Title

Two animal models of Parkinson's disease: Studies of acetylcholine and dopamine function

Date of Completion

January 1996

Keywords

Biology, Neuroscience|Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Fourteen experiments (Chapters 1-5 below) were conducted to investigate two potential animal models of Parkinson's disease. In Chapters 1-2, the effects of ventrolateral neostriatal (VLS) dopamine depletions were assessed on an operant lever pressing task. In Chapter 1, the lever pressing deficits produced by mild (29% of control) or severe (8% of control) VLS dopamine depletions were largely attributable to a dramatic increase in the average response initiation time. Only rats with severe VLS dopamine depletions showed increased average duration times. Using in vivo microdialysis in a separate group of rats, it was found that VLS dopamine release increased only modestly (21%) during lever pressing. In Chapter 2, some of the response deficits described in Chapter 1 following VLS dopamine depletion were partially alleviated by systemic pre-treatment with L-DOPA. Thus, lever pressing deficits produced by VLS dopamine depletion may be useful for the assessment of antiparkinsonian drugs. In Chapters 3-5, the involvement of the anticholinesterase tacrine in tremulous jaw movements (TJM) was studied. Using slow-motion videotape and electromyography, Chapter 3 determined that the TJM are characterized by motor activity largely in the 3-5 Hz frequency range, which is consistent with parkinsonian tremor. In Chapter 4, microinjection of the choline uptake inhibitor hemicholinium-3 into the VLS, but not overlying cortex, significantly reduced TJM produced by systemic tacrine. In Chapter 4, 5.0 mg/kg tacrine substantially increased extracellular VLS acetylcholine levels (224%); an effect that was highly correlated with TJM (r = +0.87). There was no significant effect upon extracellular dopamine levels. Thus, it seems that tacrine-induced TJM are at least partially mediated by VLS acetylcholine. Chapter 5 characterized the effect of antiparkinsonian agents upon tacrine-induced TJM. Co-administration of L-DOPA, apomorphine, APB, bromocriptine, amantadine, or benztropine decreased TJM produced by tacrine. Co-administration of SKF38393, which is not an effective antiparkinsonian agent in monkeys and humans, did not reduce tacrine-induced TJM. Together, Chapters 1-5 suggest that the lever pressing deficits resulting from VLS dopamine depletions and tacrine-induced TJM may be useful tools for studying the underlying substrates of Parkinson's disease. ^