Sensitivity to ageing of the limbic dopaminergic system: a review

Mechanisms of Ageing and Development 106 (1998) 57 – 92

Sensitivity to ageing of the limbic dopaminergic system: a review Paolo Barili a,b, Gionni De Carolis a, Damiano Zaccheo c, Francesco Amenta a,* a

Sezione di Anatomia Umana, Dipertimento di Scienze Farmacologiche e Medicina Sperimentale, Uni6ersita` di Camerino, 62032 Camerino, Italy b I.R.C.C.S. Ospedale di Riabilitazione Santa Lucia, 00178 Roma, Italy c Istituto di Anatomia Umana, Uni6ersita` di Geno6a, 16132 Genoa, Italy Received 18 March 1998; accepted 15 July 1998

Abstract The limbic system includes the complex of brain centres, nuclei and connections that provide the anatomical substrate for emotions. Although the presence of small amounts of dopamine (DA) in several limbic structures has been recognized for a long time, for many years it was thought that limbic DA represented a precursor of noradrenaline in the biosynthetic pathway of catecholamines. More recent evidence has shown that limbic centres and nuclei are supplied with a dopaminergic innervation arising from the ventral tegmental area (field A10) and in smaller amounts from the mesencephalic A9 field. The dopaminergic limbic system is sensitive to ageing. Parameters of dopaminergic neurotransmission (DA levels, biosynthetic and catabolic markers and DA receptors) undergo age-related changes which depend on the structure and species investigated and are characterized mainly by a decline of different parameters examined. In this paper, the influence of ageing on DA biosynthesis, levels, metabolism and receptors are reviewed in laboratory rodents, monkeys and humans as well as in cases of Alzheimer’s disease and Parkinson’s disease. The possibility that changes of dopaminergic neurotransmission markers in the limbic system are associated with cognitive impairment and psychotic symptoms affecting the elderly is discussed. Better knowledge of dopaminergic neurotransmission mechanisms in the so-called * Corresponding author. Present address: Dipartimento di Scienze Farmacologiche e Medicina Sperimentale; Via Scalzino 3, 62032 Camerino, Italy. Tel.: + 39 737 403311; fax: + 39 737 630618; e-mail: [email protected] 0047-6374/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0047-6374(98)00104-3

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physiological ageing and in senile dementia may provide new insights in the treatment of behavioural alterations frequently occurring in old age. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Limbic system; Dopamine; Innervation; Receptors; Ageing; Senile dementia

1. The limbic system The limbic system, known in the past as rinecephalon, includes several brain areas involved in affective and emotional behaviour, such as amygdala, prefrontal cortex, cingulate gyrus and hippocampus. These structures, which represent the neural substrate for emotions are located primarily in the medial portion of cerebral hemispheres (Fig. 1). Other telencephalic and diencephalic structures not included in the so-called rinecephalon, such as portions of basal ganglia, anterior thalamic nuclei, as well as some nuclei of epithalamus and hypothalamus, are also part of the limbic system. Some formations of olfactory pathways, such as septal nuclei and olfactory tubercle, are also included in the limbic system. The main brain centre

Fig. 1. Extension of limbic system areas (in black) in the lateral (a) and medial (b) aspect of rat (A), monkey (B) and human (C) forebrain. Table 1 Limbic brain areas Cortical areas

Telencephalic areas

Diencephalic areas

Prefrontal cortex Cingular cortex Amygdala Hippocampus Septal area Olfactory tubercle

Nucleus accumbens Islands of Calleja

Anterior thalamic nuclei Epithalamic nuclei Hypothalamic nuclei

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Fig. 2. Main centres and pathways of the limbic system according to the Papez hypothesis.

parts of the limbic system are indicated in Table 1. Since the proposal of James Papez in 1937, modern anatomical and functional studies have supported Papez’s idea and have demonstrated large and direct connections between the main limbic centres and several brain areas including the neocortex (Fig. 2). From a functional point of view, limbic areas are important for the regulation of emotional behaviour. In fact, the limbic system is a centre integrating rational and emotional activities which regulate behaviour and homeostasis.

2. Dopamine as a limbic neurotransmitter and dopaminergic innervation of limbic centres The catecholamine dopamine (DA) acts as a neurotransmitter in the limbic system. DA concentrations in the limbic system are low and for many years it was thought that limbic DA represented a precursor of noradrenaline in the biosynthetic pathway of catecholamines. Small but specific mesolimbic, mesolimbocortical and mesocortical dopaminergic projections supply limbic centres (Kohler et al., 1991). Fig. 3 shows the organization of the limbic dopaminergic system in the rat. Cell bodies of mesolimbic dopaminergic neurons (about 10000 nerve cells in the rat) are localized in the midbrain. The mesolimbic dopaminergic system originates primarily

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from the ventral segmental area (field A10). Fibres from this area mainly reach the nucleus accumbens, tuberculum olfactorium, dorsal portion of the nucleus interstitials striae terminalis, and the area of Islands of Calleja through the medial forebrain bundle (Fuxe et al., 1985). The mesolimbocortical dopaminergic innervation originates to a large extent from the ventral tegmental area (field A10) and, in a smaller percentage, from the substantia nigra (field A9). Dopaminergic fibres arising from fields A9 and A10 follow the medial forebrain bundle and end in the septal region, amygdala, prefrontal cortex and hippocampus (Lindvall and Bjo¨rklund, 1984; Fuxe et al., 1985). A few dopaminergic fibres also reach the anterior olfactory nuclei and olfactory bulb. In the hippocampus, dopaminergic fibres end in the hilum and in the CA1-subiculum region (Gasbarri et al., 1994; Goldsmith and Joyce, 1994). A sparse mesocortical neuron group innervates the prefrontal cortex (Bannon and Roth, 1983). Dopaminergic projections to the prefrontal cortex have higher firing and turnover rates, and are more susceptible to stress than those of other mesencephalic dopaminergic projections (Roth, 1984). Dopaminergic neurotransmission dysfunction is implicated in the pathophysiology of several psychiatric, neurological, and neuroendocrine disorders such as schizophrenia, Parkinson’s disease, and hyperprolactinemia.

Fig. 3. Schematic representation of dopaminergic centres and pathways in rat brain: A, olfactory bulb; B, cerebral cortex; C, cerebellum; D, thalamus; E, hippocampus; F, striatum; G, corpus callosum. A8, A9, A10, mesencephalic areas in which dopamine-containing nerve cell bodies are located: a, mesolimbocortical pathway; b, ending of dopaminergic projection in the nucleus accumbens; c, ending of dopaminergic projection in the pregenual portion of the prefrontal cortex; d, frontal cortex; e, ending of dopaminergic projection in the supragenual portion of the prefrontal cortex; f, ending of dopaminergic projection in the lateral septal nucleus; g, main dopaminergic projection supplying the dentate gyrus of the hippocampus; h, ending of dopaminergic projection in the lateral habenula; i, mesothalamic pathway. Calibration bar, 1 mm.

