John A. Foss

Facilitation and inhibition of the human startle blink reflexes by stimulus anticipation

The cutaneous eyeblink has 2 electromyographic components, 1 unilateral and early (R1) and 1 bilateral and late (R2), which are served by different neural pathways. These 2 reactions were measured when the eliciting stimulus was expected or relatively surprising. Forewarning was varied in 3 ways: Subjects received notice that the stimulus was about to occur on some trials (Experiment 1); delivered the stimulus to themselves on some trials (Experiments 2 & 3); or experienced a series of trials in which a tone was paired with the eliciting stimulus, followed by tone-alone trials interspersed with test trials (Experiment 4). In each case, forewarning enhanced R1 amplitudes while depressing R2 but reduced the latency of both components. This mixed pattern of effects reveals that the preparatory state provoked by forewarning focuses excitatory and inhibitory processes simultaneously on different reflex pathways: inhibition central and excitation peripheral.

The acquisition of passive avoidance, active avoidance, and spatial navigation tasks by animals prenatally exposed to cocaine

Pregnant Long-Evans rats were administered cocaine orally (60 mg/kg) on gestational days 14-21. One control group was administered the vehicle and another left untreated. Cocaine treatment produced some maternal lethality, and the weight gain of the surviving dams was reduced approximately 15%. Offspring of mothers treated with cocaine did not differ from those of untreated mothers in their numbers, birth weight, or growth. Weanling offspring were tested in a passive avoidance task, and adult offspring were tested for two-way active avoidance and in a spatial navigation task. Although a few animals in the cocaine group showed poor retention of passive avoidance, the group differences were not statistically significant. The adult animals showed normal performance in both the active avoidance and spatial navigation tasks.

Exploratory behavior and locomotor activity: A failure to find effects in animals prenatally exposed to cocaine

Pregnant Long-Evans rats were administered cocaine orally (60 mg/kg) on gestational days 14-21, or subcutaneously (40 mg/kg) on gestational days 8-21. The oral dosage of cocaine produced some maternal lethality and reduced maternal weight gain throughout the pregnancy by approximately 12%. The subcutaneous dosage regimen reduced the lethality but still caused a decrease in maternal weight gain. Neither dosing regimen affected the number of pups in the litter, their weight, or growth. The offspring of dams that received the oral dosage were examined as adults in an automated holeboard apparatus and were also tested at postnatal day 21 and as adults in an open field. Adult animals exposed prenatally to cocaine did not differ from untreated controls in any of the automated measures of the holeboard apparatus or in the various behaviors, including nosepokes, recorded in the open field. Animals in the vehicle control group did make fewer nosepokes in the open field than the cocaine group, which did not differ from untreated animals. The offspring of dams given the subcutaneous dosage regimen were observed in the open field at day 21. In this case, the prenatal cocaine group had a tendency to make fewer crosses into adjacent quadrants, to rear less often, and to make fewer nosepokes than the control groups. Based on these and other data from our lab, it does not appear that in the rat, prenatal cocaine exposure has pronounced effects on subsequent exploratory behavior and activity in weanling or adult animals.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

AIM To evaluate the effect of orally administered plecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models. METHODS The cyclic guanosine monophosphate (cGMP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cell-based assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid (5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium (DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic (TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout (TCRα(-/-)) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity. RESULTS Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C (GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cGMP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs (0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity (P < 0.05) and disease activity index (P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα(-/-) mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases.

Failure of acute cocaine administration to differentially affect acoustic startle and activity in rats prenatally exposed to cocaine

Pregnant rats were administered 40 mg/kg of cocaine hydrochloride subcutaneously on gestation days 14 through 21. Rats in one control group were pair-fed to the cocaine group and injected with the saline vehicle during the dosing period, while an untreated control group was simply weighed throughout pregnancy. Maternal weight gain was reduced 13% in the cocaine group and pair-fed controls, but the offspring did not differ in their numbers or growth compared to the untreated controls. The offspring were examined between postnatal days 80 and 96 in tests of the acoustic startle response and open field behavior immediately following acute administration of 0, 5, or 10 mg/kg of cocaine. The acute dosages of cocaine increased the startle response and increased behavior in the open field. There was no evidence that the prenatal treatment altered the baseline in either of these tests. Adult rats exposed prenatally to cocaine entered more quadrants in the open field and reared more frequently than the other groups following the 10 mg/kg dosage of cocaine. However, there was no evidence of an effect of prenatal treatment among the groups administered the 5 mg/kg dosage in the open field test, nor was there a systematic effect of prenatal treatment on the acute effects of cocaine in the acoustic startle test. These data do not provide evidence that prenatal exposure to cocaine can produce persistent changes in the neural systems with which it interacts in the adult.

