Long-term postnatal treatment of rats with SCH 23390 is associated with a reduction in the development of dopamine D1 receptors in the striatum. Because the tripeptide, l-prolyl-l-leucylglycinamide (PLG) attenuates the neuroleptic-induced increase in D2 receptors in the striatum in adult rats, this study was undertaken with the objective of determining whether PLG could modulate a developmental alteration in the D1 subtype of receptor. Rats were treated with the dopamine D1 receptor antagonist, SCH 23390 (R[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1-H-3benzazepine) (0.30 mg/kg/d i.p.) for 32 successive days from birth, while D1 receptors in the striatum were assessed at 5 and 8 weeks from birth. Postnatal treatment with SCH 23390 reduced in vitro binding of [3H]SCH 23390 to homogenates in the striatum by 70% at 8 weeks. Scatchard analysis at 5 weeks determined that the Bmax for the binding of [3H]SCH 23390 was reduced by 78%, while the Kd was unaltered. When PLG (1.0 mg/kg/d i.p.) was administered together with SCH 23390 for the initial 32 days from birth, the binding of [3H]SCH 23390 to homogenates of the striatum was unchanged from that of the control group at 8 weeks. Also, at 5 weeks the Bmax and Kd were unaltered from control in the group that was treated with both SCH 23390 and PLG. The binding of [3H]SCH 23390 was not altered from control in the group treated with PLG alone. Also, PLG given in vitro did not alter the binding of [3H]SCH 23390 to control homogenates of the striatum. These findings indicate that PLG is able to attenuate neuroleptic-induced alterations in dopamine d1 receptors in the striatum.

The effect of chronic postnatal treatment of rats with selective D1- and/or D2-receptor antagonists on the development of D1- and D2-receptors in the striatum was studied. When neonatal rats were treated postnatally from the day of birth for 32 successive days with the D1-receptor antagonist, SCH-23390 (0.30 mg/kg i.p.), the development of striatal dopamine D1-receptors was markedly impaired, and the development of striatal D2-receptors was slightly impaired. Alternatively, chronic treatment with the D2-receptor antagonist, spiroperidol (1.0 mg/kg i.p.), resulted in a markedly impaired development of striatal dopamine D2-receptors, and a slightly impaired development of striatal D1-receptors. Scatchard analysis revealed that chronic SCH-23390 treatment during development resulted in a 78% decrease in the Bmax for in vitro binding of [3H]SCH-23390 to striatal homogenates, while the Kd was unaltered. Similarly, chronic postnatal treatment with spiroperidol was associated with a 74% reduction in the Bmax, while the Kd for in vitro binding of [3H]spiroperidol to striatal homogenates was unchanged. These findings demonstrate that chronic selective dopamine receptor antagonism affects development of both striatal D1- and D2-receptor types. The critical period during which striatal dopamine receptor ontogeny can be altered is not restricted to prenatal periods, since suitable postnatal challenge will alter striatal dopamine-receptor development.

Because the tripeptide MIF-1 (Pro-Leu-Gly-NH2) is known to attenuate the effects of neuroleptic-induced catalepsy as well as neuroleptic-induced proliferation of dopamine (DA) receptors, we studied the related naturally occurring peptide, Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) for similar properties. Male rats were treated SC for 11 consecutive days with either the DA D1 receptor antagonist SCH 23390 HC1 (0.50 mg/kg per day), the DA D2 receptor antagonist spiperone HCl (0.30 mg/kg per day), or vehicle. Half the rats were cotreated daily with Tyr-MIF-1 (1.0 mg/kg per day). The cataleptic effects of SCH 23390 were not altered by Tyr-MIF-1. Tolerance to SCH 23390-induced catalepsy did not develop during the 11-day treatment, and Tyr-MIF-1 had no effect on SCH 23390-induced catalepsy. However, tolerance developed to spiperone-induced catalepsy, and Tyr-MIF-1 attenuated this development of tolerance (p < 0.001). Locomotor and stereotyped activities of the DA D1 and D2 agonists, SKF 39393 (3.0 mg/kg) and quinpirole (3.0 mg/kg) were not affected by Tyr-MIF-1 after treatment with the DA antagonists was discontinued. Tyr-MIF-1 did not alter the Bmax or Kd for in vitro binding of [3H]SCH 23390 and [3H]spiperone to homogenates of the striatum. These findings indicate that Tyr-MIF-1 is able to selectively affect the development of receptor tolerance to a DA D2 receptor antagonist, and that this effect is unrelated to changes in affinity or numbers of D2 receptors.

No description available.

