Biomedical subjects

R R Miller

Publications and source records attributed to R R Miller.

At least 37 records · Page 2Linked to original sources

PubMed1999

Recovery from one-trial overshadowing.

Prevailing models of associative learning can all account for multitrial overshadowing. However, they fail to account for one-trial overshadowing, which is ordinarily explained in terms of distraction of the subject by the more salient of two simultaneously trained cues from the less salient cue, which interferes with associative acquisition. In the present study, we demonstrate that recovery from overshadowing can be obtained through two techniques that have previously been found to restore responding to overshadowed cues in multitrial training situations. Specifically, recovery from one-trial overshadowing was obtained by extinguishing the overshadowing stimulus and also by administering a posttraining reminder treatment consisting of brief exposure to the overshadowed cue. The similarity of these observations to those in multitrial overshadowing suggests that one-trial and multitrial overshadowing arise from a common underlying mechanism and further augments the view that all cue competition is due (at least in part) to a failure to express acquired information, rather than to a failure to learn.

Analysis of Variance↗

PubMed1999

Interaction of diclofenac and quinidine in monkeys: stimulation of diclofenac metabolism.

The cytochrome P-450 (CYP)3A4-mediated metabolism of diclofenac is stimulated in vitro by quinidine. A similar effect is observed in incubations with monkey liver microsomes. We describe an in vivo interaction of diclofenac and quinidine that leads to enhanced clearance of diclofenac in monkeys. After a dose of diclofenac via portal vein infusion at 0.055 mg/kg/h, steady-state systemic plasma drug concentrations in three male rhesus monkeys were 87, 104, and 32 ng/ml, respectively (control). When diclofenac was coadministered with quinidine (0.25 mg/kg/h) via the same route, the corresponding plasma diclofenac concentrations were 50, 59, and 18 ng/ml, representing 57, 56, and 56% of control values, respectively. In contrast, steady-state systemic diclofenac concentrations in the same three monkeys were elevated 1.4 to 2.5 times when the monkeys were pretreated with L-754,394 (10 mg/kg i.v.), an inhibitor of CYP3A. Further investigation indicated that the plasma protein binding (>99%) and blood/plasma ratio (0.7) of diclofenac remained unchanged in the presence of quinidine. Therefore, the decreases in plasma concentrations of diclofenac after a combined dose of diclofenac and quinidine are taken to reflect increased hepatic clearance of the drug, presumably resulting from the stimulation of CYP3A-catalyzed oxidative metabolism. Consistent with this proposed mechanism, a 2-fold increase in the formation of 5-hydroxydiclofenac derivatives was observed in monkey hepatocyte suspensions containing diclofenac and quinidine. Stimulation of diclofenac metabolism by quinidine was diminished when monkey liver microsomes were pretreated with antibodies against CYP3A. Subsequent kinetic studies indicated that the K(m) value for the CYP-mediated conversion of diclofenac to its 5-hydroxy derivatives was little changed (75 versus 59 microM), whereas V(max) increased 2.5-fold in the presence of quinidine. These data suggest that the catalytic capacity of monkey hepatic CYP3A toward diclofenac metabolism is enhanced by quinidine.

Animals↗

PubMed1999

Posttraining shifts in the overshadowing stimulus-unconditioned stimulus interval alleviates the overshadowing deficit.

Two conditioned lick suppression experiments explored the effects on overshadowing of a posttraining change in the temporal relationship between the overshadowing conditioned stimulus (CS) and the unconditioned stimulus (US). Rats received either trace (Experiment 1) or delay (Experiment 2) overshadowing training. Then pairings of the overshadowing CS and US were given with either a trace or delay temporal relationship. Overshadowing was alleviated by shifting the overshadowing CS-US temporal relationship so that it no longer matched the overshadowed CS-US temporal relationship. These outcomes are explicable in terms of an integration of the comparator hypothesis, which states that cue competition effects (e.g., overshadowing) will be maximal when the information potentially conveyed by competing CSs is equivalent, and the temporal coding hypothesis, which states that CS-US intervals are part of the information encoded during conditioning.

Animals↗

PubMed1998

3-Pyridyloxypropanolamine agonists of the beta 3 adrenergic receptor with improved pharmacokinetic properties.

Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.

Adrenergic beta-Agonists↗

PubMed1998

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Adipose Tissue, Brown↗

PubMed1998

Conducting exposure treatment in multiple contexts can prevent relapse.