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3. Involvement of the limbic dopaminergic system in higher cognitive and affective functions Evidence suggests that DA is involved in motivational properties of psychostimulants such as amphetamine and cocaine. The first stimulates DA release, whereas the second inhibits its reuptake (Wise and Bozarth, 1987). Moreover, the limbic dopaminergic system is involved probably in the regulation of voluntary movements (Fibiger and Phillips, 1986; Salamone, 1992) and plays a role in memory reinforcement (Fibiger and Phillips, 1986; Wise, 1987; Wise and Bozarth, 1987; Di Chiara et al., 1992), motivation (Fibiger and Phillips, 1986; Di Chiara and Imperato, 1988; Shippenberg et al., 1991), non-specific activation (Streker and Zigmond, 1986) and goal-directed behaviour (Di Chiara et al., 1992). The hippocampus represents likely the key limbic area of activity of the dopaminergic system in learning and memory function and dopaminergic neurons may have a modulatory influence on the memory process (Taghzouti et al., 1986). Motivational functions of DA are localized in the nucleus accumbens/tuberculum olfactorium and ventro-medial portions of the caudate-putamen (the so-called limbic striatum). The mesolimbic dopaminergic system lies at the core of the brain reward mechanism involved in electrical self-stimulation, place conditioning, intracranial drug self-application, and natural reinforcement (Cooper, 1991; Wise, 1996). It probably provides the feedback basis allowing the generation of activity patterns which lead to satisfaction of appetitive needs, and plays an important role in addictive behaviour. Amygdala probably also has a role in cognitive functions involving sensory-affective integration and associative learning (Fremeau et al., 1991). Electrical stimulation of the ventral tegmental area leads to a marked inhibition of spontaneous activity of efferent neurons of the prefrontal cortex. This inhibition is mainly due to the activation of the mesolimbocortical DA system (Ferron et al., 1984; Godbout et al., 1991).The mesolimbocortical dopaminergic system also modulates excitatory synaptic transmission in the prefrontal cortex (Ferron et al., 1984; Law-Tho et al., 1994). An interaction between the mesolimbocortical dopaminergic and the hippocampus–prefrontal cortex systems was also suggested. In addition, prelimbic and medial orbital areas project to the nucleus accumbens which also receives a direct input from the hippocampus (Berendse et al., 1992). The mesolimbocortical dopaminergic system exerts an inhibitory influence on excitatory responses of prefrontal neurons induced by stimulation of hippocampus. This suggests that through the prefrontal cortex, the hippocampus controls indirectly the activity of neurons of the nucleus accumbens and ventral tegmental area (Jay et al., 1995). This observation supports the idea of the existence of hippocampus – prefrontal cortex – nucleus accumbens and hippocampus–prefrontal cortex– ventral tegmental area circuits and suggests that the hippocampus may control indirectly the dopaminergic neurons of the ventral tegmental area through the prefrontal cortex (Jay et al., 1995). Dysfunction of the mesolimbic dopaminergic system is probably involved in the pathophysiology of affective disorders such as schizophrenia (Willner et al., 1989; Joyce, 1993). Support for this hypothesis comes from the observation of strong

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antipsychotic effects of DA receptor antagonists (Seeman et al., 1976). The prefrontal cortex is the brain area more closely involved in the pathophysiology of schizophrenia. This cerebral area is also implicated in the control of working memory (Sawaguchi and Goldman-Rakic, 1991; Williams and Goldman-Rakic, 1995). Both the prefrontal cortex and hippocampus play a role in working memory (Mahut et al., 1982; Watanabe and Niki, 1985; Zola-Morgan and Squire, 1986; Friedman and Goldman-Rakic, 1988; Fuster, 1991), and working memory dysfunction in both regions is a prominent feature of schizophrenia (Weinberger, 1987; Berman and Weinberger, 1990) and Parkinson’s disease (Bradley et al., 1989). Impairment of dopaminergic innervation of the prefrontal cortex is thought to underlie some cognitive and affective symptoms associated with schizophrenia (Davis et al., 1991; Goldstein and Deutch, 1992). Physiological studies have indicated that hippocampal neurons exert a monosynaptic excitatory influence on pyramidal neurons of the prefrontal cortex (Ferino et al., 1987; Laroche et al., 1990). From an anatomical point of view, the dopaminergic innervation is particularly dense in deep layers of the prefrontal cortex (Berger et al., 1974).

4. Cognitive and affective changes of the elderly probably linked to dopaminergic dysfunction Dopaminergic regulation of cortical processes is finely tuned. This may help to explain the vulnerability of the dopaminergic system in conditions of stress (Goldstein et al., 1994), ageing (Arnsten et al., 1994, 1995), drug abuse (Bauer and Fuster, 1978) and disease (Daniel et al., 1991). The so-called physiological ageing is associated with a decline in cognitive abilities, especially of memory (McEntee and Crook, 1990). Studies in animals and in patient’s with Parkinson’s disease suggest that dopaminergic projections to the cerebral cortex may also be implicated in cognitive function (Le Moal et al., 1976; Javoy-Agid and Agid, 1980; Simon et al., 1980; Scatton et al., 1983). An age-related loss of dopaminergic neurotransmission was reported in human frontal cortex (de Keyser et al., 1990). Schizophrenia is a prime example of a disorder characterized by imbalances of mesocortical dopaminergic neurotransmission (Seeman, 1987; Davis et al., 1991). The same is true for Parkinson’s disease, Tourette’s syndrome and addictive behaviour, which are typical neurological and affective disorders characterized by dopaminergic impairment (Sen and Lee, 1988a,b). The prefrontal cortex is an area frequently considered to be altered in old age (Fuster, 1989) and schizophrenia (Buchsbaum et al., 1982; Farkas et al., 1984; Wolkin et al., 1985; Weinberger et al., 1988). Patients suffering from schizophrenia, Tourette’s syndrome, Parkinson’s disease and other attention-deficit/hyperactivity disorders exhibit symptoms ascribable to prefrontal cortex dysfunction (Gotham et al., 1988; Gedye, 1991; Shue and Douglas, 1992). The sensitivity of the prefrontal cortex to stress may underlie part of the consequences of stress-induced precipitation or exacerbation of psychosis (Bebbington et al., 1993; Deutch, 1993).

