An investigation on plasma progesterone levels during pregnancy and at parturition in the Ivesi sheep

We have investigated the toxicity of dose-escalation of BCNU, etoposide and melphalan ('BEM') chemotherapy with autologous stem cell transplantation in patients with haematological malignancies. Seventy-two patients with haematological malignancies were treated with BCNU (600 mg/m2, 450 mg/m2 or 300 mg/m2), etoposide 2 g/m2 and melphalan 140 mg/m2 followed by autologous bone marrow transplantation (ABMT), n = 51, or autologous peripheral blood progenitor cell transplantation (APBPCT), n = 21. Liver and pulmonary function was monitored pretransplant and at regular intervals post-transplant. Mucositis was graded daily during in-patient stay. There was a significantly higher incidence of symptomatic pulmonary toxicity in the patients who received BCNU at 600 mg/m2 than in the other two groups, and there was a significant increase in the incidence of asymptomatic decrease in carbon monoxide (KCO) in the patients who received BCNU 450 mg/m2. There was no significant difference between the three groups in the incidence and severity of mucositis or in the incidence of transiently abnormal liver function. We conclude that etoposide at 2 g/m2 can be used without unacceptable mucositis. BCNU at 600 mg/m2 is associated with an unacceptably high incidence of lung toxicity, but at 450 mg/m2 there is minimal symptomatic lung toxicity.     

Inhibition by gonadotropins of interleukin-1 production by rabbit granulosa and theca cells: effects on gonadotropin-induced progesterone production

BACKGROUND: School-based drug prevention programs have been criticized on methodologic grounds because the unit of analysis is often not the unit of randomization, thus increasing the likelihood of Type I errors. Application of multilevel analytic strategies appropriately corrects this biasing tendency. This study demonstrates the practical use of such analysis. METHODS: Data from 2,370 seventh-grade students participating in a substance use prevention trial were analyzed using a multilevel strategy. We examined the effectiveness of a social pressure resistance training and a normative education (NORM) intervention against an information-only control group. RESULTS: The NORM condition revealed 1-year program effects for cigarette and marijuana use with individuals as the unit of analysis and only marginal effects with classroom as the unit of analysis. No program effects were found using school as the analysis unit. A multilevel strategy revealed program effects for cigarettes and marijuana with both class and school as grouping levels. The effect for alcohol use was significant at the 2-year follow-up. CONCLUSIONS: Interventions establishing conservative drug use norms in classrooms may be an effective strategy in reducing substance use onset among adolescents. Utilization of appropriate analytic strategies is important in the analysis and interpretation of data containing nested structures.     

Neonatal lensectomy and intraocular lens implantation: effects in rhesus monkeys

PURPOSE: To compare the effects of a lensectomy with and without intraocular lens (IOL) implantation on a neonatal rhesus monkey eye. METHODS: A lensectomy and anterior vitrectomy was performed on 75 monkeys during the first 16 days of life; 21 of these monkeys also had an IOL implanted into the posterior chamber. The eyes were examined at regular intervals using biomicroscopy, applanation tonometry, and ophthalmoscopy. RESULTS: The pseudophakic monkeys were studied until they were 92.5 +/- 5.8 weeks of age and the aphakic monkeys until they were 80.4 +/- 5.7 weeks of age. Pupillary membranes (100% versus 55.5%; P < 0.01) and lens regeneration into the pupillary aperture (28.6% versus 5.6%; P = 0.02) occurred more often in the pseudophakic than the aphakic eyes. As a result, the pseudophakic eyes required more reoperations than the aphakic eyes to keep the visual axis clear (P < 0.01). There was not a significant difference in the incidence of ocular hypertension between the pseudophakic and aphakic eyes (9.5% versus 12.7%; P = 0.34). Pupillary capture of the IOL optic occurred in 52% and haptic breakage in 33% of the pseudophakic eyes. All of the eyes with broken haptics had a prominent Soemmerring's ring varying in maximum thickness from 0.6 to 2 mm. Nine of the haptics from the seven eyes with broken IOLs had eroded into the iris, two into the ciliary body, and one into the anterior chamber. CONCLUSIONS: Implanting an IOL into a neonatal monkey eye after a lensectomy and anterior vitrectomy increases the likelihood of a reoperation being necessary. Haptics frequently erode into the iris and ciliary body and may break because of stress placed on the optic-haptic junction by forward movement of the IOL.     

Acute effects of caffeine on several operant behaviors in rhesus monkeys

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.     

