Pathological gambling is a serious disorder with lifetime prevalence between 1.1-3.5%. Evidence suggests commonalities in the neurochemical basis of pathological gambling and psychostimulant addiction. However, parallel effects of gambling and a stimulant drug have not been assessed in the same subjects. This study employed a cross-priming strategy in which 12 male pathological gamblers and 11 male controls were exposed to a 15-minute slot machine game and d-amphetamine (0.4 mg/kg). Subjective, cognitive, electrophysiological, and physiological responses were assessed. Gamblers reported greater desire to gamble after both reinforcers, when baseline motivation was controlled. Conversely, gamblers exhibited diminished cardiovascular response to amphetamine. Gamblers also exhibited decreased pre-pulse inhibition (impaired sensorimotor gating), and deficits on this index predicted greater post-amphetamine desire to gamble and decreased heart rate response to the dose. Results are consistent with possible dopaminergic sensitization in pathological gamblers, but also suggest that central noradrenergic receptor deficits contribute importantly to these effects.

Arousal-biased competition (ABC; Mather & Sutherland, 2011) theory predicts that emotional arousal increases both the activation of relevant items and the suppression of irrelevant items in working memory. Study 1 tested ABC theory’s prediction in young and older adults. Suppression was measured with the Healey et al. (2010) paradigm and arousal was manipulated during interference resolution. Item accessibility was measured by comparing naming times of target and competitor words to baseline naming times. Young adults showed suppression of competitors while older adults did not. Arousal did not affect young adults’ naming times, but a mild suppression effect was seen in older adults whose arousal increased after the manipulation. A follow-up study showed that older and younger adults generally agreed on the arousing quality of the stimuli in Study 1. These studies partially support ABC theory and suggest that older adults may retain the ability to suppress irrelevant information when aroused.

MenD, a thiamin diphosphate (ThDP)-dependent enzyme, catalyzes the reaction from isochorismate (ISC) to 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC), and thus is also called SEPHCHC synthase. This conversion is the first committed step in the classical menaquinone (Vitamin K2) biosynthetic pathway, requiring 2-ketoglutarate (2-KG), ThDP and Mg²⁺. Since the biosynthesis of menaquinone is essential in some bacterial pathogens, for example <i>Mycobacterium tuberculosis</i>, MenD or the menaquinone pathway could be a target for drug development.<p> The method for the kinetic assay of the MenD-catalyzed reaction was evaluated by comparing UV spectrophotomeric measurements and HPLC analysis. It was validated that the steady-state kinetics of the MenD-catalyzed reaction can be determined by monitoring UV absorbance of ISC at 278 nm and 300 nm.<p> Phosphonate analogues of 2-KG were synthesized and assayed as inhibitors of the MenD reaction. It was found that the phosphonate analogues of 2-KG are competitive inhibitors with varied affinity for MenD. Of the inhibitors, monomethyl succinyl phosphonate (MMSP) was the most effective, with a <i>K</i>_i of 700 nM. However, the potent MenD inhibitors show no effectiveness against mycobacterial growth.<p> An analogue of isochorismate, trans-(±)-5-carboxymethoxy-6-hydroxy-1,3-cyclohexadiene-1-carboxylate ((±)-CHCD), was synthesized. The (+)-CHCD was found to be an alternative substrate for the MenD-catalyzed reaction. When CHCD was utilized in the MenD reaction, 5-carboxymethoxy-2-(3-carboxy-propionyl)-6-hydroxy-cyclohex-2-enecarboxylate (CCHC) was isolated and characterized, which was believed to be the product of spontaneous isomerization of the SEPHCHC-like analogue. The kinetic study of MenD reaction using (±)-CHCD, in association with the kinetics pattern probed by MMSP, demonstrated for the first time that the MenD-catalyzed reaction has a Ping Pong bi bi kinetic mechanism.<p> The analysis of sequence and structure of MenD from E. coli allowed the investigation of the active site residues and their catalytic functions by mutation of the individual residues. S32A, S32D, R33K, R33Q, E55D, R107K, Q118E, K292Q, R293K, S391A, R395A, R395K, R413K and I418L were prepared and assayed kinetically with respect to 2-KG, ISC, (±)-CHCD, ThDP and Mg²⁺. The values of <i>K</i>_m^a and <i>k</i>_cat^a/<i>K</i>_m^a for the mutants, in comparison with that of wild type MenD, provide valuable insight into the catalytic mechanism of MenD.