Conditions that affect the thresholds of the components of the eyeblink reflex in humans.

The threshold stimulus intensities for elicitation of the two EMG components of the eyeblink reflex were determined in human subjects under different conditions. In the first experiment subjects sat with eyelids open and were not warned about reflex elicitation. The threshold of R1 was substantially greater than that of R2. In four additional experiments subjects (a) triggered the eliciting stimulus, (b) were warned about the arrival of each stimulus, (c) had a conditioning stimulus presented before reflex elicitation, and (d) had their eyelids closed at the time of stimulus delivery. The conditions of these subsequent experiments reduced the difference between the reflex thresholds largely by lowering the R1 threshold. These results indicate that variations in the testing environmental contribute to the discrepancy between our data showing unequal threshold for elicitation of the R1 and R2 components and other reports showing equal thresholds. The results are also another illustration of the ability of complex psychological events to selectively affect different reflex pathways.

The acoustic startle response and disruption of aiming: II. Modulation by forewarning and preliminary stimuli

Four experiments examined the disruption of rifle aim by intense noise bursts. In Experiment 1 a trigger pull was followed occasionally by a noise burst. Aiming was disrupted for 1—2 s, an effect that habituated within days and recovered between days. Expected stimuli were less disruptive than were unexpected stimuli. Experiment 2 demonstrated that weak auditory prestimuli 100 ms before unexpected intense sounds also reduced noise-produced errors. Experiment 3 showed that the intratympanic reflex had not played a protective role in this effect. Experiment 4 showed that a weak tactile prestimulus increased both a muscular measure of the acoustic startle reaction and the perturbing effect of the noise burst on motor performance. In general, conditions that affect the amplitude of the acoustic startle reflex similarly influence the disruptive effect of a noise burst on motor performance, but the two measures are not correlated in the detail necessary to suggest a causative relationship.

Elicitation and modification of the acoustic startle reflex in animals prenatally exposed to cocaine

In separate experiments, pregnant Long-Evans rats were administered cocaine orally (60 mg/kg/day) on gestation days 14-21, or subcutaneously (40 mg/kg/day) on gestational days 8-21. For each route of administration, a vehicle control group was pair-fed to the group administered cocaine and another control group was left untreated. Throughout pregnancy, the dams that received cocaine gained approximately 15% less weight than the untreated controls, but none of the dosage procedures affected the size of the litters, or the weight and growth of the offspring. When the offspring reached adulthood, various assessments of reflex function were made using the acoustic startle reflex and prepulse inhibition of startle. There were no effects on startle habituation or reflex modification that could be attributed to the prenatal exposure to cocaine.

The acoustic startle response and disruption of aiming: I. effect of stimulus repetition, intensity, and intensity changes

Three experiments examined the disruption of perceptual motor performance by intense noise bursts. Subjects aimed a rifle at a fixed target for 15-s periods separated by 15 s of rest. This cycle was repeated 30 times in each of two series separated by a 15-min rest, each series containing five noise bursts. The noise bursts disrupted aiming for 1—2 s, an effect that increased with sound pressure level for 110, 120, and 130 dB stimuli. There was no difference between stimuli with energy centered on 250 Hz as opposed to 800 Hz. The effect diminished over the five bursts within the first series (but not to zero) and did not recover in the 15-min rest period. Some subjects received three days of testing; in these cases the effect of the noise bursts partially recovered after rest intervals of 24 hrs and then seven days. Other subjects received 15 trials with 110-dB stimuli, then five more trials with 130-dB stimuli. The disruption of aiming by 130 dB stimuli was not reduced by prior exposure to 110-dB stimuli.

Reproductive effects of chronic administration of murine interferon-gamma.

Daily subcutaneous doses of 0.02, 0.2, or 2 mg/kg/d of recombinant murine interferon-gamma (rmuIFN-gamma) were given to mice on postnatal days 8 through 60 to determine effects on maturation, behavioral/ functional development, and reproductive capacity. Male mice receiving 2 mg/kg/d rmuIFN-gamma had delayed sexual maturation, reduced epididymal and testes weights, reduced sperm count and concentration, and sperm abnormalities (crimped flagellum). Mating performance and fertility were also reduced in the absence of altered histopathology of the testes. Males given 0.2 and 2 mg/kg/d had swelling and ulcerative dermatitis around the urogenital area, which were observed after sexual contact and attributed to a bacterial infection. Motor activity (time spent in movement) was decreased in all mice receiving 2 mg/kg/d. No microscopic changes observed in any organs were attributed to rmuIFN-gamma administration.