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

No description available.

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.

No description available.

No description available.

Animal models have proven to be useful tools for modeling human neurochemical and behavioral responses to drugs of abuse, including cocaine. Cocaine is a psychomotor stimulant that facilitates monoaminergic neurotransmission by binding to transporters and inhibiting the reuptake of dopamine, serotonin and norepinephrine into presynaptic neurons. Many of the behavioral effects of cocaine, including its locomotor-activating and reinforcing properties, have been attributed to the ability of cocaine to enhance dopaminergic activity. In addition to its direct effects on monoamine neurotransmitters, cocaine impacts other neurotransmitter systems including the endogenous opioid system. The effects of selectively antagonizing mu opioid receptors on cocaine-induced behaviors were evaluated during this research. This research also evaluated the effect of selectively antagonizing dopamine D1 or D2 receptors on cocaine-induced mu opioid receptor occupancy by endogenous opioid ligands. This research furthered our understanding of how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. Although data support the role of mu opioid receptors in modulating cocaine-mediated locomotion and reward, the location of the mu opioid receptors involved has not been established. An evaluation of the effects of a selective mu opioid receptor antagonist administered directly into specific brain regions on cocaine-induced behaviors is important for understanding how the endogenous opioid and dopaminergic systems interact to mediate cocaine-induced behaviors. The studies outlined herein sought to determine the contribution of mu opioid receptors in specific regions of the mesocorticolimbic system to the rewarding and locomotor-activating effects of cocaine in the rat. In addition, to further understand the role of mu opioid receptors in cocaine reward, neuronal activation was studied via cFos activation following the expression of cocaine-induced place preference. Results of the research outlined herein demonstrate the importance of mu opioid receptors in cocaine-induced reward and activity, and demonstrate the anatomical selectivity of mu receptors within the nucleus accumbens, VTA and caudate putamen in this regard. These data suggest that cocaine causes the release of endogenous opioid peptides and that these peptides contribute to the rewarding and locomotor-stimulating effects of cocaine. Further, these data also suggest that opioid peptides are released in the nucleus accumbens shell during the expression of cocaine place preferences and that mu opioid receptors in this region are critical for the manifestation of this behavior. Although data demonstrate that extracellular levels of endogenous opioid peptides are increased following cocaine administration, the time- and dose-dependent occupancy of mu opioid receptors within specific brain regions had not been established in previous studies. The present research sought to determine the time- and dose-dependent occupancy of mu opioid receptors, measured indirectly by displacement of 3H-DAMGO binding, within specific brain regions. 3H-DAMGO binding was measured by in vitro autoradiography. In addition, the contribution of dopamine D1 and D2 receptors in cocaine-induced 3H-DAMGO displacement was evaluated. Results demonstrate that cocaine administration caused a dose- and time-dependent displacement of 3H-DAMGO binding to mu opioid receptors within the nucleus accumbens core and shell. This displacement was attenuated by pretreatment with a selective D2 dopamine receptor antagonist, demonstrating that cocaine, acting via D2 dopamine receptors, can cause the release of an endogenous opioid peptide that binds to mu opioid receptors within the nucleus accumbens core and shell. Previous studies have demonstrated that chronic administration of non-selective mu opioid receptor antagonists has profound effects on mu opioid receptor density and signaling. The research presented herein sought to determine whether chronic treatment with the selective mu opioid receptor antagonist, CTAP, would increase mu opioid receptor density and agonist-stimulated G-protein activation. In addition, this research sought to determine whether chronic CTAP administration would sensitize animals to the locomotor stimulating effects of cocaine. Results outlined herein demonstrate that chronic CTAP treatment sensitized animals to the locomotor effects of cocaine and that this sensitization occurred in conjunction with an increase in mu opioid receptor density within the nucleus accumbens core and shell. / Pharmacology