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Cognitive changes of Parkinson’s disease, as well as the hallmark motor impairments, were linked to DA-depleted circuits (Gotham et al., 1988; Owen et al., 1992; Stam et al., 1993). In L-DOPA-treated Parkinsonians, apomorphine can induce cognitive deficits (Ruzicka et al., 1994). These observations are consistent with the idea that excessive DA receptor stimulation can be detrimental to cognitive function (Murphy et al., 1996). DA transporter binding, which is a marker of DA-containing axons and nerve terminals (Zelnik et al., 1986; Tedroff et al., 1988), was used to measure age- and disease-related changes of dopaminergic innervation (Hitri et al., 1995). In schizophrenics, ageing is probably superimposed to the basic disease. This may induce changes in the pattern of dopaminergic innervation of the prefrontal cortex different from those occurring in subjects without coexisting psychiatric problems. In other neurodegenerative diseases associated with DA deficiency (i.e. progressive supranuclear palsy), it has been suggested that the rate of DA turnover may determine the severity of dopaminergic neuronal degeneration (Kish et al., 1992). In fact, neurons with higher metabolic rates could be subjected potentially to greater oxidative stress caused by radicals generated by DA oxidation. As a consequence of this phenomenon, progressive loss of dopaminergic neurons triggers an increased DA turnover in the remaining neurons. Hence, in schizophrenics, a higher vulnerability to ageing of dopaminergic neurons projecting to the prefrontal cortex consequent to the generation of higher levels of DA-derived oxygen radicals could occur (Spina and Choen, 1989; Kish et al., 1992). Cognitive functions are differentially influenced with advancing age. Prefrontal cortex cognitive deficits are evident early in the ageing process, and become marked in monkeys of advanced age (Bartus et al., 1978; Bartus, 1979; Walker et al., 1988; Rapp and Amaral, 1989; Bachevalier et al., 1991), while recognition memory (Rapp and Amaral, 1989) and motor skill learning (Bachevalier et al., 1991) are less affected by senescence The observed parallelism in the above neurochemical and behavioural changes suggests that DA loss may contribute to prefrontal cortex age-related cognitive decline, particularly as DA seems to be a key neurotransmitter for normal prefrontal cortex function (Brozoski et al., 1979).

5. Age-related changes of dopaminergic neurotransmission markers

5.1. Dopamine and dopamine metabolite le6els DA biosynthetic and catabolic pathways are shown in Figs. 4 and 5, respectively. DA is easily autoxidized (Graham, 1984) and excess autoxidation of may lead to accumulation of cytotoxic compounds (Hallywell, 1992). Several studies have suggested that DA autoxidation, which markedly increases with age, may play a role in the degeneration of dopaminergic neurons (Carlsson and Winblad, 1976; Fornstedt, 1990; Ben-Shachar et al., 1995). According to this hypothesis, ageing may be, at least in part, associated with anomalous dopaminergic transmission. Monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), are involved in the initial steps of DA catabolism (Fig. 5). These enzymes show

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Fig. 4. Catecholamine biosynthetic pathways.

different subcellular localization and metabolic functions (Ishikawa et al., 1982). MAO is a mitochondrial enzyme, located primarily in terminals of monoaminergic neurons. It exists in two major forms, MAO-A and MAO-B, distinguished on the basis of substrate specificity. COMT is located extraneuronally. It is hypothesized that 3-methoxytyramine (3-MT) is the metabolite of DA released from presynaptic membranes. It is immediately converted to 3-methoxy-4-hydroxy-phenylacetic acid (homovanillic acid, HVA). A part of DA is taken up (reuptake) into nerve terminals and is metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC) (Nagatsu, 1978).

5.1.1. Animal studies The majority of investigations on the influence of ageing on aminergic systems have reported the occurrence of changes of DA levels and metabolism as a function of age. Table 2 summarizes the main studies on the topic. Striatal DA, DOPAC and HVA levels were significantly decreased in aged rats, as well as tyrosine hydroxylase activity (McGeer, 1981; Toide, 1989). These data suggest a functional decline of dopaminergic neurotransmission with ageing. The simultaneous determination of the steady-state level of DA and of the intra- and extraneuronal metabolism of the transmitter indicates that changes of dopaminergic system with ageing are not uniform throughout different brain areas (Godefroy et al., 1989). The DA content

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of the anterior half of the cerebral cortex in old rats is increased, as compared to young animals (Harik and McCracken, 1986; Godefroy et al., 1989). In primates, a decrease of cortical levels of DA was found (Goldman-Rakic and Brown, 1981). MAO-B activity, which is the predominant form involved in intraneuronal degradation of DA (Stenstro¨m et al., 1987), is either decreased or unchanged in aged rats, depending on the structures examined (Strolin-Benedetti and Keane, 1980). A relationship between changes in MAO activity and variations of DA levels is unlikely as no significant modifications of DOPAC levels were observed in different brain areas (Godefroy et al., 1991). 3-MT concentrations are increased in the rat anterior cerebral cortex, suggesting an augmented release of DA (Godefroy et al., 1989). 3-MT is an index of the extraneuronal DA degradation by COMT and 3-MT levels are associated with enhanced DA release (Wood et al., 1987a,b).

Fig. 5. Dopamine catabolic pathways. COMT, catechol-O-methyl transferase; MAO, monoamine oxidase.

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Table 2 Age-related changes of dopamine and metabolite levels in the limbic system in animal studies Author

Species and strain

Age (months)

Parameter

Area

Results

Godefroy et al., 1989

Sprague-Dawley rats

Young (2.5) Old (27)

DA

  ¡   = ¡ = = ¡ ¡ ¡

Gallagher et al., 1990

Long–Evans rats

Young (7–8)

DA

Cerebral cortex Hippocampus Anterior cortex Hippocampus Hippocampus Hippocampus Cerebral cortex Prelimbic cortex Pyriform cortex Temporal cortex Prelimbic cortex Pyriform cortex Temporal cortex Cingulate cortex Hippocampus Hippocampus Hippocampus Hippocampus Nucleus accumbens Nucleus accumbens Nucleus accumbens VTA Frontal cortex Hippocampus VTA frontal Frontal cortex VTA Frontal cortex Basal forebrain

Luine et al., 1990

Fisher-344 rats

Old (28–29) Young (3)

DOPAC DA

Basal forebrain Frontal cortex

¡ ¡

Entorhinal cortex Hippocampus

¡

3-MT

Godefroy et al., 1991

Sprague-Dawley rats

Young (3) Adult (10) Old (27)

HVA DOPAC DOPAC HVA

3-MT

Santiago et al., 1988

Wistar Rats

3, 6, 12, 24, 30

Huang et al., 1995

Long Evans rats

Young (5)

DA 3-MT HVA DOPAC DA

Old (24)

DOPAC HVA

Goudsmit et al., 1990

Brown-Norway rats

5, 20, 32

DA

DOPAC HVA

Old (24–25)

DOPAC

        = = ¡ (slightly) = ¡ ¡ ¡ (not significant) = = = ¡ ¡ ¡ ¡ ¡

¡ (not significant) Frontal cortex ¡ Entorhinal cortex ¡

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Table 2 (continued) Author

Species and strain

Age (months)

Wenk et al., 1989

Rhesus monkeys

18 years 30+years

Parameter

Area

Results

HVA DA

Frontal cortex ¡ Prefrontal cortex ¡

 , increase; ¡, decrease; = , unchanged; VTA, ventral segmental area.

