The action of postponing an intended plan is often referred to as procrastination. Research on procrastination generally views the phenomenon as a form of self-regulation failure. Self-regulation refers to the conscious and non-conscious processes that enable individuals to guide their thoughts, feelings, and behaviors purposefully. Research indicates correlations between self-regulation and executive functions providing a fruitful integration. From a neuroscientific perspective, this integration generally associates the prefrontal cortex with top-down control whenever successful self-regulation is achieved. On the contrary, self-regulation failure appears to involve a bottom-up control, in which subcortical regions have greater influence on behavioral outcomes. Subcortical regions involved in emotional and rewarding processes, such as the amygdala and nucleus accumbens appears to lie at the coreof self-regulation failure, whereas cortical executive functions of regulating emotion and impulsive behaviors may contribute to successful self-regulation, thus overcoming procrastination. This thesis aims to obtain a deeper understanding of the mechanisms of procrastination, specifically investigating self-regulation failure and its relationship with executive functions and the neural underpinnings of self-regulation.

This study investigated the effects of repeated administrations of nicotine (0.7 mg/kg) on dendritic morphology in the nucleus accumbens (NAcc), prefrontal cortex (Cg 3), and parietal cortex (Par 1). Animals were habituated for 3 days to a locomotor box, and after habituation, every second day for 5 weeks rats were placed into the locomotor chamber immediately after a subcutaneous injection of nicotine or saline. Rats demonstrated tolerance to an initial hypoactive response after each nicotine injection, and this was followed by an increase in activity after each injection (behavioral sensitization). This increase in activity was still present on a nicotine challenge after a 2-week abstinence period. One week after the nicotine challenge day, all rats were perfused and brains were removed. These brains we stained using Golgi-Cox procedures, and dendrites from the nucleus accumbens (N Acc), medial frontal cortex (Cg 3) and parietal cortex (Par 1) were analyzed using the camera lucida procedure. Results showed that rats receiving nicotine demonstrated an increase in dendritic length and spine density relative to controls in the NAcc and Cg3 brain areas, but not Par 1. The increase observed in the NAcc was significantly greater than what has been found with amphetamine or cocaine, and possible underlying mechanisms were discussed.

Opioid receptors have been a target of pharmacological manipulation in alcohol use disorder (AUD) recovery protocols for many years. Aerobic exercise, a common adjunct in AUD recovery, is known to modulate opioid receptors (ORs) both during both acute and long term exposure. The three subtypes of ORs: mu (MOR), delta (DOR), and kappa (KOR) are all expressed on neurons in the mesocorticolimbic circuitry. Kappa-opioid receptors are expressed directly on dopamine (DA) neuron terminals in the nucleus accumbens (NAc). Mu and Delta ORs are expressed on cholinergic interneurons (CINs) and GABA neurons in the NAc. In alcohol dependent rodents, KORs are hypersensitized. It is theorized that this hypersensitization contributes to EtOH seeking behavior. In contrast, aerobic exercise desensitizes the KORs. Given the high degree of pharmacological overlap between opioid receptors, it is also hypothesized that EtOH and aerobic exercise may have effects on MORs and DORs as well. Here, it is investigated whether a routine of voluntary aerobic exercise decreases EtOH induced changes to KOR modulation of dopamine (DA) release in the nucleus accumbens (NAc) along with possible mechanisms through which this might occur. The responsiveness of MORs and DORs in EtOH dependence, and how aerobic exercise modulates those effects is also investigated. Exercise attenuated EtOH induced hypersensitization of KORs in the NAc. Exercise decreases expression of KORs, which may account for the changes in KOR sensitization. The MOR agonist DAMGO decreased DA reuptake ex vivo, but not signal amplitude while DOR agonist DPDPE had no effect on either reuptake or signal amplitude. Overall, dependent animals that were allowed to exercise, consumed less EtOH in a drinking in the dark model. These data suggest that exercise is a useful adjunct to AUD recovery protocols, and that its effects are likely mediated by KORs. The findings related to MORs and DORs suggest that MORs, but not DORs, may act through acetyl choline receptors to modulate DA reuptake in the NAc, however much more work is needed to characterize this effect.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20075号 / 医博第4168号 / 新制||医||1018(附属図書館) / 33191 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 林 康紀, 教授 瀬原 淳子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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Despite the fact that more men are diagnosed with substance use disorder, women escalate their drug consumption faster, exhibit higher craving during withdrawal, and have poorer treatment outcomes. Furthermore, as our cultural expectations of men and women have changed, there has been an increase in drug use in women and this increase is likely to persist. Preclinically, female rodents show stronger behavioral responses to drugs of abuse during initiation, escalation, and reinstatement of drug seeking. These behavioral differences are accompanied by alterations in structural plasticity within the mesocorticolimbic reward system. However, little is known about what functional sex differences exist in glutamate transmission in these circuits. The goal of these experiments was to determine functional sex differences in reward circuitry that may underlie behavioral sex differences in substance use disorder. We found heightened glutamate transmission in both the medial prefrontal cortex and nucleus accumbens in females compared to males. These findings corresponded with the nucleus accumbens being less plastic in females. We then investigated the role of PKMζ, a glutamatergic AMPA receptor trafficking protein, in plasticity and opioid-taking. We found PKMζ plays a role in synaptic plasticity within the nucleus accumbens and it works to blunt oxycodone-taking and motivation in a dose-dependent manner. Taken together these findings suggest there are functional sex differences at many levels within the reward system and gaining a better understanding of these differences could provide insight into improved treatments for substance use disorder. / Psychology

