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The Roman strains of rats as a psychogenetic tool for pharmacological investigation of working memory: example with RU 41656.
This study examined the effects of RU 41656, a dopaminergic D2 agonist, on the differential working memory performances and on the differential activities of the neurochemical systems of the Roman high (RHA) and Roman low (RLA) avoidance strains of rats. Compared with RLA, RHA performed worse in three tests of working memory (spontaneous alternation, radial maze and object recognition) and had higher levels of exploratory locomotor activity. Hippocampal and frontal cortex choline acetyltransferase (ChAT) activities were lower in RHA. Frontal cortex DA and DOPAC levels, hippocampal and striatal 5-HT and NA levels were higher in RHA. RU 41656 induced a significant improvement in working memory performance of RHA, whereas in RLA it had no effect. It decreased exploratory locomotor activity in both strains. ChAT activity in hippocampus was not affected by RU 41656 in either strain, whereas in frontal cortex it was increased in RHA but not in RLA. Hippocampal NA levels were decreased by RU 41656 in RHA but not in RLA. These results confirm previous data concerning the promnesic effect of RU 41656 and extend the finding that the Roman strains are a psychogenetic model for the behavioural, neurochemical and psychopharmacological study of the working memory in rats.
Strain-dependent effects of post-training GABA receptor agonists and antagonists on memory storage in mice.
Post-training administration of the GABA-A and GABA-B receptor agonists muscimol and baclofen dose-dependently impaired retention of an inhibitory avoidance response in C57 mice, while improving memory consolidation in the DBA strain. By contrast, picrotoxin (blocker of GABA-activated ionophores), bicuculline (GABA-A antagonist) and CGP 35348 (GABA-B antagonist) dose-dependently improved retention in C57 mice and impaired it in DBA mice. These effects cannot be ascribed to non-specific actions of the drugs on retention performance, as the latencies during the retention test of those mice that had not received footshock during the training were not lengthened by the post-training drug administration. The effects on retention performance induced by GABA agonists and antagonists are probably due to an effect on memory consolidation, since they are observed when the drugs are given at short, but not at long, intervals after training. These results are discussed in terms of possible interaction of GABA systems with endogenous opioid and dopamine systems, whose activation has been shown to produce strain-dependent effects on memory processes. The possible utilization of these results for a genetic behavioral approach with recombinant inbred (RI) mice is also considered.
Risk factors for invasive cervical cancer in Latino women.
Most invasive cervical cancer research in the United States has been conducted on non-Latino-White (NLW) and African-American women. Incidence, mortality, stage at diagnosis and survival indicators for invasive cervical cancer in Latino women in California are compared to NLW and African-American women. A model is presented which depicts structural, behavioral, genetic and biological risk factors for invasive cervical cancer. A literature review of risk factors and their association with invasive cervical cancer was conducted using MEDLINE and PsychINFO databases to determine if ethnic differences in risk factors explain observed differences in morbidity and mortality. Latino women experience a significantly higher incidence and mortality associated with invasive cervical cancer than NLW women. The review of risk factors found that rate differences of cervical cancer screening, early detection and human papilloma virus (HPV) type-specific infection explain much of the disparity in disease burden. Further research must clarify if ethnic differences exist in risk factors associated with ethnic variation in HPV-type prevalence in both cases and their sexual partners, in host immune responses, and multiparity.
Coming to terms with heritability.
The complex mechanisms of heredity are little-appreciated by non-specialists, in some measure, because of misunderstandings that are perpetuated when words used for technical terms have other, more widely understood, folk meanings. When a word has both technical and folk meanings, it is the responsibility of the specialist to avoid promoting confusion by either using extremely cautious and precise language when using the term or, in cases when confusion is inevitable, abandoning the term in favor of one without a widely understood folk meaning. The study of heredity is beset by such confusion, and the term heritability appears to be at the heart of some of the confusion. In this article, I discuss both the technical and folk meanings of heritability and examine the bridge between them. By continuing to use the term heritability, we risk promulgating serious misunderstanding about the workings of heredity, therefore I suggest selectability as an alternative term to avoid such pitfalls.
