Levodopa increases memory encoding and dopamine release in the striatum in the elderly

Abstract

Normal aging is associated with a decrease in dopaminergic function and a reduced ability to form new motor memories with training. This study examined the link between both phenomena. We hypothesized that levodopa would (a) ameliorate aging-dependent deficits in motor memory formation, and (b) increase dopamine availability at the dopamine type 2-like (D2) receptor during training in task-relevant brain structures. The effects of training plus levodopa (100 mg, plus 25 mg carbidopa) on motor memory formation and striatal dopamine availability were measured with [¹¹C]raclopride (RAC) positron emission tomography (PET). We found that levodopa did not alter RAC-binding potential at rest but it enhanced training effects on motor memory formation as well as dopamine release in the dorsal caudate nucleus. Motor memory formation during training correlated with the increase of dopamine release in the caudate nucleus. These results demonstrate that levodopa may ameliorate dopamine deficiencies in the elderly by replenishing dopaminergic presynaptic stores, actively engaged in phasic dopamine release during motor training.

Introduction

Normal aging is associated with decreased ability to form new memories (Hedden and Gabrieli, 2004, Jay, 2003, Kandel and Pittenger, 1999, Li and Sikstrom, 2002), most notably episodic encoding (Bailey et al., 2000, Hedden and Gabrieli, 2004, Kandel and Pittenger, 1999). A similar deficit is expressed in the motor domain, impairing the ability to encode the kinematic features of a previously practiced motor task in the primary motor cortex as a function of training (Floel et al., 2005a, Sawaki et al., 2003).

Dopamine is a major neurotransmitter that strengthens the specificity and duration of formed memories (Goldman et al., 1998, Jay, 2003, Kandel, 2001, Williams and Goldman-Rakic, 1995). Dopaminergic function, including dopaminergic receptors, transporters and overall dopaminergic metabolic activity, are reduced with normal aging (Deisseroth et al., 1995, Emborg et al., 1998, Fearnley and Lees, 1991, Jay, 2003, Li and Sikstrom, 2002, Luo and Roth, 2000, Roth et al., 1995, Volkow et al., 1998). Previous work showed that administration of the dopamine precursor levodopa could enhance training effects on motor memory formation in healthy elderly subjects (Floel et al., 2005a) and stroke patients (Floel et al., 2005b), and appears to enhance motor rehabilitation (Scheidtmann et al., 2001), as do noradrenergic agents (Martinsson et al., 2003). One relative advantage in using dopaminergic agents versus, for example, amphetamines is that they exhibit fewer side-effects and may be safer (Feeney et al., 2004, Walker-Batson et al., 2004).

The findings of enhanced memory encoding in the elderly after administration of levodopa (Floel et al., 2005a) raise the hypothesis of a mechanistic link between dopaminergic function and training-induced motor memory formation. We reasoned that if such a link exists, administration of levodopa – which increases the presynaptic availability of endogenous dopamine – prior to training would lead to parallel increments in dopaminergic neurotransmission in task-relevant brain structures (Mawlawi et al., 2001, Schlosser et al., 1998) and in motor memory formation (Butefisch et al., 2000, Classen et al., 1998). Molecular imaging using the competitive D2 receptor ligand raclopride (RAC-positron emission tomography, PET) allows direct assessment of the brain dopamine system (Cropley et al., 2006). Endogenous release of dopamine increases synaptic dopamine concentration, resulting in increased occupancy of D2 receptors, and consequently decreased availability of dopamine D2 receptors for binding the radiotracer raclopride (Laruelle, 2000).

In the present study, we evaluated the effects of training plus levodopa on motor memory formation and on dopamine availability in the striatum. We also assessed levodopa effects on resting RAC-PET in the absence of training.