioral, as well as physiological changes evoked by fearful stimuli become associated with the context in which the aversive event occurred. In general these findings also suggest that there are different learning parameters for the measures of fear examined in this paradigm.

Animals↗

A selective genetic analysis of the Syracuse high- and low-avoidance (SHA/Bru and SLA/Bru) strains of rats (Rattus norvegicus).

Selective breeding of Long-Evans rats for good and poor avoidance learning in a two-way shuttle box resulted in the Syracuse strains that differ markedly in the selected phenotypes. These phenotypes have many associated traits, five of which are studied here: emotionality (open-field defecation), Pavlovian fear conditioning (CER suppression), passive avoidance training (punishment), size (weight) of the adrenal glands and adrenal concentration of corticosterone. Specifically, animals of the low-avoidance strain are more emotional, show greater fear conditioning, exhibit faster passive avoidance learning, and have larger adrenal glands in which adrenal corticosterone levels are lower than those of the high-avoidance strain. A reciprocal dihybrid cross of the two strains produced F1 hybrids, which were used to produce the segregating second filial and high and low backcross generations from which animals displaying the extreme high- and low-avoidance phenotypes were selected for study of the associated traits. Measurement of the five traits in these high and low phenotypic animals indicated that all five remain significantly associated with the avoidance phenotypes, in the expected direction, and comparably in all three segregating generations. The results indicate that the hypothesis of a major gene controlling avoidance learning must be rejected and that the few (2-3) genetic units thought to be involved may be closely linked to those that mediate these five associated characters, or express all five pleiotropically.

Adrenal Glands↗

Control of abdominal muscles.

Abdominal muscles serve many roles; in addition to breathing, especially at higher levels of chemical drive or at increased end-expiratory lung volumes, they are responsible for, or contribute to, such protective reflexes as cough, sneeze, and vomiting, generate the high intra-abdominal pressures necessary for defecation and parturition, are active during postural adjustments, and play an essential role in vocalization in many species. Despite this widespread involvement, however, their control has, with rare exceptions, received little attention for two major reasons. First, in most anesthetized or decerebrate preparations, they are relatively inactive at rest, in part because the position of the preparation (supine or prone with abdomen supported), reduces lung volume and, therefore, their activity. Second, unlike phrenic motoneurons innervating the diaphragm, identification of motoneurons to a particular abdominal muscle is difficult. At the lumbar level, a given motoneuron may innervate any one of the four abdominal muscles; at the thoracic level, they are also intermixed with those innervating the intercostals. The two internal muscles, the internal oblique and the transverse abdominis, respond more to increases in chemical or volume-related drive than the two external muscles, the rectus abdominis and external oblique; the basis for this differential sensitivity is unknown. Segmental reflexes at the thoracic and lumbar levels are sufficient to activate abdominal motoneurons in the absence of descending drive but the basis for these reflex effects is also unknown. Neuroanatomical experiments demonstrate many more inputs to, and outputs from, the nucleus retroambigualis, the brainstem region in which the premotor neurons are located, than can be accounted for by their respiratory role alone. These other connections likely subserve activities other than respiration. Studies of the multifunctional roles of the abdominal muscles, on the basis of recent work, hold considerable promise for improving our understanding of their control.

Abdominal Muscles↗

Micturition and defensive behaviors are controlled by distinct neural networks within the dorsal periaqueductal gray and deep gray layer of the superior colliculus of the rat.

Electrical stimulation of the dorsal periaqueductal gray (DPAG) or the deep gray layer of the superior colliculus (DGSC) of rats placed in an open-field elicited either a display of tense immobility, accompanied by exophthalmus and/or defecation and micturition, or running and jumping responses. Threshold curves of each response were obtained for each structure by the logistic fitting of accumulated response frequencies. DPAG and DGSC threshold curves were compared by likelihood-ratio coincidence tests. The output of micturition was significantly higher following the stimulation of DPAG (P < 0.0005). In contrast, no differences were found for the remaining responses. These data support previous studies in anaesthetized cats suggesting the critical involvement of DPAG in the control of micturition. Furthermore, they also suggest that topographically distinct neural networks within the DPAG and DGSC control micturition and the other defensive behaviors.

Animals↗

Evidence for efficacy without increased toxicity of hypofractionated radiotherapy for prostate carcinoma: early results of a Phase III randomized trial.

