Neurochemical interactions in the basal ganglia: Studies of GABA, serotonin, acetylcholine, and dopamine and the utility of a conditionally immortalized GABA releasing cell line in an animal model of Parkinsonian tremor

This series of twenty experiments was conducted to investigate the role of several neurotransmitters in the production of tremulous jaw movements (TJMs), which are an animal model of parkinsonian tremor. The neurotransmitters investigated in these experiments were serotonin, acetylcholine, dopamine, and GABA. In Chapter 1, the effect of systemic treatment with the 5HT 2A/C antagonist mianserin was assessed, alone and in combination with the cholinergic antagonist scopolamine. Results from these experiments revealed that mianserin is effective in reducing the TJMs. The combination of mianserin and scopolamine had an additive but not a synergistic effect on TJMs. In Chapter 2, the effect of mianserin injected into the ventrolateral striaturn (VLS) or substantia nigra pars reticulata (SNr) on TJMs was assessed. Mianserin significantly suppressed TJMs when injected into the SNr but not when injected into the VLS or a dorsal SNr control site. In Chapter 3, the effect on TJMs of systemic treatment with two GABA transport (GAT) inhibitors was assessed. Both of the GAT inhibitors tested significantly suppressed TJMs. In Chapter 4, the effect on TJMs of implantation of a conditionally-immortalized GABA-releasing cell line into the SNr was assessed. These cells significantly suppressed TJMs when implanted into the SNr but not when injected into control sites. HPLC analysis revealed that these cells produce GABA in vivo. Survival studies showed that these cells maintained their effects for at least two-weeks after transplantation, but this effect was absent by the sixth week. In Chapter 5, the effect on TJMs of cell implantation and pharmacological intervention was assessed. All of the compounds tested increased the effectiveness of cell implantation to some degree. In Chapter 6, the ability to regulate gene expression in these cells in vivo was assessed. It was shown that these cells are regulatable in vivo. Together the results of these studies may aid in the development of antipsychotic medications that exhibit a low liability for extrapyramidal motor disorders, and that implantation of a GABA-releasing cell line into the SNr provides a novel approach to the treatment of PD.