Browsing by Author "Stewart, Robert"

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    ALTERATIONS IN THE SEEKING AND SELF-ADMINISTRATION OF ETHANOL AND ANXIETY-LIKE BEHAVIOR FOLLOWING EXPOSURE TO YOHIMBINE IN RATS SELECTIVELY BRED FOR HIGH ALCOHOL INTAKE
    (2011-08-16) Bertholomey, Megan Lee; Grahame, Nicholas J.; Czachowski, Cristine; Stewart, Robert; Chester, Julia A.
    Stress has been shown to contribute to alcohol drinking; however, inconsistencies in both the clinical and pre-clinical literature speak to the need for better paradigms to study this interaction. The present experiments compared animal models of the propensity to consume ethanol, the selectively bred alcohol-preferring (P) and high-alcohol-drinking (HAD) rat lines, in their response to yohimbine on ethanol seeking and self-administration and anxiety-like behavior. The P and HAD lines consume similar amounts of ethanol, yet differ in apparent motivation to drink ethanol, in anxiety-like behavior, and response to stress in alcohol drinking. Therefore, it was of interest to determine whether stress may differentially affect ethanol-motivated behaviors between the P and HAD lines. Acute administration of yohimbine, an α-2 adrenoreceptor antagonist that increases anxiety and activate stress systems, increased operant ethanol self-administration and reinstatement of ethanol seeking in P rats, and free-choice ethanol drinking in both P and HAD rats. However, acute yohimbine administration decreased ethanol drinking when given limited access in the home cage, an effect that was diminished by extending the pre-treatment interval or increasing the number of ethanol exposure sessions. Yohimbine did not alter appetitive responding during a non-reinforced trial, nor did yohimbine alter the acquisition of free-choice ethanol drinking. Exposure to alcohol deprivation resulted in modest increases in ethanol intake, but yohimbine did not potentiate this effect. While acute yohimbine administration increased anxiety-like behavior, prior experience with repeated yohimbine exposures or with repeated deprivation periods did not. P rats were shown to be more active and less anxious and to display greater responding during a non-reinforced trial than HAD rats. Taken together, the results of these experiments demonstrate that the timing of yohimbine exposure relative to ethanol access is a critical component to determining its effects on ethanol seeking and self-administration and anxiety-like behavior. Further investigation into the parameters under which stress alters the motivation to seek and consume ethanol between these selectively bred lines is warranted, and future work that incorporates therapeutic agents aimed at reducing stress reactivity and alcohol drinking could elucidate effective strategies in the treatment of alcoholism.
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    Characterization of Behavioral Profiles for Inbred P and NP and Congenic P.NP and NP.P Rats
    (2012-08-27) Jensen, Meredith; Grahame, Nicholas J.; Stewart, Robert; Czachowski, Cristine; Roman, Erika
    Alcoholism inheritance rates have been estimated as high as 60% in a human population. Many significant features of alcohol dependence have been replicated in rodent animal models of alcoholism, however not in totality. These animal models include inbred preferring (iP) and nonpreferring (iNP) rat types. Congenic rats have been engineered from the iP and iNP strains whereby a P congenic rat has in its genome a well-chosen chromosomal portion taken from an NP rat (P.NP) and, reciprocally, an NP congenic rat has acquired the analogous DNA from a P rat (NP.P). In this case, a quantitative trait locus (QTL) from chromosome 4 is the donor genetic material for the congenic rats. It is of great interest to further study this chromosome 4 QTL because it has been found to control a significant portion of ethanol consumption behavior in iP and iNP rats. This study aimed to behaviorally profile the iP, iNP and reciprocal congenic rats. As a result of the behavioral profiling of these genetically related groups, some conclusions could be made regarding which behaviors appear to be controlled by the chromosome 4 donor DNA.This study primarily utilized the Multivariate Concentric Square Field apparatus (MCSF) to characterize behavioral profiles for the inbred and congenic rats. The Open field (OF) and Elevated plus maze (EPM) supported this effort. The MCSF is valuable in that it allows for the animals to interact within an environment that has ethological value. The 12 different zones that make up the field are characterized by some functional quality in terms of type and duration of behavior performed, etc. The behavioral data is aggregated and finally represented in terms of five functional categories, the elements of the behavioral profile: general activity, exploratory activity, risk assessment, risk taking, and shelter seeking. The study hypotheses were shaped by prior research suggesting that iPs should display lower general activity and risk taking strategy than iNPs in the MCSF. Inbred Ps should be more active in the OF and spend more time in the center of the EPM. Generally, it is expected that the iP QTL confer behavioral phenotypes to the iNP strain that deviate toward a "P" behavioral phenotype and reciprocally, the iNP QTL confer behavioral phenotypes to the iP strain that deviate toward an "NP" behavioral phenotype. The results showed that iP rats performed more risk assessment and risk taking behavior and less shelter seeking and anxiety-like behavior than iNP rats. It followed that P.NP congenic rats significantly downgraded their risk assessment and risk taking behavior when compared to iP rats. This decrease can be attributed to the chromosome 4 QTL donated from the iNP breed. All together this study concludes that risk assessment and risk taking behavior in the iP rats is controlled by the same DNA region that, in part, determines voluntary intake of ethanol consumption. Further fine mapping of the QTL region should help in discovering if the same DNA sequences that influence ethanol intake also significantly influence risk behavior.
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    A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease
    (Elsevier, 2014-11) Jessen, Frank; Amariglio, Rebecca E.; van Boxtel, Martin; Breteler, Monique; Ceccaldi, Mathieu; Chételat, Gaël; Dubois, Bruno; Dufouil, Carole; Ellis, Kathryn A.; van der Flier, Wiesje M.; Glodzik, Lidia; van Harten, Argonde C.; de Leon, Mony J.; McHugh, Pauline; Mielke, Michelle M.; Molinuevo, Jose Luis; Mosconi, Lisa; Osorio, Ricardo S.; Perrotin, Audrey; Petersen, Ronald C.; Rabin, Laura A.; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M.; Sachdev, Perminder S.; de la Sayette, Vincent; Saykin, Andrew J.; Scheltens, Philip; Shulman, Melanie B.; Slavin, Melissa J.; Sperling, Reisa A.; Stewart, Robert; Uspenskaya, Olga; Vellas, Bruno; Visser, Pieter Jelle; Wagner, Michael; Department of Radiology and Imaging Sciences, IU School of Medicine
    There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
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    Exploring Potential Pharmacologic Treatments for Alcoholism: Can the Use of Drugs Selective for the µ-, δ-, and κ- Opioid Receptors Differentially Modulate Alcohol Drinking?
    (2013-07-12) Henderson, Angela Nicole; Czachowski, Cristine; Grahame, Nicholas J.; Stewart, Robert; Kinzig, Kimberly P.; Hazer, John
    Naltrexone (NTX) is clinically efficacious at attenuating alcohol intake in non-abstinent alcoholics and, to a lesser extent, craving, independent of intake. While generally regarded as a non-selective opioid antagonist, NTX has been shown to have concentration dependent selectivity with lower doses (< 1.0 mg/kg) selective for the mu receptor and doses exceeding 1.0 mg/kg capable of binding to delta and kappa receptors. Like the mu system, the delta receptor system has also been implicated in mediating the rewarding effects of EtOH. In contrast, the role of the kappa system is less clear though recent evidence suggests that kappa activation may mediate EtOH aversion. Thus, the present study sought to evaluate the effects of both mu-selective and non-selective doses of naltrexone, the selective delta antagonist naltrindole (NTI), and the selective kappa agonist U50,488H (U50) in a paradigm that procedurally separates the motivation to seek versus consume a reinforcer to assess whether these receptor-selective drugs differentially affects these behaviors in both selected (alcohol-preferring P rats) and non-selected (Long Evans) rats, and whether these effects are specific to EtOH. Rats were trained to complete a single response requirement that resulted in access to either 2% sucrose or 10% EtOH for a 20-min drinking session. In three separate experiments, rats were injected (using a balanced design) with either vehicle or 1 of 3 doses of drug: U50 (IP; 2.5, 5.0, or 10.0mg/kg), NTI (IP; 2.5, 5.0, or 10.0 mg/kg), low NTX (SC; 0.1, 0.3, or 1.0 mg/kg) or high NTX (SC; 1.0, 3.0, or 10.0 mg/kg) on both consummatory and appetitive treatment days. Following either a 20 (U50), 15 (NTI), or 30 minute (NTX) pretreatment, rats were placed into an operant chamber and intake (consummatory) or lever responses (appetitive) and response latencies were recorded. The results showed that overall: U50, NTI, and NTX attenuated intake and responding for sucrose and EtOH. Independent of reinforcer, LE rats were more sensitive to U50’s effects on intake while P rats were more sensitive to the effects on seeking. P rats reinforced with EtOH were more sensitive to NTI’s effects on intake and seeking than all other rat groups. P rats were more sensitive overall to lower doses of NTX than LE rats and lower doses of NTX were more selective in attenuating EtOH responding vs. sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results demonstrate that craving and intake may be differentially regulated by the kappa, delta, and mu opioid receptor systems as a function of “family history” and suggest that different mechanisms of the same (opioid) system may differentially affect craving and intake.