Operant methodology in the study of learning.
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A series of experiments is described in which operant methodology is used to study the effects of drugs on "learning." Emphasis is placed on the technique of repeated acquisition as a behavioral baseline for studying this type of transition state. In this technique, each subject is required to learn a new discrimination each session. Multiple-schedule procedures are also described in which acquisition is compared to a "performance" task, where the discrimination is the same each session. The learning baseline is more sensitive to the disruptive effects of a variety of drugs (e.g., cocaine, d-amphetamine, haloperidol) than is the performance baseline. This general finding obtains across procedural variations and species (pigeons and monkeys). The potential usefulness of these procedures for studying both acute and chronic behavioral toxicity is discussed. (+info)
Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone by cultured monkey lung explants.
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The metabolism of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated in short-term cultures of monkey lung. Explants from the lungs of two patas monkeys (Erythrocebus patas) and one cynomolgus monkey (Macaca fascicularis) were incubated with 10 microM [5-(3)H]NNK and aliquots were analyzed for NNK metabolites by HPLC at various time points from 1 to 24 h. F344 rat lung tissue metabolism of NNK was assayed under the same conditions. Substantial amounts of metabolites from the alpha-hydroxylation metabolic activation pathway were detected in all cultures. In two of the monkey lung cultures, these metabolite levels were significantly higher than those formed by other pathways. All cultures also metabolized NNK by pyridine-N-oxidation and carbonyl reduction. The metabolism of NNK by cultured monkey lung was generally similar to that observed in rat lung, indicating that there are not major species differences between rodents and nonhuman primates in pulmonary metabolism of NNK. (+info)
Imidazenil prevention of alprazolam-induced acquisition deficit in patas monkeys is devoid of tolerance.
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The partial allosteric modulators (PAMs) of gamma-aminobutyric acid-gated Cl(-) current intensities at gamma-aminobutyric acid type A receptors have high affinity but low intrinsic efficacy on benzodiazepine recognition sites. Unlike the full allosteric modulators (FAM), like alprazolam, triazolam, and diazepam, PAMs are virtually devoid of unwanted side effects, including tolerance. Imidazenil (IMD) is a PAM that elicits potent anxiolytic and anticonvulsant actions in rodents and nonhuman primates and retains its anticonvulsant and anxiolytic effects, even in rodents that are tolerant to FAMs. IMD antagonizes the side effects of FAMs in rodents and nonhuman primates. Using patas monkeys and a multiple schedule with repeated acquisition and performance of chain responses, we report that IMD administration for 17 days antagonized without showing tolerance ALP-induced disruption of acquisition. (+info)
Colocalization of integrin receptors and reelin in dendritic spine postsynaptic densities of adult nonhuman primate cortex.
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The expression of telencephalic reelin (Reln) and glutamic acid decarboxylase mRNAs and their respective cognate proteins is down-regulated in postmortem brains of schizophrenia and bipolar disorder patients. To interpret the pathophysiological significance of this finding, immunoelectron microscopic experiments are required, but these cannot be carried out in postmortem human brains. As an alternative, we carried out such experiments in the cortex of rats and nonhuman primates. We found that Reln is expressed predominantly in layer I of both cortices and is localized to bitufted (double-bouquet), horizontal, and multipolar gamma-aminobutyric acid-ergic interneurons, which secrete Reln into extracellular matrix. Reln secretion is mediated by a constitutive mechanism that depends on the expression of a specific signal peptide present in the Reln carboxy-terminal domain. Extracellular matrix Reln is found to aggregate in proximity of postsynaptic densities expressed in apical dendrite spines, which include also the alpha(3) subunit of integrin receptors. Most pyramidal neurons of various cortical layers express the mouse-disabled 1 (Dab1) protein, which, after phosphorylation by a soluble tyrosine kinase, functions as an adapter protein, probably mediating a modulation of cytoskeleton protein expression. We hypothesize that the decrease of neuropil and dendritic spine density reported to exist in the neocortex of psychiatric patients may be related to a down-regulation of Reln-integrin interactions and the consequent decrease of cytoskeleton protein turnover. (+info)
The DNA sequence of the simian varicella virus genome.