PURPOSE: We performed a randomized trial to compare the GI and urogenital toxicity of radiotherapy (RT) for localized (confined to the organ), early-stage (T1-T2N0M0, TNM classification) carcinoma of the prostate, using a conventional (64 Gy in 32 fractions within 6.5 weeks) vs. a hypofractionated (55 Gy in 20 fractions within 4 weeks) schedule and to determine the efficacy of the respective treatment schedules. METHODS AND MATERIALS: This report is based on an interim analysis of the first 120 consecutive patients in this Phase III trial after a median follow-up of 43.5 months (range 23-62). RT planning was based on two-dimensional CT data, and the treatment was delivered using a three- or four-field 6-23-MV photon technique. GI and urogenital toxicity (symptom questionnaires incorporating the subjective elements of the late effects of normal tissues-subjective, objective, management, analytic classification of late effects and the European Organization for Research and Treatment of Cancer sexual function questionnaire) were evaluated before RT and 1 month, 1 year, and 2 years after RT completion. The efficacy of RT was assessed clinically (digital rectal examination and radiologic imaging) and biochemically (prostate-specific antigen assay) at baseline, and every 3 months for 2 years after RT and every 6 months subsequently. RESULTS: RT, whether conventional or hypofractionated, resulted in an increase in all six symptom categories used to characterize GI toxicity and in four of five symptom categories used to document urinary morbidity 1 month after therapy completion. Sexual dysfunction (based on limited data), which existed in more than one-third of patients before RT, also increased to just more than one-half of patients 1 month after RT. The increase in urinary toxicity after RT was not sustained (diurnal urinary frequency had decreased significantly at 2 years). In contrast, all six symptom categories of GI toxicity remained increased 1 year after RT. Four of the six GI symptom categories (rectal pain, mucous discharge, urgency of defecation, and rectal bleeding) were still increased at 2 years compared with baseline. Except for a slightly greater percentage of patients experiencing mild rectal bleeding at 2 years among those who received hypofractionated RT, no differences were noted in toxicity between the conventional and hypofractionated RT schedule. The mean prostate-specific antigen level was 14.0 +/- 1.0 ng/mL at baseline and declined to a nadir of 1.3 +/- 0.2 ng/mL at a median of 16.8 months (range 0.8-28.3) after RT completion. However, it then rose in 17 patients (8 in the hypofractionated and 9 in the conventional treatment group). Only 8 of these 17 patients were found to have signs of clinical relapse (5 local, 1 regional lymph node, and 2 systemic [bony metastases]) after histopathologic and radiologic reassessment). The remaining 9 patients had biochemical relapse only (defined as three consecutive rises in prostate-specific antigen after nadir). The 4-year biochemical relapse-free survival rate was 85.8% for all patients and did not differ significantly between the two radiation dose schedules (86.2% for the hypofractionated and 85.5% for the conventional fractionation group). CONCLUSION: RT for prostate carcinoma, using a three- or four-field 6-23-MV photon technique without posterior shielding of the lateral fields, is an underestimated cause of persistent GI morbidity. The incidence of clinically significant GI and urogenital toxicity after conventional and hypofractionated RT appears to be similar. Hypofractionated RT for carcinoma of the prostate seems just as effective as conventional RT after a median follow-up approaching 4 years.

Adult↗

Anorectal anatomy and physiology.

Knowledge of anorectal anatomy is essential for understanding the normal function of the anorectum. Its physiology is more complex, however. The maintenance of continence depends on several factors, and today clinicians have a better understanding of the usual sequence of events that leads to defecation. The extensive number of investigative techniques that have evolved have permitted better understanding of the disorders of the anal sphincters, rectum, and pelvic floor.

Defecation↗

Pediatric anorectal disorders.

Anorectal disorders are common in children. It has been estimated that 10% of children are brought to medical attention because of a defecation disorder, and constipation is the chief complaint in 3% to 5% of all visits to pediatricians. Most of these children suffer from functional constipation. There are substantial differences in the approach to children and adults with anorectal disorders. This article discusses the commonest pediatric anorectal disorders, emphasizing the differences between children and adults in terms of clinical presentations, pathophysiology, diagnosis, and treatment.

Adult↗

New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation.

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.

Animals↗

Physiologic determinants of nocturnal incontinence after ileal pouch-anal anastomosis.

The goals of the ileal pouch-anal anastomosis (IPAA) operation are the construction of a fecal reservoir and the preservation of anal function, without compromising continence. Some of the patients are incontinent at night. The aim of our study was to identify the mechanisms responsible for nocturnal incontinence. We analyzed patients undergoing IPAA for ulcerative colitis, who underwent anorectal tests between 1993 and 1995. All patients were subjected to pull-through manometry and pelvic floor function studies, and 33 patients underwent overnight ambulatory manometry. Among 44 patients (27 men and 17 women), 22 had complete continence, whereas 22 had nocturnal incontinence. Mean age was 40 +/- 1 years. There were no differences with regard to sex, age, stool consistency, and ability to differentiate gas from stool between groups; only stool frequency was lower in the continent group (median [range] 6 [3 to 10] vs. 8 [5 to 25] stools/24 hours; P = 0.011). Resting and squeezing anal canal pressure did not differ (P = 0.42 and P = 0.73, respectively). Resting, squeezing, and defecating anorectal angle, percentage of pouch evacuation, and perineal descent, all measured scintigraphically, did not differ between groups (all P >0.05). Ambulatory manometry showed that the mean anal canal pressure was higher in continent patients compared to incontinent patients, both during awake (88 +/- 11 vs. 62 +/- 8; P = 0.032) and sleep (81 +/- 14 vs. 49 +/- 9; P = 0.029) periods. The motility index was similar (awake, P = 0.88; sleep, P = 0.95), as was the number of episodes where the pouch pressure was greater than the anal canal pressure (P = 0.28). In otherwise continent patients after IPAA, the combination of high stool frequency and low basal anal canal pressure may be related to nocturnal incontinence. Moreover, standard anorectal physiology tests cannot identify these subtle differences.

Adult↗

Neuropharmacological actions of some binuclear lanthanide(III) complexes.

Binuclear lanthanide(III) compounds are of great interest because of the potential of their mutual Ln(3+)-Ln(3+) electronic couplings to produce unusually sharp images in magnetic resonance and fluorescence imaging of biological tissue. The toxicity and neuropharmacological properties of the water soluble and stable neutral binuclear complex [La(api)](2) were compared with those of binuclear complexes with lower water stability, and the components used in their syntheses. The order of the 24-h LD(50) (mg/kg body wt.) of the compounds in mice was: salicylaldehyde (2.24) 160). These compounds induced convulsions, urination and defecation in mice. Due to the relatively very low toxicity of [La(api)](2), its mode of action was explored. Its proconvulsant action may possibly involve an interaction of undissociated complex with muscarinic receptors, and is reversed by atropine.

Animals↗