The role of the dopaminergic system in the ageing brain 79 .1 Dopamine synthesis and pathways

As illustrated in Figure 3, dopamine is a postsynaptic excitatory neurotransmitter of the catecholamine family. As such it is derived from the amino acid tyrosine. This amine is catalysed into dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.

This requires tetrahydrobiopterin and oxygen. DOPA is then transformed into dopamine in the cytoplasm of presynaptic terminals by DOPA decarboxylase. They are then loaded into synaptic vesicles, via a vesicular monoamine transporter (VMAT). Once in the synaptic cleft, nerve terminals or surrounding glial cells reuptake dopamine through a Na+ dependant dopamine transporter (DAT). Dopamine is then catabolised by two enzymes: mitochondrial monoamine oxidase (MAO) and cytoplasmic catechol O-methyltransferase (COMPT).⁸⁰

The principle dopaminergic systems described in the human brain are the mesocortical pathway, the mesolimbic pathway, the nigrostriatal pathway and the tuberoinfundibular pathway (Figure 4). The mesocortical pathway links the ventral tegmental area (VTA) to the prefrontal cortex. The mesolimbic pathway joins the VTA to the nucleus accumbens and other neighbouring areas of the limbic forebrain.

The nigrostriatal pathway joins the pars compacta of the substantia nigra to the caudate and the putamen (striatum). The tuberoinfundibular pathway joins the arcuate and periventricular nuclei to the infundibular region within the hypothalamus.⁸¹

Figure 4: Principle dopaminergic pathways.

3.6.2 Dopamine receptors

Five dopaminergic types of receptors have been identified and have been named D1 -D5. These subtypes have distinct anatomical distribution in the brain and are related to distinct dopamine functions.⁸² However, given their structural homology, many authors group D1 and D5 as D1 and D2-D4 as D2 because they respond to the same ligands when using positron emission tomography (PET).⁷⁹ This can lead to some

errors of interpretation as those receptors have been shown to react differently to ageing. D3 is a G-coupled receptor with very low affinity to dopamine in the absence of its ligand. However, in the presence of the G-protein, its affinity for dopamine is 20 times higher than that of the D2 receptors.⁸³

In humans, D1 receptors are located not only in the striatum but throughout the neocortex. D2 receptors are found in high concentrations in the striatum, and in lower concentrations in brain stem, the thalamus and the neocortex.^{79, 84} D3 receptors are found in the nucleus accumbens, the dorsal striatum, the frontal cortex, the islands of Calleja and the cerebellum.⁸⁵ In the neocortex, dopaminergic synapses have a bilaminar distribution in the upper and deeper strata of the cortex. Dopamine axons form symmetric synapses on the spine of pyramidal cells.⁸⁶ A small proportion of D2

and D3 receptors are found on the presynaptic terminal and serve as a regulator of dopamine release. Other than that, all other receptors are found on postsynaptic neurons.⁸⁷

In humans, stimulation of D2 receptors using bromocriptine facilitates delayed spatial working memory whereas haloperidol, a D2 receptor antagonist and fenfluramine, a serotonin agonist, impaired working memory tasks.^88-90 It is however interesting to note that behavioural responses to D1 or D2 agonist and antagonists reveal inconsistencies, depending of the dose, drug affinity and pre-experimental cognitive skills.88, 91, 92 Dopamine D1 agonist⁹³ and D2 agonist⁹⁴ have been shown to either promote or inhibit firing in the same neural network, depending of initial dopamine levels and dosage. We can nevertheless summarise that in the prefrontal cortex, D1

receptor activity plays an important role in working memory; D1 and D2 receptors work in synergy to facilitate behavioural flexibility; and that D1, D2 and D4 medial prefrontal cortex receptors play a role in decision-making.⁹⁵

Output neurones from the nucleus accumbens have a high density of D3 receptors.

