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The ability of the indirect dopamine agonist, amphetamine, to produce behavioral sensitization was assessed in adult D₁A-deficient and wild-type mice. It was originally predicted that : 1) dopamine (DA) D₁-like receptors are necessary for the occurrence of short- and long-term amphetamine-induced behavioral sensitization, 2) DA D₁-like receptors are necessary for environmental conditioning factors associated with amphetamine-induced behavioral sensitiazation, and 3) DA D₅ receptors are required for amphetamine-induced behavioral sensitization. Locomotor activity and sterotyped sniffing were assessed in each of three experiments.

Yawning in male rats is a behavior that may be induced by a group of dopamine receptors when low doses of dopamine-receptor agonists are administered. To determine whether agonist treatments during postnatal development could produce a long-lived supersensitization of these dopamine receptors, rats were treated daily for the first 28 days from birth with quinpirole HCl (3.0 mg/kg/day, IP), an agonist that acts at D2 and D3 receptors. At 8 to 10 weeks from birth the dose-effect curve for quinpirole-induced yawning demonstrated that a supersensitization of dopamine receptors for yawning behavior had occurred. Yawning at the optimal dose of quinpirole HCl (100 μg/kg, IP) was increased 2-fold. The Bmax and Kd for D2 receptor binding in rat striatum were unaltered in this group of rats. These findings indicate that dopamine receptors can be ontogenically "primed" or supersensitized, and that the phenomenon apparently is not related to changes in striatal D2 receptor binding characteristics.

Our laboratories have been investigating the reactivity of central dopamine D1 and D2/D3 receptors by their corresponding dopamine agonists (SKF-38393 and quinpirole), during development and aging in rats. By evaluating the number of oral movements (a parameter for D1 receptor activation after SKF-38393) and the number of yawns (as a parameter for D3 activation after quinpirole), we demonstrated that not only was there a dose-response activity for both drugs in the two parameters tested, but that the D3 activity was enhanced with the rats' development and aging, due to life-long persisting D3 supersensitivity. In the present study we checked whether D2 and D1 receptors were also sensitized at old age, by measuring behavioral parameters characteristic to D2 (locomotor activity and rearings) and to D1 (grooming time). In the long-term study, male Wistar rats were challenged for 18 months with increasing doses of either SKF-38393, quinpirole or saline. At the age of 19 months they were given a single injection of either drug or saline. In the short-term study, male and female rats were given four single injections of either SKF-38393, quinpirole or saline, with one week intervals, and locomotor time and number of rearings recorded. Long-term quinpirole was found to induce supersensitivity of the D2 receptor complex, demonstrated by both enhanced locomotor time and rearing behavior, while long-term SKF-38393 treatment activated the D1 receptors, as evaluated by grooming time. Short-term quinpirole enhanced supersensitivity of the D2 receptors only in female rats, as assessed by increasing both locomotor time and rearing behavior, reiterating previous results on sex-dependent monoaminergic reactivity.