Bovine plasma oestrogens, progesterone and glucocorticoids during dexamethasone induced parturition

Plasma samples were collected from jugular, uterine and utero-ovarian veins during glucocorticoid induced parturition. Plasma oestrogens, corticosteroids and progesterone were determined by competitive protein binding methods. Corticosteroids and progesterone began to decline within 8 to 10 h following DXMS treatment. Corticoids were only temporarily suppressed, while progesterone fell to minimum levels and remained low through calving. At this stage of gestation (270 days) peripheral plasma progesterone was primarily of ovarian origin. Pre-treatment with HCG appeared to support progesterone production by the CL despite DXMS treatment in 2 of 6 cows. These 2 cows failed to calve within the expected 96 h after DXMS. Plasma oestrogens did not show significant increased until 24 h after DXMS treatment. Cows which responded to DXMS treatment (calved) had significantly higher oestrogen levels than those which did not respond. It was concluded that oestrogens probably play a permissive rather than an initiating role in parturition.     

Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys

Effects of a single injection of either 150 micrograms human recombinant glial cell line-derived neurotrophic factor (rGDNF) or vehicle into the right substantia nigra were analyzed in 12 normal adult female rhesus monkeys. The studies included evaluating whole animal behavior, electrochemical recordings of striatal dopamine release, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3-week observation period following trophic factor administration were small, with blinded observers unable to distinguish between GDNF- and vehicle-treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some weight loss and four of the six GDNF recipients displayed small, but significant, increases in daytime activity levels. In vivo electrochemical recordings in the ipsilateral caudate and putamen 3 weeks after GDNF administration revealed increased potassium-evoked release of dopamine in trophic factor recipients. In a second series of animals killed at the same time, dopamine levels in the substantia nigra and ventral tegmental area of GDNF recipients were significantly increased, with ipsilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elevated in the substantia nigra, ventral tegmental area, and caudate nucleus ipsilateral to the trophic factor injection. There was a trend toward increased HVA levels in the ipsilateral putamen, nucleus accumbens, and globus pallidus in GDNF-treated animals, but the ratios of HVA to dopamine were not significantly different between vehicle- and GDNF-treated recipients. Although some tissue damage from the delivery of concentrated trophic factor was evident, dopamine neurons remained in an adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine-neuron perikaryal size was significantly increased, along with a significant increase in tyrosine hydroxylase-positive axons and dendrites. We conclude that, in the adult rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic dopamine neurons which lasts for weeks.     

Behavior of rhesus monkeys during artificial menstrual cycles.

Daily sc injections of estradiol, progesterone, and testosterone were given to 17 ovariectomized rhesus monkeys in amounts that imitated accurately the changing plasma levels of hormones in intact females with natural menstrual cycles. Because these cycles in ovariectomized, treated Ss were terminated by normal vaginal bleeding every 28 days and showed a midcycle gonadotropin surge, the authors termed them "artificial menstrual cycles." In dyadic mating tests, changes in the females' access times (leverpressing) for males, and in the males' ejaculatory performance, were closely similar during natural and artificial cycles, and there were well-marked behavioral rhythms. These rhythms were lost during 28-day control periods when ovariectomized Ss received injections of vehicle alone. Differences in ejaculatory performance during natural and artificial cycles could be accounted for by an order effect. It is concluded that the artificial cycle provides a valid and useful paradigm for a more detailed study of the neuroendocrine regulation of primate reproductive behavior. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Oral cocaine self-administration in rhesus monkeys: Strategies for engendering reinforcing effects.

Orally delivered cocaine was established as a reinforcer for 8 rhesus monkeys (Macaca mulatta). Initially, each monkey was given a choice between the water vehicle and a 0.2 mg/ml cocaine concentration. The 0.2 mg/ml solution was not consumed in preference to water. One or more acquisition procedures were used with each monkey to establish orally delivered cocaine as a reinforcer. A common feature of all but one procedure was environmental situations that lead to the elective drinking of the cocaine solution. Evidence confirming the establishment of cocaine's reinforcing effects was obtained by testing each monkey across a broad range of cocaine concentrations under conditions of concurrent access to the cocaine solution and vehicle. Over a range of concentrations, the monkeys obtained greater cocaine than vehicle deliveries. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid-mediated changes in nociceptive threshold during pregnancy and parturition in the sow