The acquisition of anxiety disorders (e.g., phobias) is often thought to be mediated by classical conditioning processes (e.g., Wolpe, 1958, Psychotherapy by reciprocal inhibition Wolpe and Rowan, 1989, Behaviour Research and Therapy, 27, 583-585). Thus, the success of exposure therapy is possibly a consequence of extinction, and factors affecting extinction in Pavlovian conditioning are potentially relevant to clinicians who administer exposure therapy. The present experiments investigated the effects of conducting extinction in multiple contexts using rats as subjects in a conditioned suppression paradigm. In Experiment 1, subjects received conditioned stimulus (CS) and unconditioned stimulus (US) pairings in one context followed by extinction of that CS in one or three other contexts. When tested in an associatively neutral context (i.e., different from those of conditioning or extinction), rats that had received extinction in three contexts exhibited less responding to the CS than rats that had received extinction in one context. In Experiment 2, CS-US training occurred in either one or three contexts, followed by extinction of that CS in three other contexts. Testing in a neutral context revealed that rats conditioned in multiple contexts showed greater responding to the CS than rats trained in a single context. The results are discussed in the framework of memory retrieval, and the clinical implications are explored.

Animals↗

PubMed1998

A developmental profile of the effects of ethanol on the levels of chick brain phospholipids.

The effects of embryonic exposure to ethanol on brain phospholipid levels were studied by injecting various concentrations of ethanol, ranging from 0 to 149 microns kg-1 egg, into fertile chicken eggs at 0 days of incubation. At 7, 9, 11, 15 and 18 days of incubation, brains were collected and the levels of total phospholipids and various phospholipid classes were measured. Although embryonic exposure to ethanol failed to influence total phospholipid levels, ethanol-induced changes in the levels of individual phospholipid classes were observed. Ethanol-induced increases in the levels of phosphatidylethanolamine (PE) and phosphatidylserine (PS) and ethanol-induced decreases in the levels of phosphatidylcholine (PC) were observed at 9, 11, 15 and 18 days of incubation. Ethanol-induced decreases in brain sphingomyelin (SP) levels were observed at 7 and 18 days of development. These ethanol-induced changes in brain phospholipid levels preceded detectable alcohol dehydrogenase (ADH) activities in both brain and liver.

Acetaldehyde↗

PubMed1998

Temporal encoding as a determinant of overshadowing.

Three conditioned lick suppression experiments explored the effects on overshadowing of the temporal relationships of two conditioned stimuli (CSs) with an unconditioned stimulus (US). Assuming overshadowing is maximal when the potential information conveyed by two competing CSs is equivalent, the temporal coding hypothesis predicts that greater overshadowing will be observed when the CSs share the same temporal relationship with the US. Rats were exposed to an overshadowing CS that had either a forward, simultaneous, or backward relationship to the US. The relationship of the overshadowed CSs to the US was either forward (Experiment 1), simultaneous (Experiment 2), or backward (Experiment 3). The greatest amount of overshadowing was observed when both CSs had the same temporal relationship to the US. The data are discussed within the framework of the temporal coding hypothesis and of alternative models of Pavlovian conditioning based on the informational hypothesis.

Animals↗

PubMed1998

The role of temporal relationships in the transfer of conditioned inhibition.

Two experiments with rats investigated the temporal relationships under which conditioned inhibition will transfer to an independently conditioned excitor (CS) in a summation test. Experiment 1 trained 2 simultaneous inhibitors with either a trace or delay excitatory CS. Transfer of inhibitory behavioral control depended on the temporal relationship of the transfer CS to the unconditioned stimulus (US). Experiment 2 extended these findings by training 2 inhibitors (1 simultaneous and 1 serial) with a single delay excitatory CS. Again, testing with trace and delay transfer CSs found that transfer of inhibitor control depended on the temporal relationship of the transfer CS to the US. In both studies, maximal inhibition was observed when the inhibitor signaled US omission at the same time as the transfer excitor signaled US presentation. The results are discussed in terms of the temporal coding hypothesis.

Animals↗

PubMed1998

Overshadowing and latent inhibition counteract each other: support for the comparator hypothesis.

In 4 conditioned lick suppression experiments with rats, the combined effects of latent inhibition treatment followed by overshadowing treatment were assessed as a test of the comparator hypothesis's (R.R. Miller & L.D. Matzel, 1988) explanations of overshadowing and latent inhibition. Experiments 1 and 2 confirmed the prediction of the comparator hypothesis that combined latent inhibition and overshadowing treatments attenuate the response deficit produced by either treatment alone. Furthermore, consistent with the comparator hypothesis, posttraining changes in the associative status of the putative comparator stimulus altered responding to the target conditioned stimulus (Experiment 3), and switching contexts between latent inhibition and overshadowing treatments (Experiment 4) eliminated the interaction between the latent inhibition and overshadowing treatments.

