Serotonin syndrome (SS) is a drug-induced toxicity caused by an excess of serotonin (5-HT) in the central nervous system (CNS). The symptoms of the disorder range from mild to severe, with the severe state evoking life-threatening hyperthermia. Autonomic dysfunction is controlled in part by serotonin receptors, with the 5-HT2A receptor responsible for increasing core body temperature (Tcor). Our results show that the 5-HT2A receptors on the preoptic/anterior hypothalamus (PO/AH) and prefrontal cortex (PFC), in particular, are sensitive to changes in ambient temperature (Tamb). The toxic increase of 5-HT is postulated to occur due to the temperature-dependent activation of these receptors that promotes a positive feedback mechanism. Our results suggest that changes in Tamb can either exacerbate or alleviate the symptom and that this is mediated by the 5-HT2A receptors. Understanding the mechanism involved in elevating Tcor is imperative in treating and preventing the disorder. / by Swapna Krishnamoorthy. / Vita. / Thesis (M.S.)--Florida Atlantic University, 2008. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2008. Mode of access: World Wide Web.

The ascending cholinergic and serotonergic projections are central to cortical activation and normal behavior. The objective of this thesis was to determine whether unilaterally damaging both of these systems would disrupt the production of skilled movements on the contralateral side of the body. Rats received unilateral damage to either the ascending cholinergic, or serotonergic, or both projections. The respective lesions reduced neocortical leveles of acetylcholine and serotonin as assessed by acetylcholinesterase reactivity and immunohistochemical staining for serotonin. Subjects were assessed on a battery of sensorimotor tasks sensitive to neocortical integrity. The cholinergic lesion produced mild deficits on some taks but damage to both together did not abolish skilled movement. The impairments are decreased in relation to the severe effects of bilateral lesions. The results show that the sensorimotor cortex remains functional following deafferentation of both cholinergic and serotonergic afferents. / vii, 166 leaves : ill. ; 28 cm.

Thesis (M.S.)--State University of New York at Binghamton, Department of Psychology, 2008. / Includes bibliographical references.

No description available.

No description available.

Damage to peripheral nerves can cause extensive functional reorganization of the adult mammalian nervous system. In fact, studies in non-human adult mammals have shown somatotopic reorganization as well as changes in receptive field properties throughout the somatosensory neuraxis following damage to peripheral nerves. Chronic changes in receptive fields and response properties have also been reported in the trigeminal brainstem nuclear complex (TBNC) following trigeminal nerve damage in both neonates and adults. Significant functional reorganization within subnucleus interpolaris (SpVi) was also apparent in rats subjected to infraorbital nerve transection. Several mechanisms have been proposed to account for many of the observed functional changes. They include: misdirected peripheral regrowth and changes in central arbor morphology of damaged primary afferents; peripheral and central sprouting of undamaged primary afferents; changes in morphology of second order neurons; and sprouting of central afferents to the TBNC. In addition, central monoaminergic neurons have been demonstrated to undergo considerable regeneration or collateral sprouting following direct damage or disruption of their sensory input. These monoaminergic neurons normally modulate the function of their targets. Thus, damage induced reorganization of monoaminergic projections to the TBNC could alter the response properties of cells within this region. The normal effects of monoaminergic inputs to SpVi have not yet been fully determined. We intend to use the neurotoxin 5,7-dihydroxytryptamine (specific for the destruction of serotonin and norepinephrine containing neurons) in combination with the antidepressant drug desmethylimipramine (used to protect norepinephrine containing neurons) to selectively destroy serotonergic fibers in SpVi in order to describe the normal functional role of serotonergic inputs to this region. This manipulation produced a significant change in : i) the types of peripheral receptor surfaces that activate cells in SpVi, and ii) rate of spontaneous activity. These changes reflect some of the functional alternatives observed after infraorbital nerve damage and suggest a role for serotonergic afferents in these changes. / Master of Science