Despite the weak dopaminergic innervation, DA turnover is higher in the hippocampus than in other brain areas (Godefroy et al., 1989). DA and HVA content are significantly reduced in the hippocampus of old rats (Godefroy et al., 1989), whereas levels of the two catabolites DOPAC and 3-MT were unchanged (Godefroy et al., 1989). Other authors have reported that DA, DOPAC and 3-MT were not markedly changed, whereas HVA levels decreased slightly in the hippocampus of old rats (Santiago et al., 1988). DA concentrations were found to be four to ten times higher in the dorsal part of the hippocampus than in other portions of it (Ishikawa et al., 1982). Reduced HVA levels were observed in prelimbic, pyriform and temporal cortices of aged rats. Significant increases in 3-MT levels were observed in the cingulate gyrus and prelimbic, prefrontal, and temporal cortex (Godefroy et al., 1991). In the nucleus accumbens, a forebrain component of the mesolimbic system, a decrease of extracellular DA and DOPAC and no significant changes of extracellular HVA were reported in old rats (Huang et al., 1995). In Brown – Norway rats, age did not affect DA levels in the ventral tegmental area, but marked reductions (30–70%) were observed in DOPAC, HVA and DOPAC/DA and HVA/DA ratios between 20 and 32 months of age (Goudsmit et al., 1990). Similar to results reported for the ventral tegmental area, no significant changes of DA levels were observed in the frontal cortex. In this cerebrocortical area, concentrations of DOPAC and HVA were significantly lower at 20 months of age in comparison with younger cohorts (Goudsmit et al., 1990). A reduction of DOPAC and HVA levels in the frontal cortex of rats aged 20 months, as well as unchanged DOPAC/DA and HVA/DA ratios, suggest a loss of dopaminergic input, or, alternatively, a decrease in DA synthesis in this area from middle age to early senescence. The reduction in HVA/DA ratio at 32 months of age suggests an impaired activity of dopaminergic terminals in the frontal cortex of aged rats (Goudsmit et al., 1990). The above observations collectively suggest a moderate decrease in DA synthesis and/or a depletion of dopaminergic terminals in the frontal cortex at middle age, and a marked impairment of this system in old age (Goudsmit et al., 1990). In rats with an age-related decline in ‘spatial learning’ ability, DA and DOPAC levels were significantly decreased in the basal forebrain (Gallagher and Burwell, 1989; Gallagher et al., 1990). Alterations of 20–60% in monoamine and metabolite

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levels, probably related with impaired spatial memory performance, were found in the frontal and enthorinal cortices and hippocampus of aged rats (Luine et al., 1990). This allows one to hypothesize that age-dependent impairment of dopaminergic neurotransmission may contribute to senescent memory decline. DA uptake into presynaptic elements is thought to be a major mechanism of inactivation of DA released by synaptic terminals. DA uptake sites, which are predominantly located on dopaminergic terminals, represent not only the major mechanism of inactivation of the neurotransmitter at the synapse, but are also good markers of dopaminergic nerve terminal function (Araki et al., 1997). A significant decline of [3H]mazindol binding sites, used as a marker of DA uptake sites (Javitch et al., 1985), was found in rat frontal cortex and hippocampus from an early stage of ageing (Araki et al., 1997). In aged primates, deficits of cognitive tasks involving prefrontal cortex functions were found (Bartus et al., 1979). DA concentrations in the prefrontal cortex are among the highest of the cerebral cortex (Brown et al., 1979). Both DA-containing fibres and DA receptors are present in the primate prefrontal cortex Berger et al., 1988; Lidow et al., 1989; Goldman-Rakic et al., 1990). In aged monkeys, a remarkable loss of catecholamines (particularly DA), as well as of the catecholamine precursor L-DOPA, were found in the prefrontal cortex (Goldman-Rakic and Brown, 1981; Wenk et al., 1989). DA decrease becomes more pronounced with advancing age and DA levels are almost undetectable in very aged monkeys (Wenk et al., 1989). Studies on aged monkeys strongly suggest that the loss of dopaminergic function in the prefrontal cortex contributes to age-related cognitive decline (Arnsten et al., 1995). In fact, aged monkeys display delayed response to items exploring spatial working memory (Bartus et al., 1978; Walker et al., 1988; Rapp and Amaral, 1989; Bachevalier et al., 1991), which critically depend on the integrity of prefrontal cortex portions around the principal sulcus (Goldman and Rosvold, 1970). Tests of recognition and associative memory, which do not rely on this area of prefrontal cortex, are less affected (Bartus et al., 1979; Rapp and Amaral, 1989).

5.1.2. Human ‘physiological ageing’ Similar to reports from studies performed on small laboratory mammals and primates, the human central monoaminergic system is sensitive to ageing. Concentrations of several monoamine transmitters and metabolites decline in various brain areas during human ageing (Carlsson et al., 1980). In the central nervous system, the best example of an impaired dopaminergic system is given by Parkinson’s disease. Changes of the central dopaminergic system in diseases considered as forms of pathological ageing (Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders) will be detailed. Here, we will outline the main changes involving the dopaminergic system in subjects experiencing a nonspecific impairment of their higher cognitive function.

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In ageing, reduction of dopaminergic nerve cell bodies in the substantia nigra, a decrease of DA and HVA levels in extrapyramidal nuclei, frontal, temporal and limbic cortices were reported (Joseph and Roth, 1983; Roth and Joseph, 1988; Morgan and Finch, 1988). Experimental studies and observations in Parkinsonians have suggested that dopaminergic projections to the cerebral neocortex may have a role in cognitive function (Javoy-Agid and Agid, 1980; Simon et al., 1980; Scatton et al., 1983). However, DA content in human neocortical regions does not change significantly with age (Adolfsson et al., 1979; de Keyser et al., 1990). An age-related reduction of DA transporter binding was found in the prefrontal cortex of normal individuals and schizophrenics (Hitri et al., 1995). This suggests that dopaminergic supply to the prefrontal cortex is impaired in ageing and in schizophrenia. Evaluation of DA catabolism in the human brain has shown that MAO-B is the predominant MAO isoform involved in DA degradation (Stenstro¨m et al., 1987) and the activity of this enzyme is increased with age (Gottfries et al., 1983). This may exacerbate the impairment of dopaminergic neurotransmission caused by loss of DA-containing neurons. Conversely to MAO-B, MAO-A does not show age-related changes (Adolfsson et al., 1980; Fowler et al., 1980; Gottfries et al., 1983).

