Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 84-100).

A procedure was developed to determine the effect of a dopamine (DA) antagonist (haloperidol) and a DA agonist (d-amphetamine) on rats' perceptions of the hedonic value of food. Eighteen rats were trained to discriminate between two quantities of sweet food pellets (1 and 4), in a forced-choice two-lever successive discrimination procedure. To control for non-specific perceptual effects of the treatments, the rats were also trained to discriminate between 1 and 4 tones. It was established that rats attended to the value of food, as well as the proportional differences in quantity, when discriminating food quantities. This was accomplished by altering the value of the food in two ways. Firstly, "hunger" was altered by changing the degree of food deprivation during testing. Secondly, unsweetened food pellets were introduced as probe cues. These two methods of altering the value of food pellets were utilized while quantity generalization gradients were determined, by presenting animals with 1,2, 3 and 4 numbers of stimuli as probe cues. Two measures were derived from these generalization gradients: the point of subjective equality (PSE), which is the calculated number of stimuli that would maintain responses equally distributed between the two levers, and the slope of the gradient. The PSE primarily reflects perceptual processes, while the slopes of the gradients provide an index of performance impairment. It was observed that decreasing the value of food by either decreasing food deprivation or reducing the sweetness of the food pellets resulted in the rats perceiving a given quantity of food as larger than before these treatments (decreased the food PSE). Neither altering food deprivation nor introducing novel tone probes had an effect on the numerical attributes of tones, as reflected by the tone PSE. Haloperidol (0.030, 0.50 and 0.083 mg/kg, i.p.) produced a statistically significant, but slight dose-dependent performance deficit, as reflected by the slope of the generalization gradients. It did not affect the perception of food pellet quantities at any dose, as reflected by the food PSE. Haloperidol decreased the number of tones a given quantity was perceived as by rats (increased the tone PSE). Amphetamine (0.25, 0.50 and 1.0 mg/kg, i.p.) decreased the perception of a given quantity of food (increased the food PSE) in a dose-dependent manner, without a significant effect on performance. Thus, amphetamine enhanced the hedonic value of food. Amphetamine also increased rats' perceptions of a given number of tones (decreased the tone PSE). It therefore appears that while d-amphetamine can enhance the perceived hedonic value of food, haloperidol has no effect on rats' perceptions of the hedonic value of food. Furthermore, evidence that DA systems are involved in the mechanism of an "internal clock" or "counter" was obtained. / Medicine, Faculty of / Graduate

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Lead (Pb²⁺) is an environmental toxin that is known to cause lasting cognitive deficits following early life exposure. Previously, our laboratory demonstrated increased sensitivity to the psychostimulant effects of cocaine in animals with elevated blood Pb²⁺ levels (BLL). This effect was abolished following introduction of dopamine (DA) receptor antagonists, indicating that the dopaminergic (DAergic) system may be a target of Pb²⁺’s toxic effects. However, the biological mechanisms through which Pb²⁺ increased sensitization to cocaine’s psychostimulant effects have not been fully elucidated. There is some disagreement regarding the magnitude and direction of Pb²⁺’s effects on the DAergic system. Furthermore, many studies to date have measured the effects of Pb²⁺ in only one sex (usually male), one exposure, and one or two time-points, making it difficult to determine any potential sex-, age-, and exposure-dependent effects. In the present study, we used a well-validated animal model and Pb²⁺ exposure paradigm that uses chronic dietary exposure to 180ppm and 1500ppm Pb²⁺ acetate (PbAC) in the diet. These levels of Pb²+ in the diet resulted in low and moderate levels of BLLs that on average approximated 4.5 and 22.0µg/dl in young adult rats. These levels of Pb²⁺ exposure are relevant to contemporary levels of BLL in intoxicated children in many cities in the United States and in many parts of the world where Pb²⁺ exposure continues to be a major public health concern. It should be noted that at the low level of Pb²⁺ exposure, the resulting BLL of 4.5µg/dl is just below the current CDC level of action. Using this well-defined rat model of chronic Pb²⁺ exposure, in Aim 1, we measured DA concentration and turnover in the dorsal striatum (STR) of juvenile (PN14), adolescent (PN28), and young adult (PN50) male and female rats. Tyrosine hydroxylase (TH) protein, the rate-limiting step in the synthesis of DA, and phosphorylation of TH at serine 40 (pser40TH) were assessed as an indirect measure of TH activity. Thus, we measured the ratio of pser40TH to total TH protein. We also measured vesicular monoamine transporter-type 2 (VMAT2) levels in the STR, nucleus accumbens (NAC), and olfactory tubercle (OT) since this protein is critical for the sequestration of DA in presynaptic vesicles and has been used as a biomarker for DA terminal integrity. In Aim 2, we examine the effect of chronic Pb²⁺ exposure on D1 and D2 dopamine receptor (D1R and D2R) in the OT, NAC, and STR. Analysis of D1R and D2R is important since the downstream effects of DA are dependent on the DA receptor subtype it activates. In Aim 1, we observed significant increases in DA and its metabolites homovanillic acid (HVA) and 3,4-Dihydroxyphenylacetic acid (DOPAC) in the STR of adolescent and young adult male rats with BLL as low as 4.5µg/dl in the absence of phosphorylation at the serine 40 residue of TH or altered VMAT2 levels. In Aim 2, a significant increase in D2R was detected in the juvenile male rat STR. We also observed increases in D1R expression in adolescent male rats in the NAC, OT, STR, and in the OT of adolescent female rats. Together, these results demonstrate that chronic Pb²⁺ exposure alters DA receptor levels in a manner characteristic of a hyperactive DAergic state. The observations presented in this work suggest that a hyperactive DAergic system underlies the heightened sensitization to cocaine we previously observed in Pb²⁺-exposed animals. This work builds upon the current understanding of how Pb²⁺ modulates the DAergic system and provides some elucidation of the mechanisms underlying increased drug sensitization our laboratory has previously observed in rats exposed to Pb²⁺.