Thesis (PhD)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: Investigations into the neurobiology of obsessive-compulsive disorder (OCD) have provided useful insights into this prevalent and disabling disorder in recent decades. Encouraging advances have also been made in the pharmacological treatment of OCD. This has improved the quality of life for many who typically endure chronic unremitting symptoms. Despite the widespread use of first-line agents selective for the serotonergic system in OCD, relatively little is known about the neurobiology of treatment response, the specific components of the serotonin system involved in symptom modulation, and the overlapping and distinct brain regions impacted by alternative treatment options. Despite the advance that selective serotonin re-uptake inhibitors have been, a significant proportion of patients still fail to respond adequately to these agents, and alternative pharmacological interventions are required. The use of dopamine antagonists, a strategy which until recently has had only limited supporting data, presents one such alternative. Little however, is known about which subsets of patients are most likely to respond to these agents. In this thesis, I will present a series of six studies that use pharmacological treatments and single photon emission computed tomography (SPECT) to make contributions to three primary areas in OCD namely; neurobiology, treatment and the intersection of the two. First, I address OCD neurobiology by examining the impact of OCD on resting brain function. I then examine the effects of pharmacological challenge of the serotonin 1B receptor using sumatriptan on regional cerebral blood flow (rCBF) and clinical symptomatology. Second, I examine the intersection of neurobiology and treatment as I explore the changes in rCBF in response to treatment with inositol, a precursor of the phosphoinositol second messenger system. I then examine the distinct and overlapping effects on rCBF of treatment for 12 weeks with the selective serotonin re-uptake inhibitor (SSRI) citalopram across anxiety disorders. Third, I address treatment of OCD by examining the efficacy of controlled augmentation of serotonin re-uptake inhibitors with quetiapine, a dopamine antagonist, in treatment refractory OCD. I then combine this data with a second similar dataset to derive a predictive model for treatment outcome with quetiapine augmentation of SRIs. I demonstrate that rCBF in OCD differs significantly from normal controls, is correlated with severity in frontal brain regions, and remains an important line of investigation for OCD pathophysiology that has yet to fully delineated. Pharmacological challenge of the 5HT1B autoreceptor with the selective agonist sumatriptan results in heterogeneous behavioural and regional brain perfusion changes in OCD. Attenuation of pre-frontal perfusion following 5HT1B agonist administration is in line with the effects of SRIs. This work suggests that direct or indirect effects of SRIs on the 5HT1B receptor may be involved in mediating a clinical response in OCD. In the section exploring the intersection of neurobiology and treatment, I show that changes in rCBF partially parallel treatment response to SSRIs across a range of anxiety disorders. These data suggest that a degree of overlap exists in the neurobiology of treatment response or indeed core neurobiology across different anxiety disorders. I then show that effective treatment with inositol in OCD results in rCBF changes that are partially in line with the effects of SRIs on brain perfusion. These data support suggestions that second messengers may form part of the common pathway of action for effective anti-obsessional compounds. In the study in which we augmented SRIs with quetiapine, no advantage over placebo was found. This data has, however, recently been combined with similar data in meta-analyses and demonstrated a benefit over placebo. Finally, we found that patients who have failed fewer SRI trials, have more severe illness, and clinical dimensions with a putative dopaminergic underpinning, may derive preferential benefit from serotonin/dopamine antagonist augmentation of SRIs. Through this series of clinical treatment and functional brain imaging studies in OCD, I have contributed to the neurobiological understanding of OCD, and its treatment in refractory populations. In addition I have explored the intersection of these two domains using novel as well as conventional treatment across other anxiety disorders. Treatment and pharmacological challenges used, either directly or indirectly impacted the monoamine systems serotonin and dopamine and advanced our understanding of their involvement in symptom generation. Future work should focus on the functional intersection of brain function, treatment response, and functional genetic polymorphisms within the monoamine systems of the brain. / AFRIKAANSE OPSOMMING: Ondersoek na die neurobiologie van obsessief-kompulsiewe steuring (OKS) het in die afgelope dekades sinvolle bydraes gelewer tot die begrip van hierdie algemene en verminkende steuring. Bemoedigende vordering is ook in die farmakologiese behandeling van OKS gemaak. Dit het tot ’n verbetering in kwalitiet van lewe van meeste pasiënte gelei wat normaalweg kronies en onophoudelike simptome moet verduur. Ten spyte van die uiteenlopende gebruik van eerste-linie behandeling wat spesifiek inwerk op die serotonien sisteem in OKS, is relatief min bekend oor die neurobiologie van respons op behandeling. So ook is min bekend oor; eerstens die spesifieke komponente van die serotonien sisteem wat betrokke is by simptoom modulasie, en tweedens die gedeeltelik samevallende en afsonderlike brein streke wat deur alternatiewe farmakologiese behandelings beïnvloed word. Ten spyte van die vooruitgang wat die selektiewe serotonien heropname inhibeerders tot gevolg gehad het, is daar nog altyd ‘n betekenisvolle proporsie van pasiënte wat nie voldoende respondeer op hierdie behandelings opsie nie. Dus word alternatiewe opsies benodig. Een so ‘n opsie is die klas dopamien reseptor blokkeerders wat tot onlangs min ondersteunende data gehad het. So ook, is min bekend oor die subgroepe van pasiënte wat die meeste voordeel uit hierdie alternatief sal trek. In hierdie proefskrif sal ek ‘n reeks van ses studies wat farmakologiese middels en enkel foton emissie rekenaar tomografie (EFERT) gebruik om ‘n bydra tot kennis in drie primêre areas van OKS te maak. By name; neurobiologie, behandeling, en die kruispunt van die twee. Eerstens spreek ek neurobiologie aan deur middel van ’n studie wat rustende brein bloed vloei (rBBV) in OKS ondersoek. Hierna ondersoek ek veranderings op rBBV en simptome na eenmalige toediening van ‘n serotonien 1B reseptor agonis, sumatriptan. Tweedens ondersoek ek die kruispunt van neurobiologie en behandeling deur die effek van behandeling met inositol, ‘n voorloper van die fosfoinositol tweedeboodskapper sisteem, op rBBV. Ek ondersoek dan die rBBV patroon van veranderinge in brein streke wat deur twaalf weke van behandeling met die selektiewe serotonien heropname inhibeerder citalopram in verskeie angversteurings bewerkstellig word. Laastens, spreek ek behandeling van OKS aan deur middel van ‘n gekontroleerde studie wat ondersoek instel na die effektiwiteit van die byvoeging van quetiapien, ‘n dopamien reseptor antagonis, tot serotonien heropname inhibeerders in behandelingsweerstandige OKS. Ek kombineer dan hierdie data met ’n soortgelyke datastel om ‘n model af te lei wat kliniese uitkoms vir hierdie behandelings opsie voorspel. Ek het gedemonstreer dat rBBV in OKS betekenisvol verskil van gesonde vergelykbare kontroles. Hierdie verskille het gekorreleer met ernstigheid van OKS in frontale brein streke. Dus bly hierdie tipe studies ’n belangrike rigting van ondersoek in OKS patofisiologie wat tot op hede nie tenvolle uitgewerk is nie. Eenmalige toediening van sumatriptan, het heterogene gedrags en rBBV veranderings in OKS tot gevolg gehad. Pre-frontale verhogings in rBBV voor behandeling is met 5HT1B sumatriptan toediening verminder, ’n effek wat in lyn staan met die effek van selektiewe serotonien heropname inhibeerders. Hierdie werk stel voor dat direkte of indirekte effekte van selektiewe serotonien heropname inhibeerders op die 5HT1B reseptore betrokke mag wees by die meganisme van behandelingsrespons in OKS. In die afdeling waarin ek die kruispunt van neurobiologie en behandeling ondersoek, demonstreer ek dat rBBV veranderings gedeeltelik oorvleuel met dié wat deur selektiewe serotonien heropname inhibeerders veroorsaak word in verskeie angsversteurings. Hierdie data stel voor dat oorvleueling in die neurbiologie van beide behandelingsrespons en kern neurobiologie van hierdie angversteurings ’n waarskynlikheid is. Ek wys ook dat effektiewe behandeling met inositol in OKS ook veranderings in rBBV bewerkstellig wat gedeeltelik in lyn staan met dié van die selektiewe serotonien heropname inhibeerders. Hierdie data ondersteun dus hipoteses van ‘n gemeenskaplike meganisme, wat tweede boodskapper sisteme insluit, wat in die behandelings respons van effektiewe anti-obsessionale middels betrokke is. Die finale deel van hierdie proefskrif handel oor behandeling van OKS. Ten spyte van die onvermoë om ‘n verskil tussen quetiapien en plasebo te demonstreer, het ons onlangs met hierdie data in ‘n reeks meta-analises wel ‘n voordeel vir hierdie intervensie getoon. Ten slote, het ons gevind dat (1) pasiënte wat minder kursusse selektiewe serotonien heropname inhibeerders gefaal het; (2) voor behandeling ‘n erger vorm van OKS gehad het, en (3) ook voordoen met simptoom dimensies wat oënskynlik ‘n dopaminerge basis het, die grootste waarskynlikheid toon om met quetiapien byvoeging tot selektiewe serotonien heropname inhibeerders te respondeer. Met hierdie reeks behandelings en funksionele breinbeeldings ondersoeke, lewer ek ‘n bydra tot die begrip van OKS. Spesifiek dra ek by tot die begrip van die neurobiologie, hantering van behandelingsweerstandige OKS asook die kruispunt van die twee. Farmakologiese middels wat ons óf eenmalig óf vir ‘n volle behandelingskursus toegedien het, het direkte of indirekte uitwerkings op die serotonien and dopamien sisteme gehad, en dus dra hierdie werk ook by tot kennis oor dié se betrokkenheid al dan nie in simptoom modulasie in OKS. Toekomstige werk in die area sal in die breë fokus op die kruispunt van breinfunksie, behandelingsrespons en funksionele genetiese polimorfismes van die monoamien sisteem.