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In nonhuman primates, simian varicella virus (SVV) causes a natural disease which is clinically similar to human varicella-zoster virus (VZV) infections. The SVV and VZV genomes are similar in size and structure and share extensive DNA homology. This report presents the complete DNA sequence of the SVV genome. SVV DNA is 124,138 bp in size, 746 bp shorter than VZV DNA, and 40.4% G + C. The viral genome includes a 104,104-bp unique long component bracketed by 8-bp inverted repeat sequences and a short component composed of a 4904-bp unique short region bracketed by 7557-bp inverted repeat sequences. A total of 69 distinct SVV open reading frames (ORFs) were identified, including three that are duplicated within the inverted repeats of the short component. Each of the SVV ORFs shares extensive homology to a corresponding VZV gene. The only major difference between SVV and VZV DNA occurs at the leftward terminus. SVV lacks a VZV ORF 2 homolog. In addition, SVV encodes an 882-bp ORF A that is absent in VZV, but has homology to the SVV and VZV ORF 4. The results of this study confirm the relatedness of SVV and VZV and provide further support for simian varicella as a model to investigate VZV pathogenesis and latency. (+info)
Effects of methamphetamine and scopolamine on variability of response location.
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Methamphetamine and scopolamine were studied in monkeys responding under a multiple fixed-ratio fixed-interval schedule of reinforcement. A response on any one of six levers could satisfy the schedule requirements. Variability of response location was evaluated in terms of switches, where a switch was defined as a response on one lever followed by a response on a different lever. Under baseline conditions the fixed-ratio schedule generated a high rate of responding and a low level of variability, while the fixed-interval schedule generated a low rate of responding and a high level of variability. Both methamphetamine (0.1 to 0.5 mg/kg) and scopolamine (2.4 to 240 microgram/kg) decreased overall response rate and increased variability of response location in each component of the multiple schedule with increasing doses of drug. At lower doses both drugs were found to decrease rate without affecting response variability. (+info)
Perinatal period and pregnancy: intervals of high risk for chemical carcinogens.
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Experiments in rodents indicate that during the post-embryonic period of prenatal development, the fetus is more sensitive than the adult to certain carcinogens, by several decimal orders of magnitude. Most such agents are direct-acting and independent of metabolism. To other substances, often those which require enzyme-mediated metabolic conversion to a chemically reactive derivative in order to effect carcinogenesis, the fetus may be less vulnerable than the adult. The neonate is also more susceptible than adults to some carcinogens, and may be more susceptible than the fetus to certain agents. Both rodent and primate studies indicate that gravid females are also at elevated risk for carcinogenesis, in part because of the presence in the placenta of trophoblastic tissue which may become malignant. The contributions of rapid growth rate, changing metabolic competence, and tissue differentiation to elevated perinatal susceptibility to carcinogens in rodents and primates are discussed, together with the implications of these findings for human beings subjected to industrial or environmental exposures to such chemicals. (+info)
An experimental analysis of the effects of d-amphetamine and cocaine on the acquisition and performance of response chains in monkeys.
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In one component of a multiple schedule of food presentation, monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). Both d-amphetamine and cocaine, at the higher doses, disrupted the behavior in the learning component; the overall response rate decreased, the overall accuracy was impaired (i.e., percent errors increased), and there was less within-session error reduction. The performance component was generally less sensitive than the learning component to the disruptive effects of both drugs on rate and accuracy. After pre-feeding or during an extended session, the response rate decreased in both components, but accuracy was generally unaffected. When the four discriminative stimuli in both components were removed, the behavior was disrupted to a greater extent in the performance component. The disruptive effects of both drugs on behavior in the learning component were attenuated when the drugs were administered during the session after the response chain had been acquired. It was concluded that the greater sensitivity of the learning component to disruptive drug effects is related to the relatively weak stimulus control and/or the lower rate of reinforcement associated with that component. (+info)