5.1.3. Alzheimer’s disease and related disorders Alzheimer’s disease (AD) and senile dementia of the Alzheimer type (SDAT) represent the most common forms of dementia affecting the elderly (Tomlinson and Corsellis, 1984). AD and SDAT are manifested behaviourally by deficits of memory and cognition, accompanied by personality and behavioural changes (Coleman et al., 1990). Typical symptoms of these diseases are diffuse deterioration of mental function, primarily in thought and memory, and secondarily in feeling and conduct (Stern et al., 1986). From a neuropathological point of view, these forms of dementia are characterized by gross atrophy of the cerebral cortex, the presence of neurofibrillary tangles, abundant neuritic plaques, and argyrophilic inclusion bodies (De Jong and Pope, 1975; Rossor, 1982), as well as remarkable loss of neurons in specific brain regions including the basal forebrain, hippocampus and neocortex. In AD and SDAT, deficits in some transmitter systems, excessive accumulation of senile plaques, vascular amyloid deposits, granovacuolar degeneration and alterations in cytoskeletal proteins were also reported (Coleman et al., 1990). The hippocampal complex, which includes the dentate gyrus and different subfields of Ammon’s horn, subiculum, enthorinal cortex, and perirhinal cortex, is the brain region most heavily affected in AD (Arnold et al., 1991; Arriagada et al., 1992). Significant reductions of DA levels were observed in certain brain regions of AD patients (Adolfsson et al., 1979; Allard et al., 1990; Reinikainen et al., 1990; Nazarali and Reynolds, 1992). Some studies have shown DA levels and metabolism are affected in different limbic areas of AD patients. Table 3 summarizes the main findings on levels of DA precursors, DA and catabolites in limbic structures. Data from different laboratories indicate a reduction of the majority of dopaminergic neurotransmission markers investigated in the amygdala (Arai et al., 1984; Storga et al., 1996), decreased DOPAC and increased tyrosine levels in the cingulate gyrus (Storga et al., 1996), unchanged or decreased DA concentrations and unchanged

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Table 3 Age-related changes of dopamine and metabolite levels in limbic areas in Alzheimer’s disease Author

Subject number and age

Parameter

Area

Results

Storga et al., 1996

n=8 46–79 years

DA

Amygdala Cingulate gyrus Amygdala Cingulate gyrus Amygdala Gyrus cinguli Amygdala Amygdala

¡ ¡ ¡ ¡     ¡ ¡

Frontal cortex Temporal cortex Frontal cortex Frontal cortex Temporal cortex Hippocampus Temporal cortex Hippocampus Hippocampus Hippocampus

= = =   ¡ ¡ = =    

DOPAC Tyr

Arai et al., 1984 Palmer et al., 1987

Reinikainen et al., 1988

n= 4 62–73 years n= 46 51–95 years

n= 20 69–92 years

L-DOPA HVA DA DOPAC HVA DA HVA HVA/DA ratio MAO-B

 , increase; ¡, decrease; = , unchanged.

DOPAC levels in the frontal cortex (Palmer et al., 1987; Reinikainen et al., 1988), and either unchanged or decreased DA and unchanged HVA in the temporal cortex (Palmer et al., 1987; Reinikainen et al., 1988, 1990). In the hippocampus, DA decreased, HVA levels increased and the HVA/DA ratio augmented in AD (Reinikainen et al., 1988, 1990). These data provided the basis for the hypothesis that mesolimbic dopaminergic systems, which supply hippocampus and adjacent cortical areas, might play a role in dementia (Joyce et al., 1993). Moreover, strong evidence indicates the occurrence of dopaminergic dysfunction in the extrapyramidal system of AD subjects, with low levels of HVA in the caudate nucleus (Gottfries et al., 1983; Nazarali and Reynolds, 1992). A rather significant number of AD patients exhibit Parkinsonian symptoms (Pearce, 1974) and between 11 to 53% of Parkinsonians are demented (Gottfries et al., 1980). A negative correlation exists between HVA concentration in the caudate nucleus and intellectual impairment. This raises important questions about the possible role of basal ganglia in higher cognitive activities. Concentrations of DA were found unaltered in the cerebral cortex of AD patients (Gottfries et al., 1983; Iversen et al., 1984; Palmer et al., 1987), as well as levels of the minor DA metabolite DOPAC (Palmer et al., 1987). Concentrations of the major DA metabolite HVA were unaltered in some areas (Gottfries et al., 1983; Palmer et al., 1987) but elevated in others (Gottfries et al., 1983; Palmer et al., 1987). Reduced HVA levels were also reported in cerebrospinal fluid of AD patients (Gottfries, 1979).

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Brain MAO-B activity is elevated in AD to a greater extent than in physiological ageing (Gottfries et al., 1983). This increase may contribute, along with reduced DA turnover, to the decrease of HVA concentrations in the neostriatum (Adolfsson et al., 1979; Gottfries et al., 1983; Yates et al., 1983; Pearce et al., 1984). MAO-B activity is also elevated in circulating platelets of AD patients. This elevation is more conspicuous than that found in non-demented aged subjects, in which enzyme activity is elevated above that of young and adult individuals (Adolfsson et al., 1980; Alexopoulos et al., 1984). Platelet MAO-B activity was correlated with psychiatric symptoms including agitation, delusion (Schneider et al., 1988) and depression (Alexopoulos et al., 1984), within groups of patients with AD. In spite of the widely accepted opinion that impairment of basal forebrain cholinergic systems is the most likely cause of the cognitive dysfunction in AD, the data reviewed suggest that the dopaminergic system is also widely affected in AD. Further work is necessary to evaluate the functional significance of DA loss reported in several limbic structures in AD and how this dysfunction could be relevant for the pathogenesis of learning or behavioural changes occurring in AD and SDAT.