Early life adversity (ELA) produces long lasting developmental changes to the postnatal brain, increasing predisposition to a number of physical and psychiatric disorders. The mechanisms through which ELA is able to create lasting detrimental changes to neuronal development remains unclear. This thesis tested the hypothesis that increases in fear generalization, a common symptom in psychiatric disorders, follows ELA exposure in age dependent and sexually dimorphic ways in alignment with the findings of clinical studies. The effects of ELA often impact fear circuitry and we confirmed, using electrophysiology and tissue imaging, that 5-HT circuitry from the median raphe nucleus (MRN), integral to fear response, was impaired following ELA. Using a transgenic mouse model that allows for modulation of serotonergic release, we showed that circumventing serotonergic pathways disrupted by ELA and increasing whole brain 5-HT release was enough to rescue hippocampal dependent fear responses and fear generalization. Involvement of the hippocampus in ELA effects, particularly the ventral dentate gyrus (vDG), in fear overgeneralization was confirmed as hyperactivity in thevDG following exposure to novel contexts was rescued by increased 5-HT release. In addition to ELA-induced hyperactivity of the vDG, known to potentiate stress susceptibility, I demonstrated that ELA resulted in an increase in passive coping strategies, HPA axis dysfunction and elevated stress hormone release. These effects were seen predominantly in adult females and rescued in those with increased 5-HT release. Together these data suggest that increased predisposition to psychiatric disorders following ELA exposure involves the disruption of fear circuitry regulated by 5-HT activity. Identifying the underlying circuits altered by ELA not only provides insight about disrupted postnatal brain development, but also increases our knowledge of the timeline, trajectory and factors affecting healthy postnatal brain development.

