The 5-HT7 receptor is the most recent addition to the 5-HT receptor family and has been linked to a variety of physiological and pathophysiological processes. Well established antide-pressant pharmaceuticals have recently been found to activate the 5-HT7 receptor, supporting the role of the 5-HT7 receptor in the antidepressant mechanism. The synthesis of potent selec-tive 5-HT7 receptor antagonists could afford a greater understanding of the 5-HT7 receptor function as well as lead to potential drug candidates. The synthesis of unfused biheteroaryl derivatives as 5-HT7 receptor ligands has been de-scribed within. These compounds have been tested for biological activity on the 5-HT6 and 5-HT7 receptors. 4-(3’-Furyl)-2-(N-substituted-piperazino)pyrimidines were found to be potent 5-HT7 receptor ligands. 4-(2’-Furyl)-2-(N-substituted-piperazino)pyrimidines have shown high se-lectivity for the 5-HT7 receptor over the 5-HT6 receptor.

Mass-analyzed ion kinetic energy (MIKE) spectra were obtained for serotonin and the polyamines. The predominant reaction observed was the loss of NH3 from the protonated species. The MIKE methodology was applied to the direct analysis of polyamines in bacteria without any sample preparation.Quantitative analysis was shown to be possible with deuterated putrescine as an internal standard.Ball State UniversityMuncie, IN 47306

<p>Adolescence is the period of transition between childhood and adulthood, and is characterized across mammalian species by changes in behavior that include increases in risk taking, novelty/sensation seeking, and social behavior. Immaturity of the central serotonergic system during adolescence could contribute to risk taking behavior by resulting in lower avoidance of aversive stimuli in adolescents than adults. The purpose of this dissertation was to investigate whether immature serotonergic function could contribute to adolescent risk taking. We studied pre- and postsynaptic serotonergic function and circuit-level mechanisms relevant to risk taking behavior using behavioral and neurochemical approaches.</p><p>Serotonergic modulation of behavior was assessed in adult (67-74 day old) and adolescent (28-34 day old) male rats in the novelty induced hypophagia (NIH), elevated plus maze, (EPM), and light/dark (LD) tests for anxiety-like behavior. Serotonin depletion with the synthesis inhibitor p-chlorophenylalanine (PCPA) produced anxiolytic effects only in adult rats in the NIH test and in both age groups in the EPM. These data showed that some serotonin-mediated behavioral inhibition is present during adolescence. However, adolescent rats were less sensitive than adults to the anxiogenic effects of the serotonin releasing drugs fenfluramine and methylenedioxymethamphetamine (MDMA) and the serotonin uptake inhibitor fluoxetine in the LD test, suggesting that serotonin is not as effective at inhibiting behavior in adolescents as it is in adults.</p><p>Microdialysis conducted in medial prefrontal cortex (mPFC) showed that adolescent rats exhibited lower increases in extracellular serotonin after treatment with the releasing drug fenfluramine, but not the uptake inhibitor fluoxetine. Further investigation of presynaptic serotonin function in adults and adolescents revealed that adolescent rats have lower tissue serotonin content than adults in several forebrain regions, but similar rates of serotonin synthesis, density of serotonin transporter (SERT)-immunoreactive innervation, and SERT radioligand binding. These data suggest that adolescents may have a lower increase in extracellular serotonin than adults after a releasing drug, but not an uptake inhibitor, due to lower tissue serotonin stores. Lower serotonin stores may limit the ability of a releasing drug to increase extracellular serotonin, but are unlikely to affect response to an uptake inhibitor. These findings also indicate that extracellular serotonin does not completely account for lower serotonin-mediated behavioral inhibition in adolescents. </p><p>Since presynaptic serotonin function did not explain age differences in the anxiogenic effects of indirect serotonin agonists, we investigated postsynaptic serotonin signaling by testing the behavioral effects of serotonin receptor agonists in the LD test. Adolescent rats were less sensitive than adults to the anxiogenic effects of the 5-HT_1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH DPAT) in the LD test, but not to the 5-HT₂ agonist meta-chlorophenylpiperazine (mCPP). No age differences were observed in <super>3</super>H-8-OH DPAT binding in prefrontal cortex, amygdala, or hippocampus between adolescents and adults, and infusion of 8-OH DPAT into mPFC (prelimbic cortex), ventral hippocampus, or basolateral amygdala was unable to replicate the systemic effects of 8-OH DPAT. These data suggest that lower adolescent sensitivity to the anxiogenic effects of 8-OH DPAT is not due to age differences in receptor expression, and show that 5-HT_1A stimulation in mPFC, ventral hippocampus, and basolateral amygdala alone is not sufficient to mimic the effects of systemic 8-OH DPAT. </p><p>We tested the circuit-level effects of fluoxetine and 8-OH DPAT, since stimulating 5-HT_1A receptors in single brain regions failed to reproduce age differences in systemic 8-OH DPAT administration. Both drugs activated regions of the amygdala more in adults than adolescents, and 8-OH DPAT also produced greater prefrontal cortical activation in adults. Fluoxetine produced greater expression of the immediate early gene c-Fos in regions of the extended amygdala in adult rats, and 8-OH DPAT produced greater activation of the lateral orbital cortex and central amygdala in adult rats. Lower activation of cortical and amygdala brain regions could underlie the lower behavioral effects of these drugs in adolescents, as these brain regions are important in mediating behavioral inhibition and anxiety-like behavior. These data are also consistent with human studies showing immature cortical and amygdala function during adolescence. </p><p>This dissertation shows that adolescents are less sensitive than adults to serotonin mediated behavioral inhibition, and that this may be due to immature activation of neural circuits modulated by the 5-HT_1A receptor between the prefrontal cortex and amygdala. This immature serotonin mediated behavioral inhibition could contribute to adolescent risk taking, drug abuse, and increased risk for suicidality during SSRI therapy for depression and mood disorders.</p> / Dissertation