Animals↗

PubMed1998

Temporal coding in Pavlovian conditioning: Hall-Pearce negative transfer.

The Hall-Pearce (1979) negative transfer effect in rats was used to examine whether temporal relationships are coded as part of the informational content of associations that results from CS-US pairings. The transfer effect consists of a deficit in conditioned responding following CS-USstrong pairings in Phase 2 that results from prior CS-USweak pairings in Phase 1. Using conditioned bar-press suppression, we found that gaps of different duration between CS termination and US onset in the two training phases resulted in less of a Hall-Pearce negative transfer effect than did an equivalent gap in the two training phases. The results are discussed with respect to the temporal coding hypothesis (Matzel, Held, & Miller, 1988), the Pearce and Hall (1980) model, and Bouton's (1993) interference model.

Animals↗

PubMed1998

Closed rupture of the anterior tibial tendon. A case report.

Closed subcutaneous rupture of the anterior tibial tendon is a relatively uncommon injury that requires a thorough clinical examination to diagnose correctly. The authors report a case of this disorder and provide a review of the relevant literature. A method of surgical repair not previously described in the literature is also presented.

Age Factors↗

PubMed1998

Disposition of L-732,531, a potent immunosuppressant, in rats and baboons.

L-732,531 is a semi-synthetic analog of the macrolide tacrolimus (Prograf(R)). Like tacrolimus, L-732,531 is a potent immunosuppressant. In this study, its absorption, distribution, metabolism, and excretion were studied in rats and baboons. In rats, its blood and plasma levels were similar, whereas in baboons, its blood levels were, on average, twice as high as those in plasma. This was consistent with the in vitro blood-to-plasma ratio of L-732, 531, which in these two species, as well as in humans, was much lower than that of tacrolimus and showed a minimal concentration dependence. After iv administration to rats, the blood and plasma clearance of L-732,531 decreased from approximately 60 ml/min/kg at 0.2 mg/kg to 30 ml/min/kg when dosed at 1 and 3 mg/kg. After oral administration, plasma area under the concentration vs. time curve (AUC) and maximal plasma concentration (Cmax) increased more than proportionally to the dose. At 1, 5, and 15 mg/kg, plasma AUC was 29, 466, and 2832 ng.hr/ml, respectively, and Cmax was 10, 129, and 304 ng/ml, respectively. Bioavailability, although compromised by nonlinear kinetics, was estimated to be between 8% and 18%. In baboons, the clearance of L-732,531 was lower than that in rats, especially when calculated from blood concentrations (12 ml/min/kg at 0.2 mg/kg and 8 ml/min/kg at 1 mg/kg). After oral dosing, baboon plasma AUC and Cmax were much lower than those in rats, but as in rats, they increased more than proportionally with increasing doses. The bioavailability of L-732,531 in baboons was estimated at 3%, 9%, and 24% when animals were dosed at 5, 15, and 26 mg/kg po, respectively. After oral administration of [3H]L-732,531 at 5 mg/kg, approximately 32% of the radioactivity was recovered in bile and urine of rats, compared with 9% in baboons. High-performance liquid chromatography profiles of rat and baboon plasma, bile, urine, and feces indicated that L-732,531 was metabolized extensively to a complex mixture of products. Some intact parent drug was observed in feces of orally dosed animals, indicating incomplete absorption. In vitro, L-732,531 was metabolized more extensively by baboon liver microsomes than rat or human microsomes. Its metabolism in human liver microsomes was shown to be catalyzed primarily by cytochrome P450 3A isozymes.

Animals↗

PubMed1998

Comparator mechanisms and conditioned inhibition: conditioned stimulus preexposure disrupts Pavlovian conditioned inhibition but not explicitly unpaired inhibition.

Three conditioned lick-suppression experiments with rats examined the effects of pretraining exposure to the conditioned stimulus (CS) on behavior indicative of conditioned inhibition. After CS-preexposure treatment, subjects received either Pavlovian conditioned inhibition training or explicitly unpaired inhibition training with the preexposed CS. The inhibitory status of the CS was then assessed with a retardation (Experiment 1) or a summation (Experiment 2) test. Experiment 3 controlled for the unconditioned stimulus-preexposure effect being a potential confound in Experiments 1 and 2. As predicted by the comparator hypothesis (R. R. Miller & L. D. Matzel, 1988), the CS-context association that developed during the CS-preexposure phase disrupted the expression of Pavlovian conditioned inhibition but not the expression of explicitly unpaired inhibition.

Animals↗

PubMed1997

Subchronic inhalation studies of styrene in CD rats and CD-1 mice.

Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived) rats were exposed to styrene vapor at 0, 200, 500, 1000, or 1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrene had no effect on survival, hematology, or clinical chemistry. Males at 1500 ppm weighed 10% less after 13 weeks and males and females at 1000 and 1500 ppm consumed more water than controls. Histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. Groups of 20 male and 20 female CRL CD-1 and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60, 250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortality was observed in both CD-1 and B6C3F1 mice exposed to 250 or 500 ppm; more female mice, but not males, died from exposure to 250 ppm than from 500 ppm. Groups of 10 male and 10 female CRL CD-1 mice were exposed to styrene vapors at 0, 50, 100, 150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Two females exposed to 200 ppm died during the first week. Liver toxicity was evident in the decedents and in some female survivors at 200 ppm. Changes were observed in the lungs of mice exposed to 100, 150, or 200 ppm and in the nasal passages of all treatment groups, those exposed to 50 ppm being less affected. Satellite groups of 15 male rats and 30 male mice were exposed as described above for 2, 5, or 13 weeks for measurement of cell proliferation (BrdU labeling). No increase in cell proliferation was found in liver of rats or mice or in cells of the bronchiolar or alveolar region of the lung of rats. No increase in labeling index of type II pneumocytes was seen in mouse lungs, while at 150 and 200 ppm, an increased labeling index of Clara cells was seen after 2 weeks and in occasional mice after 5 weeks. Large variations in the labeling index among animals emphasize the need for large group sizes. For nasal tract effects, a NOAEL was not found in CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For other effects, the NOAEL was 500 ppm in rats and 50 ppm in mice.

Administration, Inhalation↗

PubMed1997

Ethanol alters brain phospholipid levels which correlate with altered brain morphology.

The effects of embryonic exposure on brain phospholipid levels were studied by injecting various concentrations of ethanol into fertile chicken eggs at 0 days of development. At 18 days of development, the levels of total phospholipids and various phospholipid classes were assayed in brain tissue and correlated to neuron densities within the cerebral hemispheres and the optic lobes. Although ethanol concentrations ranging from 0 to 3700 microns/Kg egg wt. failed to influence either total brain weight or total brain phospholipid levels, ethanol-induced changes in the levels of individual phospholipid classes were observed. When injected with 7 microns of ethanol/Kg egg wt., a 2- to 3-fold increase in brain phosphatidylethanolamine (PE) levels were observed with reduced levels of brain phosphatidylcholine (PC) and brain sphingomyelin (SP). When injected with 74 microns of ethanol/Kg egg wt., ethanol-induced increases in brain phosphatidylserine (PS) and PE were observed with ethanol-induced decreases in brain PC and SP. Cell fractionation studies demonstrated ethanol-induced increases in brain PE and PS and ethanol-induced decreases in brain PC and SP in nuclear, mitochondrial, and microsomal membranes. These ethanol-induced alterations in brain phospholipid profiles correlated with ethanol-induced reductions in neuron densities within the cerebral hemispheres and optic lobes.

Animals↗

PubMed1997

CSs and USs: what's the difference?

Differences in processing representations of conditioned and unconditioned stimuli (CSs and USs) may result from either their temporal order in training (i.e., CSs precede USs) or the greater biological significance of USs. The CS- and US-preexposure effects were used to probe this question. These effects are similar except that context extinction between preexposure and training more readily attenuates the US- than the CS-preexposure effect. In Experiments 1, 2, and 5, context extinction following preexposure to the stimulus that later served as Event 1 in Event 1-->Event 2 pairings alleviated the response deficit due to Event 1 preexposure if Event 1 was biologically significant. In Experiments 3 and 4, context extinction alleviated the response deficit due to Event 2 preexposure if Event 2 was biologically significant. Thus, biological significance and not temporal order determines how a representation will be processed.

Acoustic Stimulation↗

PubMed1997

Blocking of subsequent and antecedent events.

Stimulus competition (e.g., blocking) has been observed between antecedent events (i.e., conditioned stimuli or potential causes), but recent evidence within the human causal learning literature suggests that it could also be obtained between subsequent events (i.e., unconditioned stimuli or potential effects). The present research tested this hypothesis with rat subjects. To avoid confounding the antecedent versus subsequent variable with the affective value of the events involved (i.e., unconditioned stimuli are ordinarily of greater affective value than conditioned stimuli), a preparation was used in which antecedent and subsequent events all lacked affective value during the blocking phases of the study. This was achieved through the use of sensory preconditioning. Blocking of subsequent events as well as antecedent events was observed. The challenge to most associative theories that is provided by blocking of subsequent events is discussed.

Affect↗