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such as amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMPreleases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) - induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP(attenuation of hyperlocomotion) were produced by m-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect of m-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried

O transtorno obsessivo-compulsivo (TOC) é um transtorno psiquiátrico freqüentemente crônico caracterizado pela presença de obsessões e/ou compulsões. Tratamentos de primeira linha, que incluem os inibidores seletivos da recaptura de serotonina (ISRS) e a terapia cognitivocomportamental com técnicas de exposição e prevenção de respostas não conseguem melhora satisfatória em até 40% dos pacientes. Para estes casos, existem evidências que apóiam o uso de antipsicóticos como a quetiapina, na potencialização dos ISRS. No entanto, os antipsicóticos são eficazes para apenas um terço dos pacientes e estão associados a eventos adversos preocupantes no longo prazo. Este estudo tem como objetivo comparar a eficácia da potencialização do ISRS fluoxetina com a clomipramina, um inibidor de recaptura da serotonina não-seletivo, ou quetiapina, versus placebo. Para inclusão neste estudo, os pacientes precisavam: relatar os sintomas de TOC como sendo seu problema principal; estar em uso da dose máxima tolerada ou recomendada de fluoxetina por pelo menos oito semanas; ter um escore total na escala Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) de pelo menos 16; e ter tido uma redução do escore inicial da YBOCS menor do que 35% após tratamento com fluoxetina. Os pacientes (N=54) foram alocados por meio de um método de minimização em três grupos: quetiapina (até 200mg/dia) com fluoxetina (até 40mg/dia) (QTP/FLX) (N=18); clomipramina (até 75mg/dia) com fluoxetina (até 40mg/dia) (CMI/FLX) (N=18); e placebo com dose máxima de fluoxetina (até 80mg/dia) (PLC/FLX) (N=18). Avaliadores cegos obtiveram os escores da YBOCS nas semanas 0 e 12. As análises foram realizadas por intenção de tratar, com imputação do tipo hot-deck para os dados faltantes. Teste de Wald por ANCOVA não paramétrico para medidas ordinais repetidas foi utilizado para avaliar efeitos de grupo, tempo e interação para os resultados da YBOCS e desfechos secundários, tendo as medidas iniciais como co-variáveis. Os resultados da impressão clínica global de melhora (ICG-M) foram utilizados para classificar os pacientes como respondedores ou não-respondedores. O teste qui-quadrado foi utilizado para avaliar a freqüência de respondedores em cada grupo. Foram feitos gráficos de percentis e análises de sensibilidade. Quarenta pacientes (74%) completaram o seguimento. Não foram observados efeitos adversos graves. Pacientes dos grupos PLC/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=49%, DP=0.49) e CMI/FLX (YBOCS final: média=10, DP=4; redução em relação ao inicial: média=46%, DP=0.51) melhoraram significativamente e tiveram uma melhor resposta quando comparados aos do grupo QTP/FLX (YBOCS final: média=13, DP=3; redução em relação ao inicial: média=18%, DP=0.20; p=0.001). Não foram encontradas diferenças significativas para as medidas secundárias. Os gráficos de percentis confirmaram que os pacientes do grupo QTP/FLX pioraram com maior freqüência e melhoraram menos do que os pacientes dos outros dois grupos. Análises de sensibilidade demonstraram que outros métodos de análise não modificaram significativamente os resultados. Este é o primeiro estudo duplo-cego controlado de potencialização de ISRS com clomipramina em TOC e também o primeiro a comparar a eficácia de potencialização com quetiapina à de outro potencializador. Limitações deste estudo incluem o uso de doses baixas dos potencializadores, taxas de abandono diferentes para os três grupos e período curto de seguimento. Apesar dessas limitações, nossos resultados apóiam o uso da clomipramina como potencializador (principalmente para aqueles que não toleram doses altas de fluoxetina) e o aumento do período de seguimento com fluoxetina em dose máxima antes de uma potencialização medicamentosa ser tentada / Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried