Elsevier

The Lancet Neurology

Volume 5, Issue 11, November 2006, Pages 974-983
The Lancet Neurology

Personal View
A convergent model for cognitive dysfunctions in Parkinson's disease: the critical dopamine–acetylcholine synaptic balance

https://doi.org/10.1016/S1474-4422(06)70600-7Get rights and content

Summary

Parkinson's disease is classically characterised as a motor neurodegenerative disorder. Motor symptoms in the disorder are secondary to an altered dopamine–acetylcholine balance due to reduced striatal dopaminergic tone and subsequent cholinergic overactivity. In the past, anticholinergic drugs were given to improve motor aspects of the disease. There is now an increasing interest in the cognitive and non-motor symptoms of Parkinson's disease and in cholinesterase-inhibitor therapy for dementia associated with Parkinson's disease. In this Personal View, we reconsider the dopamine–acetylcholine balance theory and look at recent clinical findings and the possible cooperative role of dopamine and acetylcholine in the induction and maintenance of the long-lasting changes of striatal and cortical synaptic plasticity. We also discuss a convergent versus parallel model to explain cognitive dysfunctions in Parkinson's disease according to dopamine–acetylcholine dependent alterations in synaptic plasticity.

Introduction

In the original description given by James Parkinson, the well-known neurodegenerative disorder was essentially conceived as a motor disease1 and the presence of cognitive impairment in Parkinson's disease was neglected for many years. However, the classic motor symptoms usually coexist with impairment in cognitive domains ranging from subtle deficits to overt dementia. In patients with Parkinson's disease, both the dopaminergic and cholinergic systems undergo degeneration, which leads to deficits in dopamine and acetylcholine at synapses.

The classic clinical hypothesis is that the reduced dopaminergic input to the striatum causes a relative cholinergic overactivity. This theory has been used to explain the improvement of some motor signs such as tremor, reported after muscarinic receptor blockade.2 However, this hypothesis does not explain the selective cognitive vulnerability of patients to subthreshold doses of anticholinergic drugs3 and the improvement in the cognitive performance of patients after administration of acetylcholinesterase inhibitors.4 This suggests that a cooperative, rather than an opposite, role may occur between acetylcholine and dopamine in cognition.

It is now established that long-lasting, activity-dependent changes in the efficacy of synaptic communication underlie learning and memory. Because distinct forms of brain synaptic plasticity, such as long-term potentiation and long-term depression, need the concomitant activation of both dopamine and acetylcholine receptors,5, 6, 7 abnormalities in the dopamine–acetylcholine interactions may impair the physiological induction of synaptic plasticity and therefore lead to the onset of cognitive impairment.

Here, we discuss the possible molecular, synaptic, and behavioural mechanisms underlying the dopamine–acetylcholine synergistic function in maintaining physiological synaptic plasticity in the basal ganglia and their potential role in cognitive changes associated with Parkinson's disease.

Section snippets

Cognitive dysfunction in Parkinson's disease

The assessment of cognitive impairment associated with Parkinson's disease has shown various results owing to differences in case selection methods and diagnostic criteria.

The core feature of neuropsychological deficits is represented by an impairment of executive functions.8 Deficits in planning, sequencing, and execution of complex goal-directed behaviour are usually described. Particularly, these patients have difficulties in the maintenance of new sequence patterns after the shift from a

Anatomy of cortical and striatal systems

The striatum and cortex both receive dopaminergic and cholinergic inputs. However, this innervation arises from distinct origins (figure 1).

Symptomatic treatment of Parkinson's disease

Many drugs are now available for the symptomatic treatment of Parkinson's disease. Treatments with opposing biochemical effects such as anticholinergic drugs and acetylcholinesterase inhibitors are given to improve, respectively, motor symptoms and cognitive dysfunctions associated with Parkinson's disease.

The blockade of acetylcholine receptors by anticholinergic drugs improves some motor symptoms such as tremor, probably by counterbalancing the reduced dopaminergic influence on medium-sized

Cholinergic function in Parkinson's disease

Patients with Parkinson's disease usually develop abnormalities of the neural circuitries that underlie central cholinergic transmission. Both cortical and subcortical cholinergic systems are impaired and the neuronal loss correlates with the decline of cognitive functions.37 The basal forebrain cholinergic cell groups, including the nucleus basalis of Meynert, undergo degeneration in Parkinson's disease16 and the neurodegenerative process is also reported in the pedunculopontine tegmental

Striatal dopamine–acetylcholine interactions

In the striatum—the main input station of the basal ganglia—dopamine and acetylcholine strongly interact at several presynaptic and postsynaptic sites (figure 2) and the acquisition of motor and cognitive action sequences depends on the intrastriatal dopamine–acetylcholine balance.

Striatal cholinergic interneurons express both D1 and D2 dopamine receptors.52, 53 Dopamine seems to modulate striatal cholinergic tone via both excitatory and inhibitory actions. The activation of D1 receptors

Role of acetylcholine and dopamine in synaptic plasticity

The formation of memory traces in the brain may involve enduring changes in synaptic strength. Long-term potentiation and depression are described as a cellular model of learning and are crucial in several brain areas for the storage and retrieval of neural information. These two classic forms of synaptic plasticity have both been reported at corticostriatal synapses where they seem to underlie motor-skill learning and cognitive performances.65

Changes in both synaptic strength and intrinsic

Deficits in cognitive domains

The core feature of cognitive decline associated with Parkinson's disease is represented by impairment of executive functions. The frontostriatal circuit subserves processes underlying goal-directed behaviour, including motor and cognitive action plans.84 Striatal activity is crucial during the formation of habits and skills85 and to learn the contingencies between goal-directed responses and rewarding or punishing outcomes.86 The frontal cortex contributes to the coordination of thoughts and

Conclusions

There are many different models to explain the onset of cognitive impairment in Parkinson's disease. In patients, both the dopaminergic and cholinergic systems undergo degeneration. The classic parallel model suggests a direct correlation between a single neurochemical change and a distinct cognitive deficit and it is probably too simplistic (figure 4).

Because dopamine and acetylcholine interact at the anatomical (figure 1), biochemical (figure 2), and physiological (figure 3) level to induce

Search strategy and selection criteria

References for this Personal View were identified by searches of PubMed from 1966 until March 2006 with the terms “long-term potentiation”, “long-term depression”, “striatum”, “synaptic plasticity”, “dopamine and acetylcholine”, “Parkinson's disease and cognition”, “Parkinson's disease and dementia”. Among these references the most relevant for the discussed hypothesis were selected. Only papers published in English were reviewed.

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