Thesis (MBA)--Stellenbosch University, 2005. / ENGLISH ABSTRACT: To compete in today’s ”new” economy, Centocor R&D SCH has to attain and maintain a competitive advantage within the global Pharma/biotech industry. With their drive to become a centre of excellence in the fields of fill-finish of biologics and particle characterization, it is important that an analysis of the status quo be done, and that efficient systems and structures are implemented to achieve world class performance. In this project, the approach to business excellence is discussed. Business excellence is more than a simple accumulation of a range of best practices. It can only be achieved by implementing a structured approach towards business performance. This begins with an internal self-assessment; as well as an assessment of the customer/partner needs: these of which are incorporated into the organization’s policies and strategies. Their perceptions are evaluated since these “quality chains” are what ultimately drive a business. The organization must align its culture, processes, inputs, and capabilities with the vision, goals and strategy; and promote and display a mind-set for innovation, and continuous improvement. In this way, the desired business results may be achieved. This is all driven by leadership; and a quality and performance culture; and provides an opportunity to view the organization holistically. The developed model for Centocor R&D SCH is a framework for measuring their business excellence towards achieving performance excellence, and from there a well-paved route for developing the centre of excellence. It is developed on the basis of the European Foundation for Quality Management Model as well as that of the global J&J Process Excellence Competitive Assessment Model; and is supported by the criteria that support those. Strengths are identified, and areas of improvement are viewed as opportunities where the teams can improve on to ensure leadership and excellence in those arenas. / AFRIKAANSE OPSOMMING: Om in vandag se “nuwe” ekonomie mededinge te kan wees, moet Centocor R&D SCH ‘n mededingende voordeel in die globale farmakologiese/biotegnologie industrieë bereik en handhaaf. Met die dryfveer om ‘n sentrum van uitnemendheid in die velde van lyofilisasie and partikel karakterisasie te word, is dit belangrik dat ‘n ontleding oor die status quo gedoen word, en dat doeltreffende stelsels en strukture geïmplementeer word om wereldklas prestasies te behaal. In hierdie projek word die benadering om tot sake-uitnemendheid te vorder, bespreek. Sake-uitnemendheid is meer as net ‘n eenvoudige akkumulaise van ‘n reeks beste praktyke. Dit kan slegs bereik word deur die implementering van ‘n gestruktureerde benadering tot sake resultate. Hierdie proses begin met ‘n interne self-ondersoek, asook ‘n beoordeling van die behoeftes van kliënte en vennote: dit wat in die organisasie se se beleide en strategieë geïnkorporeer is. Hulle persepsies word ge-evalueer want dit is juis hierdie waardekettings wat uiteindelik die sake-onderneming voortstu. Die organisasie moet sy kultuur, prosesse, insette en vermoeëns met die visie, doelwitte en strategie belyn; en ‘n ingesteldheid op innovasie en deurlopende verbetering toon en uitbou. Op so ‘n manier kan die gewensde sake resultate behaal word. Dit word alles beheers deur leierskap en ‘n kultuur van kwaliteit en prestasie, en skep die geleentheid om die organisasie holistoes te benader. Die model wat vir Centocor R&D SCH ontwikkel is, is ‘n raamwerk waarmee hulle hul sake-uitnemendheid kan meet, met die oog om uitmuntende prestasie te lewer, en om van daar af tot ‘n sentrum van uitnemendheid te ontwikkel. Die model is gebasser op die European Foundation for Quality Management Model asook die globale J&J Process Excellence Competitive Assessment Model, en word gedar deur die criteria van daardie modelle. Sterkpunte word geïdentifiseer, en areas vir ontwikkeling word gesien as geleenthede vir die spanne om te verbeter en na leierskap en uitnemendheid in daardie gebied te streef.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Psychological disorders such as autism, obsessive-compulsive disorder, drug addiction, and attention-deficit/hyperactivity disorder involve atypically persistent behavior and atypical activity of the neurotransmitter dopamine. Behavioral momentum theory states that the persistence of behavior in a context is determined by the reinforcement received previously in that context. Contexts previously associated with higher rates of reinforcement yield greater persistence of behavior than contexts previously associated with lower rates of reinforcement. According to a prominent hypothesis in behavioral neuroscience, dopamine mediates the incentive salience of a stimulus. A synthesis of behavioral momentum theory and the incentive salience hypothesis proposes similar roles for dopamine activity and reinforcement in determining the persistence of behavior in a context. The aim of this dissertation was to determine the extent to which a history of dopamine modulation in a context affects the subsequent persistence of behavior in extinction and relapse. Three groups of rats were trained to press a lever for food in two alternating contexts of a multiple schedule. Following a stable baseline, rats entered a treatment phase in which they received a drug or saline injection before and after sessions in each context. In the drug context, rats received the indirect dopamine agonist amphetamine, dopamine D1 antagonist SCH 23390, or a combination of amphetamine and SCH 23390 prior to the session and a saline injection following the session. The injection schedule was reversed for the saline context such that rats received a saline injection prior to each session in the saline context and a drug injection following the session. During an extinction phase, access to food was withheld. Response-independent food was then provided in each context to trigger reinstatement of responding. A history of dopamine agonism in a context increased the relative persistence of behavior, while a history of dopamine antagonism at D1 receptors and a combination of dopamine agonism and dopamine antagonism had little impact on the relative persistence of behavior. Likewise, reinstatement was relatively greater in a context previously associated with dopamine agonism. This effect was blocked when dopamine agonism was preceded by D1 antagonism. A history of D1 antagonism alone did not affect reinstatement. These results suggest that dopamine plays a role in the persistence of behavior in extinction and relapse, but that different dopamine receptors mediate these effects.