MenD, a thiamin diphosphate (ThDP)-dependent enzyme, catalyzes the reaction from isochorismate (ISC) to 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC), and thus is also called SEPHCHC synthase. This conversion is the first committed step in the classical menaquinone (Vitamin K2) biosynthetic pathway, requiring 2-ketoglutarate (2-KG), ThDP and Mg²⁺. Since the biosynthesis of menaquinone is essential in some bacterial pathogens, for example <i>Mycobacterium tuberculosis</i>, MenD or the menaquinone pathway could be a target for drug development.<p> The method for the kinetic assay of the MenD-catalyzed reaction was evaluated by comparing UV spectrophotomeric measurements and HPLC analysis. It was validated that the steady-state kinetics of the MenD-catalyzed reaction can be determined by monitoring UV absorbance of ISC at 278 nm and 300 nm.<p> Phosphonate analogues of 2-KG were synthesized and assayed as inhibitors of the MenD reaction. It was found that the phosphonate analogues of 2-KG are competitive inhibitors with varied affinity for MenD. Of the inhibitors, monomethyl succinyl phosphonate (MMSP) was the most effective, with a <i>K</i>_i of 700 nM. However, the potent MenD inhibitors show no effectiveness against mycobacterial growth.<p> An analogue of isochorismate, trans-(±)-5-carboxymethoxy-6-hydroxy-1,3-cyclohexadiene-1-carboxylate ((±)-CHCD), was synthesized. The (+)-CHCD was found to be an alternative substrate for the MenD-catalyzed reaction. When CHCD was utilized in the MenD reaction, 5-carboxymethoxy-2-(3-carboxy-propionyl)-6-hydroxy-cyclohex-2-enecarboxylate (CCHC) was isolated and characterized, which was believed to be the product of spontaneous isomerization of the SEPHCHC-like analogue. The kinetic study of MenD reaction using (±)-CHCD, in association with the kinetics pattern probed by MMSP, demonstrated for the first time that the MenD-catalyzed reaction has a Ping Pong bi bi kinetic mechanism.<p> The analysis of sequence and structure of MenD from E. coli allowed the investigation of the active site residues and their catalytic functions by mutation of the individual residues. S32A, S32D, R33K, R33Q, E55D, R107K, Q118E, K292Q, R293K, S391A, R395A, R395K, R413K and I418L were prepared and assayed kinetically with respect to 2-KG, ISC, (±)-CHCD, ThDP and Mg²⁺. The values of <i>K</i>_m^a and <i>k</i>_cat^a/<i>K</i>_m^a for the mutants, in comparison with that of wild type MenD, provide valuable insight into the catalytic mechanism of MenD.

Attempting to retrieve a target from memory via a retrieval cue can cause competition from the cue's associates, which might block the target. A 1994 study by Anderson, Bjork, and Bjork demonstrated retrieval-induced forgetting for competing associates and suggested that inhibitory control resolving competition causes the forgetting. A 2011 study by Storm, Angello, and Bjork found forgetting for incorrect associates following creative problem solving. This thesis investigated whether such forgetting is also the result of inhibitory control. Competition was manipulated by instructing participants to remember or forget incorrect associates before working on a Remote Associates Test problem. If problem-solving-induced forgetting is caused by inhibition, then to-be-remembered associates should suffer more forgetting than to-be-forgotten associates. Overall, forgetting occurred for incorrect associates participants were instructed to remember and forget. However, the first quartile of trials showed forgetting only for to-be-remembered associates following longer problem solving durations, suggesting a possible role of inhibitory control as an active means to overcome fixation in creative problem solving.

Inositol dehydrogenase (IDH, EC 1.1.1.18) from <i>Bacillus subtilis</i> catalyzes the reversible NAD⁺-dependent oxidation of the axial hydroxyl group of <i>myo</i>-inositol to form 2-keto-<i>myo</i>-inositol, NADH and H⁺. IDH is the first enzyme in catabolism of myo-inositol, and <i>Bacillus subtilis</i> is able to grow on <i>myo</i>-inositol as the sole carbon source. Our laboratory has previously shown that this enzyme has an unusual active site that can accommodate large hydrophobic substituents at 1L-4-position of <i>myo</i>-inositol.<p> In this dissertation, the further characterization of this IDH is described, with focus on the mechanism, inhibition, kinetics, substrate binding, and alteration of substrate specificity. A kinetic isotope effect study revealed that the chemical step of the reaction was not rate-limiting. In order to probe the inositol-binding site, five inositol analogues were synthesized and evaluated as competitive inhibitors. Recently the crystal structures of the <i>apo</i>-IDH, <i>holo</i>-IDH and ternary complex have been solved. Using structural information, as well as modeling and sequence alignment approaches, we predicted the active site structure of the enzyme. On the basis of these predictions, coenzyme specificity was converted from entirely NAD⁺-dependent to 6-fold preference for NADP⁺ over NAD⁺ by site-directed mutagenesis. The critical residues for coenzyme recognition were therefore identified. Besides coenzyme specificity alteration, eleven amino acid residues in and around the proposed <i>myo</i>-inositol active site were also modified to test their roles in order to improve our understanding of substrate binding and activation.

Recent conceptualizations of procrastination suggest that procrastination is akin to self-regulatory failure wherein the effect of good intentions is attenuated for individuals who tend to procrastinate. Some researchers speculate that this effect is due to subtle neurological deficits that make it more difficult for procrastinators to follow through with completing tasks. The present work examines this claim while also investigating two factors that should theoretically weaken the effect of intentions for engaging unpleasant, but important, tasks – namely habitual avoidance and the executive function of inhibition. Study 1 investigated the question of whether chronic avoidance patterns may become so entrenched that they take on the qualities of a habit. This is important because habits are known to be less reliant on intentions because they are triggered in a relatively automatic fashion. Habit indices were created which assessed the degree to which the experience of avoiding particular tasks was automatic and self-descriptive in nature (Verplanken & Orbell, 2003). The results confirmed the expectation that more frequent avoidance patterns are experienced as occurring relatively automatically. Habit-like avoidance can be measured reliably and is related to other constructs in expected ways. For example, habit-level predicts reduced task quality and lower rates of task completion above-and-beyond motivational variables (e.g. intentions). Finally, habit-like avoidance patterns were more often associated with stable features identified by participants as being present in the environment. Using a prospective design, Study 2 assessed the degree to which existing habitual-avoidance patterns weakened the effect of good intentions to carry out unpleasant tasks over the course of a week. Several computer tasks at Time 1 were also used to assess inhibitory control or the degree to which participants could inhibit prepotent responses. In addition to personality traits which purportedly moderate the intention-behaviour relation (e.g. trait procrastination), the moderating effects of habitual avoidance and inhibitory control were also tested. Trait-level procrastination did not weaken the effect of one’s intentions to carry out unpleasant tasks. However, habitual avoidance and inhibitory control jointly moderated the effect of intentions on behaviour such that poor inhibitors had difficulty overcoming previous avoidance habits in order to complete unpleasant tasks during the week. In contrast, good inhibitors were able to behave according to their intentions irrespective of habit-like avoidance patterns. These findings point to the importance of recognizing the joint influence of avoidance patterns and regulatory capacities involved in self-control when understanding procrastination behaviour.

Practicing the retrieval of some information can lead to poorer retrieval of other related information; this phenomenon is called retrieval-induced forgetting. This pattern has been explained as the result of inhibition of the related information during retrieval practice (Anderson, 2003). A core assumption of this inhibition account is that, to be suppressed, the related information must compete with the target information at the time of practice. Four experiments are reported that test this competition assumption. Two experiments showed that retrieval-induced forgetting did not occur without specific retrieval practice of the target items, replicating and extending prior findings. Two further experiments then showed that retrieval-induced forgetting did occur, however, when competition between target information and related information during retrieval practice was eliminated, undermining the competition assumption and hence the inhibition account. A new explanation of retrieval-induced forgetting is introduced that emphasizes context change between study, retrieval practice, and test.

Thèse doctorat : Neurosciences : Strasbourg 1 : 2006. / Titre provenant de l'écran-titre. Bibliogr. 31 p.

Thèse de doctorat : Psychologie : Nancy 2 : 2005. / Bibliographie. Index.