This study aimed to investigate if pregnancy-induced hypoalgesia occurs in the sow, and to examine the role of endogenous opioids which are known to be released in response to nociception. Sixteen Large White x Landrace multiparous sows were tested in straw bedded pens (2.5 x 2.5 m) during weeks 4, 8 and 12 of pregnancy and over the farrowing period. Testing involved thermal stimulation of eight areas on the rear-quarters of the sows with a CO2 infra-red laser until a physical response was seen (tail flick, leg move or muscle twitch) or for a maximum of 16 s. Over the farrowing period testing was more frequent, and at 3.75 h after the birth of the first piglet, half the sows received an injection (i.m.) of an opioid antagonist naloxone (N) (1 mg kg(-1) body weight) with the remainder receiving a control dose of saline (S). Responses were recorded 15 and 30 min post-injection. There was no significant difference between response times over weeks 4, 8 and 12 of pregnancy (P = 0.152), however a significant rise was seen from week 12 to 5 days before parturition (P = 0.002). Response times continued to rise until the birth of the first piglet by which time the majority of sows had stopped responding within 16 s (P < 0.001). Response times fell over days 1, 2 and 7 post-partum. After administration of naloxone response times fell compared to control animals at 15 min (P < 0.001) and 30 min (P < 0.01) post-injection. These results suggest that nociceptive threshold increases during late pregnancy in the sow, perhaps as an endogenous defence against labour pain, and that during parturition this change in nociceptive threshold is, at least in part, opioid-mediated. Oxytocin is known to be inhibited by endogenous opioids at parturition, thus future research should consider the potential role of increased nociception at birth as a negative feedback to oxytocin release.     

Secretion of progesterone and 20 alpha-dihydroprogesterone during pregnancy in goats

The relationships between the secretion of progesterone and 20 alpha-dihydroprogesterone and the sites of their production in pregnant goats were investigated. The progesterone concentration in the peripheral plasma increased after the goats mated, and was high from day 10 to day 140 of pregnancy. The 20 alpha-dihydroprogesterone concentration increased gradually from day 0 to day 140 after mating. The progesterone concentration before parturition decreased rapidly on day 1 prepartum, but the 20 alpha-dihydroprogesterone concentration remained high until the day of parturition and then began to fall. The ratio of progesterone to 20 alpha-dihydroprogesterone decreased and fell to less than one on day 1 prepartum. The plasma concentrations of progesterone in ovarian vein and of 20 alpha-dihydroprogesterone in the ovarian vein, umbilical vein, and umbilical artery were higher than those in the jugular vein. The ratio of progesterone to 20 alpha-dihydroprogesterone in placental tissue was less than one. These results suggest that in pregnant goats the main production site is the ovary for progesterone and the ovary and feto-placental unit for 20 alpha-dihydroprogesterone, and 20 alpha-dihydroprogesterone may take help to regulate progesterone production within the ovary and the feto-placental unit.     

Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys.

Modafinil is a central nervous system stimulant used to promote wakefulness, and it is being evaluated clinically as an agonist medication for treating stimulant abuse. This is the first report of the effects of modafinil on the abuse-related effects of cocaine in nonhuman primates. The behavioral effects of modafinil were examined in three studies. First, the discriminative stimulus effects of modafinil (3.2–32 mg/kg) were evaluated in rhesus monkeys (Macaca mulatta) trained to discriminate either low (0.18 mg/kg, IM) or high (0.4 mg/kg, IM) doses of cocaine from saline. Modafinil dose-dependently substituted for cocaine in 6 of 7 monkeys. In the second study, the effects of chronically administered modafinil (32–56 mg/kg/day, IV) on food- and cocaine-maintained (0.001–0.1 mg/kg/inj) operant responding were examined. Modafinil was administered 3 times/hr for 23 hr/day to ensure stable drug levels. Chronic treatment with 32 mg/kg/day modafinil selectively reduced responding maintained by intermediate and peak reinforcing doses of cocaine, but responding maintained by higher doses of cocaine was unaffected. Food-maintained behavior did not change during chronic modafinil treatment. In a third study, modafinil (32 and 56 mg/kg/day, IV) was examined in a reinstatement model. Modafinil transiently increased responding during extinction. These findings indicate that modafinil shares discriminative stimulus effects with cocaine and selectively reduces responding maintained by reinforcing doses of cocaine. In addition, modafinil reinstated cocaine-seeking behavior, which may reflect its cocaine-like discriminative stimulus effects. These data support clinical findings and indicate that these preclinical models may be useful for predicting the effectiveness of agonist medications for drug abuse treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Combined effects of buprenorphine and an alternative nondrug reinforcer on phencyclidine self-administration in rhesus monkeys.