According to Dorst and Dijkhuis (1995) the two principal paradigms governing design activity discourse, are Simon's rational problem solving, and Schon's theory of design as a 'reflective conversation with the situation'. The rational problem solving view, that a fixed problem space structures design activity, has reduced the designer to a 'missing person' within design activity research (Dorst & Reymen 2004). This thesis aims to highlight the agency of the designer in structuring and motivating socially situated design activity. Dorst's (2006) framework of 'design paradoxes' suggests that design problems are evolving and unknowable. Design situations are determined through the designer's reinterpretation of the social discourses underpinning design situations, in a similar way to 'problem setting' within 'reflection-in-action' (Schon 1983). While Dorst suggests interpretation relies on intuition, problem setting relies on 'professional artistry' which is 'bounded' by the 'appreciative system' (personal knowledge, values and beliefs) and is essentially 'learnable' (Schon 1983). This thesis explores the correspondence between Schon's theory and contemporary frameworks including 'design paradoxes' (Dorst 2006), 'designerly ways of knowing' (Cross 1982), 'organising principles' (Rowe 1987), and 'creative problem construction' (Mumford et al 2004). It investigates the agency of the designer as evidenced in the use of the 'appreciative system'. This is elucidated using case study analysis of a novice designer, within a tertiary design degree. The case reveals the structured and motivated use of the designer's appreciative system. It indicates the deployment of 'appreciative goals' are fundamental to the 'linking behaviour of designers' (Dorst 2006), enabling design to begin in the absence of 'repertoire' or domain knowledge (Schon 1983), and the acquisition of new repertoire knowledge. These emergent findings offer new pedagogical perspectives both in terms of design expertise, which is normally associated with domain knowledge, and educating domain independent, multidisciplinary designers. Frames or similar 'organising principles' operate in most design fields, and create a 'principle of relevance' for knowledge from multiple domains and disciplines (Buchanan 1992). An awareness and acknowledgement of the objective function of subjective personal and social knowledge is essential in order to locate the 'missing' designer and understand innovative design activity.

On the morning of the first day of pregnancy, Wistar rats were administered a single IP injection of either zinc sulfate (10.0 mg/kg) or saline. For the remainder of pregnancy, half the rats in each group then consumed filtered tap water while the other half consumed filtered tap water with 50 ppm of cadmium (CdCl2). At eight weeks after birth, the behavioral profile of male offspring was assessed in the following way: Apomorphine (non-selective dopamine receptor agonist), (+)-7-hydroxy-2-(di-n-propylamino) tetralin (7-OH-DPAT) (D3 agonist) and (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393) (D1 agonist) were used to evaluate stereotyped behavior, yawning activity and oral movements - indices for these respective agonists. In addition, two dopamine receptor antagonists, haloperidol (D2 antagonist) and 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzapine (SCH 23390) (D1 antagonist) were used to evaluate cataleptogenic activity. Additional behavioral parameters studied were locomotor activity, irritability and reaction to a painful stimulus. Dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were quantified in the striatum, hippocampus and in the frontal cortex of the brain by means of HPLC/ED technique. In addition, cadmium levels were analyzed in the brain, liver, kidney and bone of newborn rats. Our results indicate that prenatal exposure of pregnant rats to cadmium produced alterations in the reactivity of central dopamine receptors and modulated the level of dopamine and its metabolites in the offsprings' brains. A single injection of zinc, preceding cadmium consumption, attenuated some of the effects of cadmium on the offsprings' dopaminergic system. Zinc also reduced cadmium deposition in the brain, kidney and bone, but enhanced its accumulation in liver. In summary, zinc may exert some neuroprotective effects against cadmium neurotoxicity.

Previous reports have indicated that prenatal, but not postnatal, haloperidol impairs the ontogenic development of striatal dopamine D-2 receptors. In the present study a specific D-2 receptor antagonist, spiroperidol (1.0 mg/kg i.p.) and/or a specific D-1 receptor antagonist, SCH 23390 (0.30 mg/kg i.p.), was administered to rats for 32 successive days from birth. Postnatal spiroperidol and SCH 23390 treaments markedly impaired the development of striatal dopamine D-2 and D-1 receptors, respectively, at 12 weeks after birth. Spiroperidol did not affect D-1 receptor development and did not modify the effect of SCH 23390 treatment. Also, SCH 23390 did not affect D-2 receptor development and did not modify the effect of spiroperidol treatment. When rats with impaired development of striatal D-2 receptors were challenged at 12 weeks with spiroperidol (1.0 mg/kg per day i.p. × 17 days) D-2 receptors did not up-regulate. However, when rats with impaired development of striatal D-1 receptors were challenged at 12 weeks with SCH 23390 (0.30 mg/kg per day i.p. × 17 days) D-1 receptors did up-regulate. These findings demonstrate that postnatal treatment with D-1 and D-2 receptor antagonists can permanently impair the development of striatal D-1 and D-2 receptors. Moreover, the ability of developmentally impaired striatal D-1 receptors to up-regulate in adulthood appears to be greater than that for the developmentally impaired striatal D-2 receptors.