Differences in vulnerability and susceptibility to dexamphetamine in Nijmegen high and low responders to novelty: a dose-effect analysis of spatio-temporal programming of behaviour.
Susceptibility to behavioural effects of dexamphetamine (0.5-2.0 mg/kg, SC) was analyzed in Nijmegen high responders to novelty (HR) and Nijmegen low responders to novelty (LR), using an automated ethological analysis. The main results were that, first, dexamphetamine was more toxic in HR than LR: 5.0 mg/kg dexamphetamine was lethal in 75% HR, respectively, 25% LR. Second, dexamphetamine had effects in HR at doses far lower than in LR: a dose of 0.5 or 1.0 mg/kg dexamphetamine was already sufficient to produce ceiling effects in HR, whereas a minimum dose of 2.0 mg/kg dexamphetamine was required to reach effects of a similar magnitude in LR. Third, the behavioural responses to 2.0 mg/kg dexamphetamine did not differ between HR and LR. These data show that HR are both more vulnerable and more susceptible to the toxic and behavioural effects of intermediate doses of dexamphetamine than LR. It is concluded that knowledge acquired previously about the neurochemical differences between Nijmegen HR (APO-SUS) and Nijmegen LR (APO-UNSUS) rats can be used to analyze further the mechanisms of action underlying individual-specific differences in drug abuse in animals and man.
Different behavioral effects of daily or intermittent dexamphetamine administration in Nijmegen high and low responders.
Outbred strains of Wistar rats contain both high responders to novelty (HR) and low responders to novelty (LR). Male HR and LR selected from the Nijmegen outbred strain of Wistar rats differ in their sensitivity to acute administration of dexamphetamine (AMPH). Sub-chronic administration of AMPH sensitizes rats to this agent, and this sensitization (SENS) increases when an intermittent, instead of continuous, regimen is used. Thus, the question arose whether HR and LR also differ in the development of sensitization to AMPH. AMPH (0.5 mg/kg SC) was given five times either each consecutive day (daily: DAY) or each alternate day (intermittent: INT). Drug-induced changes in the spatio-temporal patterning of open field behavior were assessed for a period of 45 min. Three sets of data were found: i) in the AMPH-DAY conditions: total number of excursions with 0 stops increased in time: this SENS was far greater in HR than in LR: ii) the effects under AMPH-DAY conditions were far greater that those under AMPH-INT conditions, especially in HR: iii) under AMPH-INT conditions a new phenomenon was observed: following a period in which SENS occurred, a period marked by desensitization appeared which, in turn, was followed by a period with SENS being greater than the SENS seen during the first time; this effect was far more pronounced in HR than in LR. It is concluded that AMPH-INT induces time-dependent changes marked by consecutive periods of SENS and desensitization. This has far-reaching consequences for hypotheses about processes giving rise to the development of (1) SENS to psychostimulants and, consequently, (2) certain aspects of addiction to these drugs.
LONI visualization environment.
Over the past decade, the use of informatics to solve complex neuroscientific problems has increased dramatically. Many of these research endeavors involve examining large amounts of imaging, behavioral, genetic, neurobiological, and neuropsychiatric data. Superimposing, processing, visualizing, or interpreting such a complex cohort of datasets frequently becomes a challenge. We developed a new software environment that allows investigators to integrate multimodal imaging data, hierarchical brain ontology systems, on-line genetic and phylogenic databases, and 3D virtual data reconstruction models. The Laboratory of Neuro Imaging visualization environment (LONI Viz) consists of the following components: a sectional viewer for imaging data, an interactive 3D display for surface and volume rendering of imaging data, a brain ontology viewer, and an external database query system. The synchronization of all components according to stereotaxic coordinates, region name, hierarchical ontology, and genetic labels is achieved via a comprehensive BrainMapper functionality, which directly maps between position, structure name, database, and functional connectivity information. This environment is freely available, portable, and extensible, and may prove very useful for neurobiologists, neurogenetisists, brain mappers, and for other clinical, pedagogical, and research endeavors.