<p>Negotiating the complex decisions that we encounter daily requires coordinated neu- </p><p>ronal activity. The enormous variety of decisions we make, the intrinsic complexity </p><p>of the situations we encounter, and the extraordinary flexibility of our behaviors </p><p>suggest the existence of intricate neural mechanisms for negotiating contexts and </p><p>making choices. Further evidence for this prediction comes from the behavioral al- </p><p>terations observed in illness and after injury. Both clinical and scientific evidence </p><p>suggest that decision signals are carried by electrical neuronal activity and influenced </p><p>by neuromodulatory chemicals. This dissertation addresses the function of two puta- </p><p>tive contributors to decision-making: neuronal activity in posterior cingulate cortex </p><p>and modulatory effects of serotonin. I found that posterior cingulate neurons respond </p><p>phasically to salient events (informative cues; intentional saccades; and reward deliv- </p><p>ery) across multiple contexts. In addition, these neurons signal heuristically guided </p><p>choices across contexts in a gambling task. These observations suggest that posterior </p><p>cingulate neurons contribute to the detection and integration of salient information </p><p>necessary to transform event detection to expressed decisions. I also found that </p><p>lowering levels of the neuromodulator serotonin increased the probability of making </p><p>risky decisions in both monkeys and mice, suggesting that this neurotransmitter con- </p><p>tributes to preference formation across species. These results suggest that posterior </p><p>cingulate cortex and serotonin each contribute to decision formation. In addition, the </p><p>unique serotonergic pro jections to posterior cingulate cortex, as well as the frequent </p><p>implication of altered serotonergic and posterior cingulate function in psychiatric dis- </p><p>orders, suggest that the confluence of cingulate and serotonergic activity may offer </p><p>key insights into normal and pathological mechanisms of decision making.</p> / Dissertation

1. Institute of Marine Biology, National Sun Yat-sen University 2. Department of Biology, National Changhua University of Education Abstract Brain serotonin (5-hydroxytryptamine; 5-HT) generally serves an inhibitory role in aggressive behavior. But little is known about how 5-HT works during agonistic interaction and where the related works take place in the brain. Paradise fish has regular and ritual process of agonistic interaction which can be separated into three phases, namely, initial phase, threatening phase, and fighting phase. In initial phase, two fish encounter and swim close to each other. In threatening phase, two fish display shaking, head-tail swimming to threat their opponent. In fighting phase, two fish bite each other. With its stereotyped pattern of agonistic behaviors and amenability for pharmacological manipulation, paradise fish represents an excellent model for studies on neurochemical basis of aggressive behaviors. The results suggested that proper visual stimulus stemming from the interacting opponents elicits a socially stressful state that activates the telencephalic serotonergic system of the receipting paradise fish. The elevated serotonergic activity appears to inhibit the interacting individuals from entering fighting phase by constraining them to threatening phase. Presumably, diminishing activity of the telencephalic serotonergic system ushers in physical fighting behaviors.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / "May 2001." Typescript. Vita. Includes bibliographical references (leaves 66-80). Also available on the Internet.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Medicinal Chemistry. Title from title-page of electronic thesis. Bibliography: leaves 141-177.

Thesis (Ph. D.)--University of Massachusetts Amherst, 2009. / Open access. Includes bibliographical references (p. 89-87). Print copy also available.

Thesis (Ph. D)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 65-78).

The brain is inherently bisexual, differentiating during development so that in adulthood, males mount receptive females. Yet, vestiges of this bisexuality persist in adults, with heterotypical behaviors (females mounting and males being receptive) observed in some species. Consequently, differences in sexual behavior between the sexes, and between individuals of the same sex, are reflective of the predisposition and degree to which these behaviors are exhibited. How one behavior is facilitated and its complement simultaneously suppressed during a reproductive encounter suggests that behavioral expression is gated in some manner. Because male and female vertebrates typically display behavior characteristic of their own sex, simultaneous study of neural circuits gating homotypical and heterotypical behaviors in conventional animal models has received scant attention. The whiptail lizard species, Cnemidophorus uniparens, comprises individuals that are genetically and hormonally female, and that naturally display both types of behavior. Using High Pressure Liquid Chromatography (HPLC), immunocytochemistry, in situ hybridization, intracranial surgeries, as well as pharmacological and behavioral analyses, I report that serotonin levels, and signaling via distinct serotonergic receptors at behaviorally relevant brain nuclei might allow the system to switch between either behavioral repertoire. The use of the same molecule to mediate the reciprocal inhibition of complementary behavioral repertories within the same sex is evidence of a phenomenon of molecular parsimony underlying a striking form of behavioral plasticity. This dissertation also illustrates that sexually differentiated traits such as male and female-typical sexual behaviors are sculpted by neurochemical signaling at neural substrates present in both sexes. / text