Serotonin (5-HT) is a neurotransmitter in the central nervous system. Decrease in the brain 5-HT level could induce depression, showing a state of low mood, aversion to motion and feeling of worthlessness. About 12 million adults in the United States have depression. Antidepressants, such as monoamine oxidase inhibitors and selective serotonin reuptake inhibitors, can alleviate the depressive mood by increasing the brain's 5-HT activity, however they can also induce a potentially life-threatening side effect, namely 5-HT syndrome. This syndrome is manifested by neuromuscular hyperactivities, mental disorders and autonomic dysfunctions. Clinical studies have demonstrated that 5-HT2A receptor antagonists could effectively block severe symptoms of patients with the 5-HT syndrome. To understand the underlying mechanisms, in this study we examined the activity of the 5-HT2A receptor in rats with the 5-HT syndrome evoked by a combined injection of clorgyline, a monoamine oxidase inhibitor , and paroxetine, a selective 5-HT reuptake inhibitor. The major findings from my study were that: (1) Chronic clorgyline treatment significantly exacerbated 5-HT2A receptor-mediated symptoms of the 5-HT syndrome animals; (2) The 5-HT2A receptor-mediated symptoms were also aggravated when the 5-HT syndrome animals were housed in warm (32 ÀC) ambient temperature; (3) Blocking 5-HT2A receptors in the medial prefrontal cortex alleviated the 5-HT syndrome through a circuit between raphe serotonergic neurons and medial prefrontal cortex glutamatergic neurons. Taken together, my data demonstrate that the activity of 5-HT2A receptors may be enhanced by chronic antidepressant treatment and warm environmental temperature. / The sensitized 5-HT2A receptor in the medial prefrontal cortex may exacerbate the syndrome through a positive-feedback circuit between medial prefrontal cortex and raphe nuclei, which would result in excessive 5-HT in the brain. This study casts a new light on the underlying mechanisms of the 5-HT syndrome. / by Gongliang Zhang. / Thesis (Ph.D.)--Florida Atlantic University, 2010. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2010. Mode of access: World Wide Web.

Methylenedioxymethamphetamine (MDMA) popularly known as "Ecstasy" continues to gain popularity as a recreational drug that has been shown to increase serotonin and dopamine levels. The present study has demonstrated that repeated exposure to MDMA produces long-term damage to serotonergic and dopaminergic neurons in various regions of the rat brain.