The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages.
We use findings from the behavior genetics literature about how genetic factors (latently) influence alcohol dependence and related disorders to develop and test hypotheses about the risk associated with a specific gene, GABRA2, across different developmental stages. This gene has previously been associated with adult alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA) sample [Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. K., Nurnberger Jr., J. I., O'Connor, S. J., Reich, T., Rice, J., Schuckit, M., Porjesz, B., Foroud, T., and Begleiter, H. (2004). Am. J. Hum. Genet. 74:705-714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B:104-109; Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., and Gelernter, J. (2005). Alcohol. Clin. Exp. Res. 29:493-498]. In a sample of children and adolescents ascertained as part of the COGA project, we find that GABRA2 is significantly associated with childhood conduct disorder symptoms, but not with childhood alcohol dependence symptoms. A consistent elevation in risk for alcohol dependence associated with GABRA2 is not evident until the mid-20s and then remains throughout adulthood. GABRA2 is also associated with other drug dependence in our sample, both in adolescence and adulthood.
Serum uric acid as a cardiovascular risk factor for heart disease.
Cardiovascular risk factors are those environmental, behavioral, genetic, and/or personal factors whose presence indicates a heightened risk of subsequent vascular disease events. Smoking, hypertension, and hyperlipidemia, initially identified by astute clinicians, were all subsequently confirmed and defined as risk factors through formal prospective epidemiologic study, long before evidence of causality was available. Ultimately, clinical trials demonstrated a reversible contribution of both high blood pressure and elevated lipids to stroke and heart disease. As a result, these risk factors are now the cornerstones for both assessment of relative cardiovascular risk and targets for preventive intervention. The criterion for risk factor status is a strong, consistent, timely, and statistically significant association to disease events that is independent of and unconfounded by other known risk factors. The purpose of this review is to assess available data to determine whether or not serum uric acid meets the standard for designation as a risk factor.
Childhood trauma and personality disorder: toward a biological model.
Cross-sectional and prospective associations of personality disorder with childhood trauma provide an important clue regarding the biological mechanism of personality disorder. In this review, empirical literature from several domains is summarized. These include relevant findings from behavioral genetics, preclinical models of early life parental care, and clinical translational studies of personality disorder. Identification of the biological mechanism by which childhood trauma exerts an effect on personality disorder may require modification of the conceptualization of personality disorder, either as a set of categories or dimensions.
Epidemiology of prostatitis.
Prostatitis is the third most important condition of the prostate. Problems in the diagnosis and classification of this condition, however, have hindered epidemiologic research. Consequently, our understanding of the incidence of prostatitis and factors that increase its probability is limited. Recent studies suggest that the prevalence of prostatitis is 5% to 9% among unselected men in the community. Based on estimates from national data, approximately 2 million men in the United States seek treatment for prostatitis each year. A number of recent studies suggest that genetic, behavioral, and environmental factors; age; inflammatory mediators; and oxidative stress may be risk factors for prostatitis. However, findings from most of these studies may at best be considered preliminary because of problems with small sample sizes or lack of generalizability. Nonetheless, these studies suggest hypotheses that should be tested in well-designed population-based studies.
Individual (constitutional) differences in sleep patterns in rats.
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Locomotor acitvity in Drosophila. V. A comparative biochemical study of selectively bred populations.
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Strain differences in the elicitation of electrocortical after-discharges.
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Behavioral effects of handling rabbits in infancy.
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Septal damage and muricide: effects of stain and handling.
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Tail pinch induced eating: psychogenetic comparison of Roman high- and low-avoidance rats.
Consummatory behavior elicited by mild tail pinch in the presence of solid food was studied in male Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats. RLA/Verh rats, characterized as the more emotional of the two rat lines, exhibited significantly shorter latencies to bite and eat solid food during tail pinch than the RHA/Verh rats. Treatment with 6, 12 and 24 mg/kg sodium pentobarbital prior to tail pinch failed to increase the elicited eating in either rat line.