Ph.D. / Omslagstitel: Metabotropic glutamate receptor 4 activation and expression.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 104-118).

Ph.D.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "December 2002." Typescript. Vita. Includes bibliographical references (leaves 121-148). Also issued on the Internet.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2007. / Title from title page screen (viewed on June 20, 2008). Research advisor: Jeffery D.Steketee, Ph.D. Document formatted into pages (xi, 89 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 71-89).

Huntington's disease (HD) is an inherited autosomal-dominant neurodegenerative disease caused by the abnormal expansion of CAG repeats in exon 1 of the huntingtin gene located on chromosome 4. This disease is characterized by the premature loss of medium spiny neurons in the striatum and behavioural deficits that typically manifest at middle-age. Despite the identification of its cause decades ago, there is still no disease modifying treatment available for HD patients. Current evidence indicates that exacerbated glutamate signalling in the striatum plays a key role in the pathophysiology of HD. Within the striatum, metabotropic glutamate receptor (mGluR) 2/3 are predominantly expressed on presynaptic terminals, whereas mGluR5 is predominantly localized to postsynaptic terminals. Here, we show that both the activation of mGluR2/3 and the inhibition of mGluR5 can improve HD symptoms in the zQ175 HD mouse model. Specifically, treating zQ175 HD mice with either the mGluR2/3 agonist LY379268 or the mGluR5 negative allosteric modulator (NAM) CTEP rescues motor deficits, reduces mutant huntingtin aggregate formation, improves neuronal survival and alleviates microglia activation. We also provide evidence that shows sex can influence the progression of HD symptoms and the efficacy of therapeutic agents. We found that chronic administration of LY379268 differentially activated and inactivated cell signalling pathways in male and female zQ175 mice. Furthermore, female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Using FDNQ175 mice, a newer HD mouse model derived from the zQ175 line, we demonstrated that female FDNQ175 mice were less susceptible to decline in limb function than male mice but showed higher levels of insoluble mutant huntingtin aggregates at a younger age.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 121-148). Also issued on the Internet.

Schizophrenia is a serious psychiatric disorder that affects 1% of the population. Current theories implicate NMDA receptor hypofunction as a contributor to the symptomology and pathological alterations in schizophrenia. Cognitive impairments are increasingly recognized as not only fundamental to schizophrenia, but the strongest predictor of patient functional outcomes. Current antipsychotics do not improve the cognitive symptoms of the disorder; however, recent efforts have resulted in the identification of novel drug targets. One target is metabotropic glutamate receptors as they interact with and modulate NMDA receptors. Another approach focuses on dopamine, the neurotransmitter system targeted by traditional antipsychotics. Tetrahydroprotoberberines, such as D- and L-govadine, are synthetic compounds derived from traditional medicine that have demonstrated efficacy in treating schizophrenic symptoms. The present study assessed the effects of CDPPB (a metabotropic glutamate receptor 5 positive allosteric modulator), D- and L-govadine, and the typical antipsychotic haloperidol on the Paired Associates Learning (PAL) task in rats. The PAL task is impaired in patients with schizophrenia, has been adapted for use with rodents using touchscreen-equipped operant chambers, and has been promoted by MATRICS as a promising behavioural task with the potential to further translational health research in schizophrenia. The objectives of this study were: 1) examine the effects of acute NMDA receptor antagonism with MK-801 as a model for schizophrenia on performance of the PAL task; 2) test the effects of the putative antipsychotics, CDPPB and D- and L-govadine on reversing the effects of NMDA receptor antagonism on the task; and 3) to compare these novel therapeutics to a classic antipsychotic. Two squads of male Long-Evans rats were trained to perform the PAL task in touchscreen-equipped operant chambers. After the rats reached criterion the following treatment schedules were divided between the two squads: 1) vehicle (10% cyclodextrin; i.p.), and CDPPB (1.0, 3.0, and 10.0 mg/kg, i.p.); or 2) vehicle (10% cyclodextrin; i.p.), CDPPB (3.0 mg/kg, i.p.), the NMDA receptor antagonist MK-801 (0.15 mg/kg, i.p.), and CDPPB with MK-801; or 3) vehicle (50% DMSO; s.c.), MK-801, D-govadine (1.0 mg/kg; s.c.), L-govadine (1.0 mg/kg; s.c.) and MK-801 with each isomer of govadine; or 4) vehicle (sodium acetate and acetic acid, pH 5.0, s.c.), and haloperidol (0.05 and 0.1 mg/kg, s.c.). Acute MK-801 significantly reduced the number of trials completed, impaired accuracy, and increased the number of errors in the PAL task. CDPPB had no effect on the PAL task and did not improve the MK-801 induced impairments. Administration of L-govadine, but not D-govadine, prior to MK-801 improved accuracy and reduced errors compared to MK-801 alone. L-govadine alone, but not D-govadine, reduced total responding compared to vehicle. Haloperidol caused a dose-dependent decrease in all activity in the task confounding interpretation of the results in regard to cognition. These data establish disruptive effects of acute MK-801 treatment on PAL task performance and demonstrate that L-govadine is capable of cognitive enhancement in a rodent model of schizophrenia.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Immunohistochemical studies were conducted to assess the subunits of ionotropic and metabotropic glutamate receptor present in the rostral ventrolateral medulla (RVLM) of the rat. Double labeling the medullary sections with polyclonal GluR1, GluR2/3, GluR4, NMDAR1, NMDAR2A/B, mGluR1α, and mGluR2/3 antiserum and monoclonal tyrosine hydroxylase (TH) antiserum revealed nearly all TH immunoreactive (irTH) cells and many TH-negative neurons were immunoreactive to GluR2/3 (irGluR2/3), NMDAR1 (irNMDAR1), and NMDAR2A/B (irNMDAR2A/B). A few RVLM neurons were immunoreactive to GluR1 (irGluR1) and GluR4 (irGluR4), but they were generally TH-negative. Immunoreactivity to mGluR1α (irmGluR1α) appeared to be localized exclusively to fiber-like elements in the RVLM area. Our results show that neurons in the RVLM, including irTH, are endowed mainly with GluR2/3 and NMDAR1 or NMDAR2A/B ionotropic receptor subunits, and that irmGluR1α splice variant appears to be located on nerve fibers ramifying within the RVLM. Moreover, TH-negative neurons in the RVLM appear to bear similar subunits of ionotropic glutamate receptors.