These dopamine neurones receive input from the ventral tegmentum area, the cerebral hippocampus and the amygdala, and constituting feed-forward loops towards the entorhinal and prefrontal cortices, the ventral palladium and mediodorsal thalamus and the ventral tegmentum area.^{96, 97} These loops are believed to modulate attention, memory and emotions.^{85, 98} However, blocking D3 receptors improves visual recognition and spatial memory, suggesting D3 receptors have an entirely different role than D2 receptors.^{98, 99}

3.6.3 Dopamine, cognition and ageing

In animal studies, the destruction of dopaminergic nerve terminals within the mesocorticolimbic system has been shown to engender impairment in spatial attention,¹⁰⁰ set shifting,¹⁰¹ control of goal-directed behaviour,¹⁰² object recognition memory,^{103, 104} spatial memory¹⁰⁵ and inhibitory functions (i.e. reduced modulation of impulsive behaviour,¹⁰⁶ increased latent inhibition¹⁰⁷, delayed extinction of fear conditioning^{108, 109}, hypoactivity¹¹⁰).

An important role that has been attributed to dopamine systems is to facilitate switching between targets within and between neural networks.^111-113 In other words, striatal dopamine neurones, could help select relevant signals by reducing the background noise relying on negative priming.¹¹⁴ This could explain why deficient

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dopaminergic modulation has been the most successful model of age-related cognitive deficits in neurocomputational science.¹¹⁵

With normal ageing, there is a progressive loss of neurons in the substantia nigra and subthalamic nucleus of about 4.7% per decade.^{116, 117} Similar rates (4%-8% per decade) have been observed for post-mortem decreases in concentrations of D1 and D2 receptors with ageing within the caudate nucleus and the putamen (Figure 5),

118-121 that was also observed in vivo (7%-10% decrease per decade).^122-126 Similar observations were made in the frontal cortex¹²⁷ and to a lesser degree in limbic regions especially in early phases of degenerative diseases.¹²⁸ Interestingly, decreased concentration of D1 and D2 receptors is associated to a decrease of DAT.¹²⁹ This loss with age is due to reduced DAT mRNA¹³⁰ suggesting neurones are selectively down-regulating the expression of DAT with ageing. As a result, initial increases in dopamine could lead to a functional down-regulation of these dopamine neurones.^131,

132 Therefore, reduced dopamine activity could reflect oxidative damage^{133, 134} or simply an age-related decrease in functional demand.^{135, 136}

Figure 5: Striatum dopamine receptor reduction with age. Modified from Rinne et al. (1990).¹²⁰ Samples of the caudate nucleus and the putamen from 65 human brains were collected before having D1 receptors bound to [³H]SCG22390 ligands and D2 receptors to [³H]SCG22390 ligands. The concentration of D1 and D2 receptors was then measured using a full Scatchard analysis.

Interestingly, striatum dopamine synthesis has been shown to be associated to activity in the opercular part of the inferior frontal gyrus – the region believed to be involved in selective response suppression.¹³⁷ Braskie et al¹³⁸ relied on positron emission tomography (PET) radiotracer 6-[¹⁸F]fluoro-L-m-tyrosine (FMT) to quantify

D1 receptors

D2 receptors

[3H]Spiroperidol binding[3H]SCH23390 binding

difference in aeromatic amino acid decarboxylase (AADC), a dopamine-synthesising enzyme in the striatum. They found a U-shape association with age and concluded that an increased FMT signal within the striatum was the indication of a compensation mechanism related to the dysfunctioning of the dopamine system within the striatum and functionally connected regions. This was confirmed in a second study coupling PET and functional magnetic resonance imaging (fMRI) in which they showed improved performance for those with higher functional connectivity between the caudate and the inferior frontal gyrus and reduced caudate FMT signal.¹³⁹ This striatal-increased capacity in dopamine synthesis with ageing is believed to reflect the difficulties in the system adequately compensating for other age-related changes in the dopamine system. In other words, the age-related loss of dopamine neurones and receptors enhance an up-regulation of dopamine synthesis in the striatum.¹³⁶

During the delay period of working memory tasks, prefrontal cortico-thalamic loops sustain the activity in the prefrontal neurones. This is achieved by activating the caudate nucleus that in turn disinhibits the thalamus, thereby causing reverberation.¹⁴⁰ The dopaminergic system plays an important role on corticostriatal synapses by filtering out less active inputs and regulating incoming signals from the thalamus to the cortex.^141-144 Therefore, the frontostriatal network and the striatal loss of dopamine neurones could play an important role in dedifferentiation observed with ageing.