5.1.4. Parkinson’s disease Parkinson’s disease is a progressive neurodegenerative disorder characterized by the deposition of Lewy bodies and Lewy neurites in brain tissue, degeneration of neuromelanin-rich DA-containing cells of the substantia nigra and cellular depletion in major nuclei (right and left nuclei paranigralis and nucleus interfascicularis) of the ventral tegmental area (Dymecki et al., 1996). This results in a significant decrease of forebrain DA levels and in the loss of dopaminergic projections to the forebrain (Hagan et al., 1997). Tremor, rigidity, slowed movements (bradykinesia) and delayed movement initiation are common presenting symptoms, although tiny handwriting (micrographia) can also be an early manifestation. Impaired gait, postural instability and the full range of symptoms have been described elsewhere (Hoehn and Yahr, 1967). Cognitive disturbances, particularly bradyphrenia (slowness of thought) and dysfunction in frontal lobe tasks, are a common feature with some evidence for long-standing pre-morbid behavioural traits. Parkinson’s disease can affect cognitive function, causing circumscribed intellectual deficits (El Awar et al., 1987; Fisher et al., 1990; Stern et al., 1993) and even frank dementia (Martilla and Rinne, 1976; Pirizzolo et al., 1982; Taylor et al., 1985; Stern and Mayeux, 1986). Cognitive function impairment was observed in approximately 22% of patients with idiopathic Parkinson’s disease (Bayles et al., 1996). Non-demented Parkinsonians exhibit cognitive abnormalities (Brown and Marsden, 1987). A reduction in declarative memory performance was reported as well (Heindl et al., 1989; Dubois et al., 1990; Raoul et al., 1992). Deficits in working memory occur in Parkinson’s disease and schizophrenia (Bradley et al., 1989; Park and Holzman, 1992). These symptoms are probably related to the reduced dopaminergic function of the prefrontal cortex. The observation that DA depletion in primate prefrontal cortex impairs working memory supports this hypothesis (Brozoski et al., 1979).

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In Parkinson’s disease, brain DA levels are reduced (Javoy-Agid and Agid, 1980; Scatton et al., 1983). Using tyrosine hydroxylase immunoreactivity as a marker of the brain dopaminergic system, loss of dopaminergic neurons in the ventral tegmental area and a remarkable reduction of tyrosine hydroxylase-immunoreactive fibres in dopaminergic terminal fields (primarily the perforant pathway of the hippocampus) were found in Parkinsonians (Torack and Morris, 1992). The reduction of the dopaminergic innervation of the perforant pathway in Parkinson’s disease is associated with the occurrence of neurofibrillary tangles in this structure (Torack and Morris, 1992). Both Parkinson’s disease and progressive supranuclear palsy are characterized by a marked loss of DA transporter sites in the neostriatum (about 75%) and in the nucleus accumbens (about 65%) (Chinaglia et al., 1992).

5.2. Dopamine receptors Biological actions of DA are mediated through the interaction with specific receptor sites (Fig. 6A). These receptors mediate actions of DA, including movement control, generation of emotion, and neuroendocrine modulation. Brain and peripheral DA receptors were divided into DA D1-like and D2-like receptor superfamilies on the basis of their interaction with cellular effector systems (Sibley and Monsma, 1992; Gingrich and Caron, 1993; Strange, 1993). DA D1-like receptors are coupled positively with adenylate cyclase (Kebabian and Calne, 1979; Sibley and Monsma, 1992; Gingrich and Caron, 1993) (Fig. 6B). DA D2-like receptors are coupled negatively or uncoupled with adenylate cyclase (Fig. 6C) (Kebabian and Calne, 1979; Sibley and Monsma, 1992; Gingrich and Caron, 1993). The application of molecular biology to DA receptor research has shown that the picture of DA receptors is more complicated than that it was considered until a few years ago and DA receptors consist of at least five subtypes (Sibley and Monsma, 1992; Gingrich and Caron, 1993). The DA D1-like receptor super family includes two receptor subtypes, the D1 and D5 sites (named D1A and D1B in the rat) (Fig. 6B). DA D2-like receptors include two isoforms of the D2 receptors (D2S and D2L), as well as a DA D3 and D4 receptor (Sibley and Monsma, 1992; Gingrich and Caron, 1993) (Fig. 6C).

5.2.1. Animal studies Uneven changes occur throughout the brain of aged rats in receptor binding for various neurotransmitters compared with younger cohorts (Nabeshima et al., 1994). Changes in neurotransmitter receptor binding may be responsible of the decline of brain function in aged rats (Nabeshima et al., 1994). The central dopaminergic system is particularly sensitive to ageing (for a review, see Amenta et al., 1991). In spite of the large amount of information available on age-dependent changes of the dopaminergic nigro-striatal system, less data are available on the influence of ageing on the dopaminergic system of other brain areas. The density and distribution of DA receptors in the limbic system were analyzed using different methodological approaches including radioligand binding assay and autoradiography, immunohistochemical and molecular biology techniques.

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A high concentration of immunoreactive D1 receptors occurs in the limbic system (cingulate, piriform, and entorhinal cortices; septal nucleus; hippocampus; amygdala; mammilliary complex; medial dorsal nucleus) and in the fibre bundles connecting these areas (cingulum, fornix, stria terminalis). This observation sug-

Fig. 6. (A) Synaptic ending of a dopaminergic neuron with a schematic representation of synaptic vesicles containing dopamine (DA), mitochondrial localization of monoamine oxidase (MAO) and presynaptic and postsynaptic receptors. (B) Nomenclature of dopamine D1-like receptor subtypes and a schematic representation of the sequence of rat D1A receptor. (C) Nomenclature of dopamine D2-like receptor subtypes and a schematic representation of sequence of human D2L and rat D3 receptors.

