Title

Striatonigral cholinergic and dopaminergic receptor mechanisms involved in the modulation of Parkinsonian tremor

Date of Completion

January 1998

Keywords

Biology, Neuroscience|Health Sciences, Pharmacology|Health Sciences, Pathology

Degree

Ph.D.

Abstract

Considerable evidence suggests that there is an interaction between central dopamine and acetylcholine systems in the modulation of parkinsonian symptoms. A similar interaction occurs in the modulation of tremulous jaw movements in rats, a rodent model of parkinsonian tremor. This research examined the receptor mechanisms underlying dopamine/acetylcholine interactions involved in the modulation of tremulous jaw movements, in order to gain insight into the receptor mechanisms involved in the modulation of parkinsonian tremor in humans.^ Tremulous jaw movements induced by acute administration of the acetylcholinesterase inhibitor tacrine occurred in the same 3 to 7 hertz frequency range as human parkinsonian tremor. Furthermore, tacrine-induced tremulous jaw movements were reversed by central but not peripheral muscarinic receptor antagonism. These studies also suggested that the anatomical locus for the generation of tacrine-induced tremulous jaw movements was the ventrolateral striatum. Thus, increasing striatal levels of acetylcholine by inhibiting acetylcholinesterase results in the production of tremulous jaw movements via stimulation of striatal muscarinic receptors.^ The reversal of tremulous jaw movements induced by the muscarinic agonist pilocarpine by selective muscarinic antagonists was consistent with the in vitro affinity of the antagonists for M4 muscarinic receptors. Therefore, muscarinic receptor stimulation may increase tremulous jaw movements via M4 muscarinic receptors. The reversal of pilocarpine-induced tremulous jaw movements by the D1 dopamine receptor agonist SKF 82958 was dependent on stimulation of D1 receptors in the ventrolateral striatum and the substantia nigra pars reticulata. The actions of SKF 82958 were mimicked by increasing ventrolateral striatal cyclic AMP levels and antagonized by blocking GABA receptors in the substantia nigra pars reticulata. Therefore, D1 stimulation may decrease tremulous jaw movements by increasing ventrolateral striatal cyclic AMP which ultimately increases GABA in the substantia nigra pars reticulata.^ Thus, one way in which tremulous jaw movements may be modulated is via reciprocal actions of M4 and D1 receptor stimulation on ventrolateral striatal cyclic AMP, leading to reciprocal actions on GABA release in the substantia nigra pars reticulata. This M4/D1 receptor interaction may therefore represent one mechanism by which dopamine and acetylcholine interact in the modulation of parkinsonian tremor in humans. ^