Six rhesus monkeys self-administered orally delivered phencyclidine (PCP; 0.35 mg/ml) with saccharin (0.3 or 0.03 % wt/vol) or water under concurrenl fixed-ralio (FR) schedules. During daily 3-hr sessions, subjects had concurrent access to liquids: PCP versus water, PCP versus saccharin. or saccharin versus water. The FR of both liquids was varied (4, 8, 16, 32, and 64) in nonsystematic order and when behavior was stable at each FR, buprenorphine (0.005 mg/kg) was injected intramuscularly for 5 days. Buprenorphine treatment decreased PCP deliveries by 16–65% across the range of FR values when compared with the no-treatment baseline, and concurrent saccharin reduced PCP deliveries from 34 to 63%. Combining buprenorphine treatment and concurrent availability of saccharin produced decreases in PCP deliveries of 70–87% from the no-trealmenl baseline across the FR values. Greater reductions were found at the highest FR values. Pmax values were shifted to the left under all treatment conditions, suggesting that the reinforcing efficacy of the drug was reduced. These findings suggest that pharmacological and behavioral treatments produce additive reductions in drug self-administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Further analysis of S-R separation effects on visual discrimination performance on normal rhesus monkeys and monkeys with superior colliculus lesions.

Tested the orientation and attention hypotheses by requiring 4 monkeys with superior colliculus lesions and 2 controls to discriminate between stimuli presented in different parts of the visual field, at durations either too brief or sufficiently long to permit fixation. Findings indicate that before the lesions, Ss discriminated between 2 color-differentiated stimuli presented on a screen only when they fixated the center of the screen. The stimuli were presented 8, 20, or 32° from the screen's center, for 2 sec or 100 msec, a duration too brief to permit their fixation. Performance declined when the response sites, located either centrally or peripherally, were separated from the stimuli, whether they were presented for 2 sec or 100 msec. Findings suggest that the stimulus-response separation effect is due to selective attention to the response sites and not to fixating them during stimulus presentation. Following superior colliculus lesions, Ss were impaired in discriminating between peripheral stimuli, but only when they responded centrally. This deficit was not due to a failure to fixate the stimuli, for it occurred when the stimuli were 100 msec or 2 sec, or to reduced sensory capacities, since it disappeared when Ss responded peripherally. It is concluded that this deficit may reflect deficient attentional shifts from the response sites to the stimuli. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired steroidogenesis in the luteal phase of the reproductive cycle and during pregnancy in rhesus monkeys immunized with the beta-subunit of ovine luteinizing hormone

Monkeys immunized with the beta-subunit of ovine luteinizing hormone (oLH beta) develop antibodies which cross react with rhesus chorionic gonadotropin (rhCG) and luteinizing hormone (rhLH). Immunization causes shortened menstrual cycles and reduced fertility. Fertility can be restored by administration of medroxyprogesterone acetate (MPA) during the first 5 weeks of pregnancy. In the present study, we have measured the effects of circulating oLH beta-antibodies on peripheral estradiol, progesterone and 17 alpha OH-progesterone (17OH-P) concentrations throughout the menstrual cycle and during gestation in monkeys which became pregnant following MPA-treatment. Progesterone concentrations were markedly reduced during the luteal phase in cycling animals and the luteal phase of the cycle was significantly shorter as compared to non-immunized controls. Concentrations of estradiol and 17OH-P in the peripheral circulation were not affected by the oLH beta-antibodies. In immunized monkeys which became pregnant following MPA-treatment, progesterone and 17OH-P levels were consistently lower and estradiol concentrations were increased during the second and third trimesters. Our results show that circulating antibodies to oLH beta have multiple endocrinological effects. Corpus luteum function is impaired in cycling monkeys and during the early part of pregnancy. In addition, the pattern of steroid secretion remains abnormal in pregnant monkeys even after the luteal-placental shift.     

Short- and long-term effects of repetitive mother–infant separations on social development in rhesus monkeys.

Rhesus monkey mother–infant dyads were each subjected to 16 4-day physical separations between the infants' 3rd and 9th mo of life. Infants displayed protest behavior following each separation but only minimal signs of despair. Their protest diminished somewhat over repeated separations. The mothers' separation reactions were considerably milder (and changed little) over repeated separations. The separations appeared to retard the development of normal mother–infant relationsips: Relative to nonseparated control dyads, separated infants displayed excessive levels of infantile behaviors, although their mothers did not differ from control mothers in levels of any behavior. Near the end of their 1st yr, all infants were permanently separated from their mothers and housed as peer groups. Over the next 30 wks during peer housing, few behavioral differences emerged between previously separated and control Ss. However, when exposed to their mothers during preference tests, previously separated Ss seemed to avoid their mothers in sharp contrast to the mother-seeking activity displayed by control infants. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contrasting effects of lateral striate and superior colliculus lesions on visual discrimination performance in rhesus monkeys.