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gests that this receptor may be important in mediating functions associated with memory, learning, and cognitive processing (Huang et al., 1992). Despite the low to moderate levels of D1 receptor binding reported by earlier investigations (Cortes et al., 1989b), a recent study has shown that limbic forebrain neurons exhibit high levels of D1-like receptor mRNA (Fremeau et al., 1991). The DAD1 receptor may have also a significant role in mediating dopaminergic neurotransmission in the amygdaloid complex (Fremeau et al., 1991). Immunohistochemical studies examining regional and cellular distributions of the DA D1B receptor subtype using an anti-receptor antiserum (Ariano et al., 1997) have confirmed the presence of receptor immunoreactivity in limbic areas including the frontal cortex, hippocampus and dentate gyrus. Lesser amounts of receptor protein were seen in the olfactory tubercle (Ariano et al., 1997). Hippocampus expresses both D1-like (Gingrich et al., 1992; Huang et al., 1992) and D2-like (Brouwer et al., 1992; Mengod et al., 1992; Yokoyama et al., 1994) receptors. DA D1-like receptors, which represent the receptor family most largely represented in the hippocampus, are primarily of the D5 (D1B in the rat) subtype (Dawson et al., 1986; Meador-Woodruff et al., 1992; Niznik and Van Tol, 1992; Laurier et al., 1994; Sokoloff and Schwartz, 1995). In the rat, the highest density of D1-like receptors was observed in the molecular layer of the dentate gyrus, followed by the pyramidal cell layer of CA1 and CA3 subfields (Hersi et al., 1996). Most of these receptors are postsynaptic and located on dendritic spines (Huang et al., 1992; Smiley et al., 1994; Bergson et al., 1995). There is a laminar distribution of [3H]SCH 23390 binding sites. The receptor density of the molecular layer of the dentate gyrus is approximately five times higher than of other areas of hippocampal formation (Dawson et al., 1986). Memory deficits induced by the muscarinic receptor antagonist are attenuated by DA receptor antagonists acting at the D1 receptor (McGurk et al., 1988; Levin et al., 1990). Cognitive impairments resulting from a nicotinic receptor blockade are exacerbated by the D2 receptor antagonist (McGurk et al., 1988, 1989). Studies using DA-sensitive adenylate cyclase as a marker of DA receptors reported in rat hippocampus, a decrease of D1 receptors between youth and maturity. D2 receptors, which are impaired in the striatum, were unchanged in the hippocampus as a function of age (Amenta et al., 1990a). Other authors, using radioligand binding techniques, did not observe significant differences in rat hippocampal D1-like binding levels between young and aged cohorts (Hersi et al., 1995). Nevertheless, the maintenance of normal receptor densities does not necessarily mean that these receptors are functionally intact. For instance, the efficiency of receptor transduction mechanism could be altered with age, and in various diseases (Nalepa et al., 1989; Flynn et al., 1991; Tandon et al., 1991; Parent et al., 1995). Molecular biology studies performed in Sprague–Dawley and Wistar rats have found an age-related reduction in the steady-state levels of messenger RNA for D2 receptor in different brain areas (Della Vedova et al., 1992). A recent radioligand binding study extended to several brain areas including the hippocampus, did not find changes of DA D1-like receptors in any brain area in aged rats (Araki et al., 1997). The same investigations did not report changes of limbic DA

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D2-like receptors labelled with [3H]spiperone, except for a transient increase of binding in the nucleus accumbens and in the CA1 subfield of the hippocampus of adult-mature rats (Araki et al., 1997). The discrepancy of these findings is due probably to methodological problems and to the assessment of rather different parameters by various laboratories. In view of the probable role of the hippocampal dopaminergic system in higher cognitive functions, a reinvestigation of the topic through an interdisciplinary approach would be desirable. Dense DA D1-like receptor sites were found in the nucleus accumbens and in the olfactory tubercle of young adult rats (Morelli et al., 1990). A marked decrease of these receptors was found in 11- and 24-month-old rats in comparison with younger animals (Morelli et al., 1990). A marked age-related decrease of D2-like receptors was found in the nucleus accumbens and in the olfactory tubercle of 24-month-old rats, whereas no changes were observed between 3 and 11 months of age (Morelli et al., 1990). The amygdala, entopeduncular nucleus, anterior cingulate and suprarhinal prefrontal cortices of young-adult rats (3 months) contain a moderate density of D1-like receptors, which do not decrease significantly in aged rats (Morelli et al., 1990). No changes in the number of D1-like and D2-like receptors were observed in the entopeduncular nucleus and fronto-parietal cortex of 11- and 24-month-old rats (Morelli et al., 1990). Another area investigated for age-related changes of dopaminergic indices is the frontal cortex, where mesocortical dopaminergic projections end. The rat medial prefrontal cortex has a relatively high concentration of D1-like receptors in comparison with other cortical areas (Reader et al., 1988; Fremeau et al., 1991) and has the highest D1-like/D2-like receptor ratio measured in the brain (Boyson et al., 1986). D2 receptor gene expression was topographically more restricted than that of the D1 receptor gene (3-4 times), and D2 labelled neurons were found almost exclusively in the fifth layer (Gaspar et al., 1995). Functional interaction and synergy between D1 and D2 receptors have also been shown in the rat frontal cortex (Retaux et al., 1991). D2-like autoreceptor stimulation inhibits DA release from terminals in the rodent prefrontal cortex (Plantje et al., 1987), while stimulation of post-synaptic D2-like receptors inhibits prefrontal cortex cell firing (Thierry et al., 1986; Sesack and Bunney, 1989). The DA-sensitive cyclic AMP generating system in membrane particles of the frontal cortex showed a decreased coupling between the D1-like receptor and cyclic AMP generation in adult and aged rats in comparison with young animals, and an age-dependent increased coupling between the D2-like receptor and cyclic AMP inhibition (Amenta et al., 1990b). Glutamate release is probably mediated by DA receptors, mainly of the D1 type, which are located on glutamatergic neurons. Altered DA–glutamate interactions with age with impairment of cortical DA D1 receptors was found in the rat prefrontal cortex (Porras et al., 1997). It was also shown that DA D1 receptor mediated processes are altered in 18- and 26-month-old rats (Parfitt et al., 1990). In the prefrontal cortex of aged monkeys, a loss of endogenous D1 receptor stimulation was found, as well as a D1 receptor decrease with age (Arnsten et al., 1994).

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In the rat mesolimbic areas, the greatest density of the DA D2-like sites labelled with the receptor agonist [3Hlquinpirole was found in the nucleus accumbens and olfactory tubercles. A moderate receptor density was observed in the substantia nigra/ventral tegmental area and septal area. Low levels of [3H]quinpirole were demonstrated in other limbic areas such as the hippocampus, prefrontal cortex, amygdala, cingulate, entorhinal and pyriform cortices (Levant et al., 1992). Both the nucleus accumbens and olfactory tubercle show an independent pattern of D2 mRNA development (Srivastava et al., 1992). The D2 receptor mRNA levels in the caudate-putamen and nucleus accumbens follow the same developmental pattern, albeit with some quantitative differences such as a steeper decline in mRNA levels of nucleus accumbens at 6 months and 1 year of age (Srivastava et al., 1992). In the olfactory tubercle, D2 mRNA levels are quite low at 1 and 3 days after birth, rise sharply through days 7 and 14, peak at 28 days and then decrease rapidly at 6 months and 1 year (Srivastava et al., 1992). The expression of DA D2 receptors changes as a function of age in some rat brain areas, such as the corpus striatum and substantia nigra, whereas no age-related changes in the levels of D2S or D2L receptor mRNA were detected in the olfactory tubercle and hippocampus (Valerio et al., 1994). D2 agonists have both pre- and postsynaptic effects in the brain, including the prefrontal cortex. Hence, these compounds can be used to assess the status of presynaptic elements as well as postsynaptic D2 function (Arnsten et al., 1995). The magnitude of cognitive improvement and the incidence of ‘hallucinatory-like’ behaviour induced by DA D2-like receptor agonists were reduced in aged primates. This indicates the occurrence of changes of postsynaptic D2 receptor function with ageing (Arnsten et al., 1995). Recent studies have suggested that the limbic DA D2 receptor has a facilitatory role on memory consolidation (Sigala et al., 1997). A D3 receptor mRNA was found in the rat forebrain. The signal was particularly enriched in the nucleus accumbens, islands of Calleja (Sokoloff et al., 1990; Bouthenet et al., 1991; Levesque et al., 1992; Mengod et al., 1992; Kung et al., 1994; Damask et al., 1996), olfactory tubercle and prefrontal cortex (Ariano and Sibley, 1994). A study using in-situ hybridization has revealed that D3 receptor mRNA is not confined to the islands of Calleja, but is present in areas receiving projections from the A10 cell group, such as the nucleus accumbens, olfactory tubercle, bed nucleus of stria terminalis and other limbic regions (Bouthenet et al., 1991). Other authors observed the highest levels of the D3 signal in the hippocampus, hypothalamus, and nucleus accumbens. Lower levels were detected in the prefrontal cortex and olfactory bulb (Richtand et al., 1995). In terms of functional correlates, it was suggested that DA D3 receptor can regulate mesolimbic DA synthesis (Nissbrandt et al., 1995), release (Rivet et al., 1994), and neuronal activity (Lejeune and Millan, 1995). Different to the D2 receptor, the limbic D3 site has an inhibitory role on memory consolidation in the rat (Sigala et al., 1997). The D3 receptor shows a progressive reduction with age in the olfactory tubercle (Valerio et al., 1994). The density of DA D3 receptors in the nucleus accumbens was significantly increased (29%) in aged Fisher-344 and Brown–Norway rats compared to young-adult animals (Wallace and Booze, 1996). The D3 receptor exhibits the