Animals respond to changes in the environment and internal states to modify their behavior. The basal ganglia, including the striatum contribute to action selection by integrating sensory, motor and reward information. Therefore, dysregulation of striatal function is common in many neuropsychiatric disorders, including Parkinson’s disease, Huntington disease, schizophrenia, and addiction. Here, using fiber photometry, pharmacology, and behavioral approaches in transgenic mice, I explored the cellular and circuit mechanisms underlying key striatal functions. In Chapter 1, I begin by presenting the existing literature on the anatomy and physiology of the striatum. Next, I review the important functions of the striatum. Within this general review, I highlight the specific roles that striatal (DA) and acetylcholine (ACh) play in striatal circuitry and function. In Chapter 2, I demonstrate the naturally evoked ACh dip has a DA component and a non-DA component. Specifically, I show that DA via cholinergic DA D2 receptors (D2Rs) modulate the length of the ACh dip and rebound ACh levels following the dip. In addition, I show that DA coordinates the activity between DA and ACh during behavior. Finally, I present data that supports a role for ACh in motivated behavior. In Chapter 3, I show that cholinergic D2Rs are not necessary for reward learning but do facilitate reversal learning in a probabilistic choice task. In addition, I show that changes in DA and ACh levels contribute to reversal learning in a probabilistic choice task. Finally, in Chapter 4, I discuss the general conclusions and study implications, as well as future directions.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21006号 / 医博第4352号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 濵﨑 洋子, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cellular biophysics deals with, among other things, transport processes within cells. This thesis presents two studies where mathematical models have been used to explain how two of these processes occur. Cellular membranes separate cells from their exterior environment and also divide a cell into several subcellular regions. Since the 1970s lateral diffusion in these membranes has been studied, one the most important experimental techniques in these studies is fluorescence recovery after photobleach (FRAP). A mathematical model developed in this thesis describes how dopamine 1 receptors (D1R) diffuse in a neuronal dendritic membrane. Analytical and numerical methods have been used to solve the partial differential equations that are expressed in the model. The choice of method depends mostly on the complexity of the geometry in the model. Calcium ions (Ca2+) are known to be involved in several intracellular signaling mechanisms. One interesting concept within this field is a signaling microdomain where the inositol 1,4,5-triphosphate receptor (IP3R) in the endoplasmic reticulum (ER) membrane physically interacts with plasma membrane proteins. This microdomain has been shown to cause the intracellular Ca2+ level to oscillate. The second model in this thesis describes a signaling network involving both ER membrane bound and plasma membrane Ca2+ channels and pumps, among them store-operated Ca2+ (SOC) channels. A MATLAB® toolbox was developed to implement the signaling networks and simulate its properties. This model was also implemented using Virtual cell. The results show a high resemblance between the mathematical model and FRAP data in the D1R study. The model shows a distinct difference in recovery characteristics of simulated FRAP experiments on whole dendrites and dendritic spines, due to differences in geometry. The model can also explain trapping of D1R in dendritic spines. The results of the Ca2+ signaling model show that stimulation of IP3R can cause Ca2+ oscillations in the same frequency range as has been seen in experiments. The removing of SOC channels from the model can alter the characteristics as well as qualitative appearance of Ca2+ oscillations. / Cellulär biofysik behandlar bland annat transportprocesser i celler. I denna avhandling presenteras två studier där matematiska modeller har använts för att förklara hur två av dess processer uppkommer. Cellmembran separerar celler från deras yttre miljö och delar även upp en cell i flera subcellulära regioner. Sedan 1970-talet har lateral diffusion i dessa membran studerats, en av de viktigaste experimentella metoderna i dessa studier är fluorescence recovery after photobleach (FRAP). En matematisk modell utvecklad i denna avhandling beskriver hur dopamin 1-receptorer (D1R) diffunderar i en neural dendrits membran. Analytiska och numeriska metoder har använts för att lösa de partiella differentialekvationer som uttrycks i modellen. Valet av metod beror främst på komplexiteten hos geometrin i modellen. Kalciumjoner (Ca2+) är kända för att ingå i flera intracellulära signalmekanismer. Ett intressant koncept inom detta fält är en signalerande mikrodomän där inositol 1,4,5-trifosfatreceptorn (IP3R) i endoplasmatiska nätverksmembranet (ER-membranet) fysiskt interagerar med proteiner i plasmamembranet. Denna mikrodomän har visats vara orsak till oscillationer i den intracellulära Ca2+-nivån. Den andra modellen i denna avhandling beskriver ett signalerande nätverk där både Ca2+-kanaler och pumpar bundna i ER-membranet och i plasmamembranet, däribland store-operated Ca2+(SOC)-kanaler, ingår. Ett MATLAB®-verktyg utvecklades för att implementera signalnätverket och simulera dess egenskaper. Denna modell implementerades även i Virtual cell. Resultaten visar en stark likhet mellan den matematiska modellen och FRAP-datat i D1R-studien. Modellen visar en distinkt skillnad i återhämtningsegenskaper hos simulerade FRAP-experiment på hela dendriter och dendritiska spines, beroende på skillnader i geometri. Modellen kan även förklara infångning av D1R i dendritiska spines. Resultaten från Ca2+-signaleringmodellen visar att stimulering av IP3R kan orsaka Ca2+-oscillationer inom samma frekvensområde som tidigare setts i experiment. Att ta bort SOC-kanaler från modellen kan ändra karaktär hos, såväl som den kvalitativa uppkomsten av Ca2+-oscillationer. / QC 20101111

To explore associations of neostriatal (NST) endogenous levels of dopamine (DA) and serotonin (5-HT) with sensitivity of their receptors, graded doses of 6-hydroxydopamine HBr (0 to 400 μg, ICV; 6-OHDA; desipramine pretreatment, 20 mg/kg IP) were given to rats between birth (P 0) and P 42. Numbers of vacuous chewing movements (VCMs) induced by SKF 38393 or m-chlorophenylpiperazine (m-CPP), respective DA D1 and 5-HT2 agonists, were subsequently determined. Enhanced SKF 38393-induced VCMs occurred when NST DA was reduced 97%-98% by high dose 6-OHDA (100-134 μg) at P 0 or P 3, but not in rats with 95%-97% loss in DA produced by 6-OHDA at P7 (134 μg) or P3 (67 μg). Enhanced m-CPP-induced VCMs occurred even when NST 5-HT content was not elevated after 6-OHDA (134 μg at P 10). Accordingly, D1 and 5-HT receptor sensitivity is not correlated with respective NST DA and 5-HT contents. The stage of ontogeny at the time of DA denervation may be the governing influence on receptor sensitivity.

There is considerable evidence to suggest that dopamine (DA), in addition to its role as a precursor of norepinephrine (NE) and ephinephrine, has important physiological actions in its own right. One physiological action of DA seems to be that of a neurotransmitter in the mammalian brain (Hornykiewicz, 1966). In addition, there is evidence that abnormalities of dopaminergic transmission in the central nervous system (CNS) may be of clinical importance. For example, dopaminergic over activity in the mesolimbic forebrain may be a primary feature in the etiology of schizophrenia (Meltzer and Stahl, 1976). The drugs used to treat schizophrenia act as DA antagonists in the brain (Snyder et al., 1974; Robinson et al., 1979). Drugs such as phenothiazines and butyrophenones have been shown in clinical studies to be effective in treating the fundamental symptoms of psychosis (Snyder et al., 1974). The results of animal experiments indicate that their principal mode of action is blockade of DA receptor sites in the CNS (VanRossum, 1966). However, these neuroleptics are generally nonspecific in their effects upon DA neurons and thus, cause major undesireable side effects. If new drugs could be discovered that were more structurally selective for different DA systems, then, perhaps these undesireable side effects could be eliminated. In order to develop such drugs, a closer look would have to be made at different DA systems in an attempt to demonstrate DA receptors which are topographically distinct and can thus be selectively regulated by both agonistic and antagonistic agents. The demonstration of more than one DA receptor in mammalian CNS is the subject of the research presented in this thesis.

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