Tested 3 rhesus monkeys with lesions of lateral striate cortex (LSC), 4 monkeys with superior colliculus (SC) lesions, and 3 unoperated monkeys for retention of a preoperatively acquired pattern discrimination. The 3 groups of monkeys were then tested in 2-choice, color discrimination tests, 1 involving varying degrees of stimulus–response (S–R) separation and the other, administered several months later, involving various directions of S–R separation. Ss were also tested in a series of 2-choice pattern discriminations, following each of which they were tested for relearning when the patterns were masked with bars or circles. LSC lesioned Ss were moderately retarded in retention of the pattern discrimination, whereas those with SC lesions were not. SC lesioned Ss, but not those with LSC lesions, were impaired in both S–R separation tests, which demonstrates that their deficit was not transient or solely due to a difficulty in shifting the gaze in 1 direction. The LSC Ss, unlike those with SC lesions, were deficient in relearning discriminations between masked patterns. Findings suggest that SC and LSC may be involved in 2 different aspects of attention, respectively: shifting attention (and orientation) from 1 spatial locus to another and maintaining attention on fixated stimuli. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aging in rhesus monkeys: Different windows on behavioral continuity and change.

Rhesus monkeys were observed longitudinally from 6 to 20 years of age, the period encompassing early to late adulthood in this species. Repeated-measures analyses of the monkeys' behavioral repertoire revealed 3 quite different pictures of the aging process. First, there were significant systematic changes in the levels of many categories of behavior with increasing age, although the direction and timing of change varied from category to category. Second, for most categories, individual differences among the monkeys were highly stable from early to late adulthood. Finally, there was remarkable consistency within individual behavioral profiles across the entire study such that each monkey retained its distinctive behavioral features (personality) throughout its adult years. Thus, aging in rhesus monkeys is characterized by both continuity and change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug dependence study on vigabatrin in rhesus monkeys and rats

The dependence potential of vigabatrin (gamma-vinyl GABA; R(-)/S(+)-4-amino-5-hexenoic acid, CAS 60643-86-9, MDL 71,754) was assessed in rhesus monkeys and rats. In the test of cross physical dependence potential, morphine- and barbital-dependent monkeys were both withdrawn from the respective drugs and the ability of vigabatrin to suppress the withdrawal signs was assessed. In morphine-dependent monkeys, subcutaneous doses of vigabatrin at 256 and 1000 mg/kg did not suppress withdrawal signs while subcutaneous doses of codeine phosphate at 4 and 8 mg/kg clearly suppressed the withdrawal signs. In barbital-dependent monkeys, subcutaneous and intravenous dose of vigabatrin, both at 1000 mg/kg, did not suppress the withdrawal signs, while intragastric doses of diazepam at 8 and 16 mg/kg clearly suppressed them. Thus, while the cross-physical dependence potential of codeine/morphine and of diazepam/barbital was clearly observable, vigabatrin appeared to have no such potential. In the test of physical dependence-producing potential with the drug-admixed food method in rats, vigabatrin and diazepam were given to rats mixed with food for 28 days in an increasing dosage schedule, followed by feeding a drug-free diet to observe withdrawal signs for 7 days. Upon withdrawal, no decrease in food intake or body weight was observed in the vigabatrin-treated groups, and the gross condition of the animals did not differ from that in the control group. In contrast, food intake and body weight decreased markedly in the diazepam group, and most rats showed hyperreactivity to external stimuli. Thus, while the physical dependence-producing potential of diazepam was clearly demonstrated, such potential was not shown with vigabatrin. In the test of reinforcing effect, 4 monkeys were allowed to self-administer pentobarbital at 1 mg/kg/infusion, or vigabatrin at 16, 32, and 64 mg/kg/infusion, intravenously through an indwelling catheter. Each drug was preceded and followed by saline self-administration for at least 7 days. Active self-administration of pentobarbital was observed in all monkeys tested, while the self-administration rate of vigabatrin did not differ from saline. Thus, while the reinforcing effect of pentobarbital was clearly observed, such effect was not observable with vigabatrin. Based on these results, it was considered that vigabatrin was devoid of dependence potential.     

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.

The study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys. (PsycINFO Database Record (c) 2010 APA, all rights reserved)