Regulation of striatal acetylcholine concentration by dopamine receptors

Abstract

IMPAIRMENT of the coordinated activities of cholinergic and dopaminergic neurones in the brain has been implicated in the pathophysiology of Huntington's chorea, drug-induced dyskinesias, Parkinsonism, schizophrenia and manic-depressive psychosis1–6. Physostigmine, a drug which increases brain acetylcholine by inhibiting acetylcholinesterase, has been reported to improve the neurological status of patients with Huntington's chorea, tardive dyskinesias and L-dopa-induced dyskinesia7–9. The hyperkinetic involuntary movements in these disorders are thought to be related to a denervation hypersensitivity of dopamine receptors in the striatum10. On the other hand, in diseases with decreased dopaminergic activity, such as idiopathic and phenothiazine-induced Parkinsonism, intravenous injection of small doses of physostigmine exacerbated rigidity and tremors11,12. A similar aggravation of Parkinsonian-like symptoms by physostigmine can be observed in rats pretreated with phenothiazines or reserpine and in dogs pretreated with intracisternal 6-hydroxydopamine13,14. L-Dopa blocks the adverse neurological effects of physostigmine in Parkinsonian patients and in animals pretreated with reserpine or 6-hydroxydopamine11–14. These observations suggest that the response to central cholinergic stimulation depends on the functional activity of inhibitory dopamine receptors in the striatum. The diminished striatal dopamine receptor stimulation in Parkinsonism15 may secondarily produce cholinergic hyper-activity in the striatum; the converse may exist in dyskinetic and choreiform disorders. Striatal dopamine receptors could regulate cholinergic activity by modulating intrastriatal acetylcholine synthesis and release by cholinergic neurones. We have now tested this hypothesis by investigating the effect of dopamine receptor agonists and antagonists on striatal acetylcholine concentration.