Figure 6: Representative DAT distribution with age. Illustration from Erixon-Lindroth et al. (2005).¹⁴⁵ PET sections of summation of radioactivity 9-63 minutes following injection of [¹¹C]β-CIT-FE binding to DAT.

Recent research has found a striking consistency between dopamine markers and age-related cognitive changes.⁷⁹ Wang and al.¹²⁴ have shown a clear relationship between D1 receptor concentrations in the caudate (R²=0.27) and the putamen (R²=0.46) with psychomotor functioning (Purdue Pegboard Test) during normal ageing. In ageing humans, Volkow et al. ¹⁴⁶ showed D2 caudate and putamen concentrations of D2

receptors to be associated to the Wisconsin Card Sorting Test perseveration errors (R²=0.26; R²=0.34), the Stroop Colour-Word Test interference (R²=0.23; R²=0.23), the oral Symbol Digit Modalities Test (R²=0.28; R²=0.19), and the Finger Tapping

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Test (R²=0.44; R²=0.44). D1A-48G and D3Ser9Gly genotypes were also linked to decreased perseveration errors in the Wisconsin Card Sorting Tests.¹⁴⁷ Bäckman et al.¹⁴⁸ also showed striatal D2 to be associated to episodic memory - Word (R²=0.38) or Face (R²=0.48) Recognition, and perceptual speed–Dots Test (R²=0.61) and Trail Making A Test (R²=0.55). Interestingly, both these studies showed striatal D2

concentration to be a much better indicator of performance than age itself.

Furthermore, this phenomenon might not only be limited to the striatum, as cortical brain glucose metabolism, (a recognised marker of neural activity), was associated with the loss of D2 receptors in the frontal cortex, the anterior cingulate gyrus, the temporal cortex and the caudate.¹⁴⁹ Presynaptic DAT striatal concentration, also affected by ageing (Figure 6), is also related to word recall (R²=0.46), figure recall (R²=0.49), face recognition (R²=0.40), working memory (R²=0.49) and word fluency (R²=0.30).^{145, 150}

With age, adults are less influenced by incentive programs¹⁵¹ and become more prone to erroneous financial decision-making.¹⁵² This has been shown to be associated with the alteration of the dopamine system and its role in reinforcing reward mechanisms.¹⁵³ Chowddhury et al.¹⁵⁴ tested the role of dopamine in observed difficulties in a Two-Armed Bandit Task. The testing revealed that older adults show an unusual functional response to expected rewards in the nucleus accumbens, coupled with poorer performance in decision-making (Figure 7). Diffusion tensor imaging showed this to be linked to connectivity of the striatum to the substantia nigra and the ventral tegmental area. Providing dopamine precursor levodopa (L-DOPA) restored learning rate and task performance, suggesting these alterations were indeed closely linked to the dopamine system and were reversible.

Figure 7: Average observed gain in a Two-Armed Bandit Task. Illustration from Chowdhury et al.¹⁵⁴ : Tasks consisted of 220 trials in which participants were asked to choose one of two random fractal pictures, each picture been associated with a probability of winning

£0.10 following a different Gaussian random walk. Participants were randomised to receive either L-DOPA or a placebo before performing the task. * P<0.05. Error bars indicate ±1 SEM.

Age-related impaired dopaminergic functions¹¹⁷ are believed to induce reduced activational aspects of motivation,¹⁵⁵ reduce ability to signal changes or errors in the prediction of future salient and rewarding events,¹⁵⁶ reduced novelty-related exploratory behaviour,¹⁵⁷ and loss of action vigor.¹⁵³