Atrial Naturietic Peptide (ANP) is a neuropeptide that regulates function of the hypothalamic-pituitary-adrenal (HPA) axis, immune and neuroimmune system, and epigenetic factors. Research has indicated that ANP may mediate alcohol intake, withdrawal, and craving like behaviors. ANP receptors are present in the mesocorticolimbic (MCL) reward pathway of the brain, which includes the nucleus accumbens (Acb) and the ventral tegmental area (VTA). The objectives of the present study were to examine the effects of ANP microinjected into Acb subregions (Shell (Sh), Core (Co), ventral to AcbSh) on operant ethanol (EtOH) self-administration and into posterior VTA (pVTA) on EtOH-seeking behavior of female alcohol-preferring (P) rats. In the first experiment, ANP (0, 10 μg, or 100 μg) was microinjected into subregions of the Acb to determine its effects on EtOH self-administration. In the second experiment, ANP was microinjected into pVTA to determine its effects on Pavlovian Spontaneous Recovery (PSR) of responding, a measure of context-induced EtOH-seeking behavior. Administration of ANP directly into the AcbSh significantly reduced EtOH self-administration compared to vehicle, whereas ANP into the AcbCo or areas directly ventral to the AcbSh did not alter responding for EtOH. Microinjection of ANP into the pVTA significantly reduced responding on the EtOH-associated lever during the PSR test. The data indicate that activation of ANP systems in the (a) AcbSh can inhibit EtOH intake, and (b) in the pVTA can inhibit EtOH-seeking behavior. The results suggest that manipulations of the ANP system could be a potential target for pharmacotherapeutic intervention to treat alcohol use disorder. Supported in part by AA07462, AA07611, AA10717, AA10721, AA013522, AA019366, AA020908, AA022287, and AA024612.

Background: The prevalence of adolescent obesity has increased drastically in the last few decades, spurring research examining causes and consequences of this chronic health condition. Neuroimaging techniques are being used to determine possible neural correlates of obesity that could help inform research in this field. However, the research among adolescents is not as abundant and findings so far are contradictory. This study sought to examine the association of the shape and volume of subcortical brain structures involved in reward processing with weight status in adolescent females. Additionally, this study sought to determine if the shape and volume of these structures were correlated with the Power of Food Scale (PFS), a self-report measure of food reward sensitivity. Method: The shape and volume of the nucleus accumbens (NAc) and amygdala were examined in 89 adolescent females ranging from normal weight to obese. MR scans were acquired using a high-resolution T1-weighted (MPRAGE) sequence. Shape was estimated using Large Deformation Diffeomorphic Metric Mapping. Seemingly unrelated regression models (SUM) were used for both brain structures with shape and volume as outcome variables and zBMI as the predictor variable. Pairwise correlation coefficients were determined for PFS score and both regions of interest (ROI). Results: SUM results revealed that zBMI was significantly associated with the shape of the left amygdala (β = -1.1, p<.021, 95% confidence interval [CI] = -2.02, -.16). When we controlled for age on the relationship between zBMI and left amygdala shape, we found the following partial correlation: r = -.24, p = .03. The PFS was found to have weak correlations with the volume and shape of the right NAc that approached significance (r = .20, p = .06; r = .19, p = .08, respectively). Conclusions: Our study suggests that there is an association between higher zBMI and aberrations in the shape of the left amygdala. We did not find associations between zBMI and the shape of our other reward-related ROIs, nor did we find any associations with zBMI and ROI volume. These findings suggest that variation in the shape of certain ROIs implicated in reward processing is associated with weight status in adolescents. Our findings also suggest that the shape and volume of the NAc could be a neural correlate of the PFS warranting further investigation. These findings may elucidate an important neural link between weight status and reward processing that could help to inform obesity research in adolescents.

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