Bildgebende Studien haben gezeigt, dass bei schizophrenen Patienten Positivsymptome mit Veränderungen mesolimbischer Aktivierungsmuster unter Einbeziehung des Nucleus accumbens in Zusammenhang stehen. Hierbei ist von besonderem Interesse, dass der Nucleus accumbens Teil des Belohnungssystems ist, wobei die integrale „Bewertung“ belohnungsanzeigender Reize präfrontalen kortikalen Strukturen, insbesondere dem anterioren Zingulum, zuzurechnen ist. Bereits in der Antizipationsphase potentiell belohnender Reize, werden vermutlich zur Berechnung von Prädiktionsabweichungen dopaminerge Signale in der VTA generiert und modulieren den Nucleus accumbens. Es gibt zahlreiche Hinweise, dass glutamaterge Neurone des anterioren Zingulums die Dopaminausschüttung im Nucleus accumbens beeinflussen, und dass diese Modulation bei Erkrankungen wie der Schizophrenie beeinträchtigt ist. Ziel der vorliegenden Arbeit war es, mittels funktioneller Magnetresonanztomographie und Protonen Magnetresonanzspektroskopie, Hinweise über den Zusammenhang zwischen der glutamatergen Neurotransmission des ACC und belohnungsassoziierter Dopaminausschüttung im Nucleus accumbens bei 23 gesunden Probanden und bei 23 unmedizierten schizophrenen Patienten zu erlangen. Die Ergebnisse weisen darauf hin, dass die gegenseitige Modulation von anteriorem Zingulum und Nucleus accumbens bei schizophrenen Patienten gestört ist. Dieses und weitere Ergebnisse wurden im theoretischen Rahmen der NMDA-Rezeptor-Hypoaktivität und einer gestörten Balance zwischen Dopamin-D1- und Dopamin-D2-Rezeptor-Aktivität als pathophysiologische Korrelate schizophrener Erkrankungen diskutiert. / Imaging studies have demonstrated that for schizophrenic patients a correlation exists between positive symptoms and changes in the patterns of mesolimbic activity. Especially the changes in the ncl. accumbens (Nac) were interpreted in connection with the reward system. The signals indicating reward are thought to be processed by the anterior cingulum (ACC). These structures attribute meaning to the reward signals. In the anticipation phase of a potentially rewarding stimulus, dopaminergic signals from the VTA are generated in prediction of expected or aberrant outcome, thus modulating the Nac. Data indicate a direct modulation of the Nac. by glutamatergic neurons of the anterior cingulum. A major aim of this thesis is to establish a connection between the reward associated dopaminergic signals of the ncl. accumbens and the glutamatergic projections of the acc in unmedicated schizophrenic patients and healthy controls. The methods included measurements of proton magnetic resonance spectroscopy (1H-MRS) and functional MRI-scans done at a 3-Tesla tomograph. The paradigm applied was a modified version of the monetary incentive delay paradigm (Knutson et al. 2000). In healthy volunteers we found a significant negative correlation between the glutamate concentration in the ACC and the BOLD-contrast in the Nac (reward versus neutral), in contrast to the findings in schizophrenic patients. A significant higher BOLD-contrast was seen in the anticipation phase in healthy controls. The results were incorporated in a model of NMDA-R-Hypoaktivity. In addition to discussing the functional aspects for the structures involved the model was further expanded to include the hypothesis of a disturbed balance between dopamine-D1- and -D2-receptor activity and a dysfunctional hippocampal gating-process. The so constructed model suggests a profound striato-thalamo-cortical filter disturbance as the basis of the observed aberrations in the reward processing in schizophrenic disorders.

The amphetamine derivative, 3,4-methylenedioxymethamphetamine (MDMA), is a popular drug often taken by young adults at dance clubs or rave parties. Laser light shows, fast-paced electronic music, and hot crowded dance floors are characteristic of these events, and Ecstasy users report that the acute effects of the drug are potentiated by these stimulatory conditions. However, it remains largely unknown how environmental stimuli impact the neurochemical and physiological effects of MDMA. The aim of the first study presented in this dissertation was to investigate how auditory stimuli (music, white noise, and no additional sound) influence MDMA conditioned place preference (CPP), self-administration, and nucleus accumbens (NAcc) dopamine (DA) and serotonin (5-HT) responses. Findings revealed a significant CPP for animals exposed to white noise during MDMA conditioning trials. After self-administration of MDMA (1.5 mg/kg), NAcc DA and 5-HT were highest in rats exposed to music during the test session. The second study aimed to investigate the effects of ambient temperature (23°or 32°C) on long-term MDMA self-administration and neurochemical responses. Results indicated no difference in self-administration or locomotor activity rates for the high versus room temperature groups across sessions. However, MDMA (3.0 mg/kg) administered in high ambient temperature resulted in significantly greater NAcc serotonin release compared to when taken at room temperature, but no differences in dopamine response was determined between the two conditions. Overall, these results indicate that auditory and thermal stimuli can effect MDMA-induced behavioral and neurochemical responses. The last aim tested a novel apparatus and method for use in animal models of drug reinforcement. By combining traditional CPP and self-administration procedures, this approach provided more informative data and circumvented some inherent drawbacks of each method alone. In addition to confirming the ability to produce drug conditioned place preferences after short- and long-term experiments, the long-term version of the procedure revealed a significant positive relationship between lever response rate and CPP magnitude. Therefore, this experimental design can be used to identify subgroups of rats that may vary in sensitivity to drug motivational effects. Further study of these populations may be useful in the development of behavioral and pharmacological therapies for drug addiction. / text