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characteristics of presynaptic autoreceptors in the nucleus accumbens (Gilbert et al., 1995). Some findings suggest a unique function for the D3 receptor during the ageing process, perhaps serving to compensate for the loss of D2 receptor (Wallace and Booze, 1996). D4 mRNA was detected in a few central nervous system regions such as the olfactory bulb, frontal cortex, and hypothalamus. Relatively low levels of D4 mRNA were observed in the rat hippocampus (O’Malley et al., 1992). No detectable D4 mRNA levels were found in the striatum or neocortex (Damask et al., 1996). An autoradiographic study on rat brain using the putative D4 selective ligand [3H]NGD 94-1 revealed the greatest accumulation of the compound in the entorhinal cortex, lateral septal nucleus, hippocampus and the medial preoptic area of the hypothalamus (Primus et al., 1997). Other autoradiographic studies reported the highest density of putative DA D4 receptor in the rat hippocampus, followed by the neostriatum, olfactory tubercle, substantia nigra, nucleus accumbens core, and cerebral cortex (Defagot and Antonelli, 1997). D4 receptor immunoreactivity was mainly associated with nerve cell bodies with a widespread distribution throughout the central nervous system. D4-immunoreactive neurons were also found in most areas of the neocortex (Defagot et al., 1997). A strong immunoreactivity was detected in the hippocampus and entorhinal cortex (Defagot et al., 1997). In the anterior cortical and posterolateral cortical portions of amygdala, D4-immunoreactive neurons were also found (Defagot et al., 1997). These recent investigations have contributed to the increased knowledge on the anatomical distribution of the DA D4 receptor, but unfortunately only sparse information is so far available on the sensitivity ageing of this DA receptor subtype.

5.2.2. Human ‘physiological ageing’ The human prefrontal cortex contains appreciable amounts of DA D1-like receptors (Farde et al., 1987; Cortes et al., 1989b; Goldman-Rakic et al., 1990) and relatively low or negligible amounts of D2-like receptors (Farde et al., 1987; Camps et al., 1989; Goldman-Rakic et al., 1990). In this cerebrocortical area, no age-related loss of DA levels was found (Adolfsson et al., 1979), whereas a substantial decrease in the number of DA D1-like receptors was reported (de Keyser et al., 1990; Suhara et al., 1991). Age-related reduction of D1-like receptor may contribute to cognitive impairment of the elderly (de Keyser et al., 1990). Through the D1 receptor, DA can selectively regulate the mnemonic component of prefrontal cortical function without affecting normal sensorimotor processing of this area (Williams and Goldman-Rakic, 1995). In the human prefrontal cortex, D1 and D4 mRNAs are the most abundant. Lower levels of the other three transcripts (D1, D2, and D3 mRNAs) were also found (Meador-Woodruff et al., 1996). The D3 receptor, although present in an apparent low overall density, has its mRNAs highly expressed in the nucleus accumbens and islands of Calleja (Landwehrmeyer et al., 1993; Meador-Woodruff et al., 1994). Radioligand binding studies of limbic areas reported the highest density of DA D3 receptor in the nucleus accumbens and the lowest density in septal nuclei (Murray et al., 1994; Herroelen et al., 1994). No D3 receptor binding

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Table 4 Dopamine receptor changes in limbic areas in Alzheimer’s disease Author

Subjects (number) and age

Parameter Area

Results

Cortes et al., 1988

n= 7 84 years n= 11 78 years

D1-like receptors D2-like receptors

¡

n= 7 79 years

D2-like receptors

Ryoo and Joyce, 1994

Joyce et al., 1993

Hippocampus (CA1, CA3, DG) (a) Hippocampus: (1) DG molecular layer (2) DG granular and plexiform layers (3) CA3/CA4 (4) subiculum (b) Entorhinal cortex (c) Perirhinal cortex Amygdala Hippocampus

¡ = ¡ ¡ = ¡ ¡ ¡

 , increase; ¡, decrease; = , unchanged; DG, dentate gyrus.

was detected in neocortex or hippocampus (Murray et al., 1994). A quantitative autoradiography study with [3H]7-OH-DPAT as a ligand reported a high DA D3 receptor density in human ventral striatum/nucleus accumbens, followed by the remainder of neostriatum, and cerebral neocortex. A low density of D3 receptor was found in the amygdala and hippocampus (Herroelen et al., 1994). DA D4 mRNA was found primarily in the human subthalamic nucleus as well as in the amygdala, hippocampus and hypothalamus (Matsumoto et al., 1996). Low levels of D4 mRNA were observed both in the human striatum and cerebral cortex (Matsumoto et al., 1996). These observations suggest that the density and pattern of the above DA receptor subtypes in the human limbic system are different from those reported in rats (O’Malley et al., 1992) and monkeys (Van Tol et al., 1991). High-affinity [3H]NGD 94-1 binding was found in several human brain regions, including the hippocampus, hypothalamus, dorsal medial thalamus, entorhinal and prefrontal cortices, and lateral septal nucleus (Primus et al., 1997). Similar to that mentioned in Section 5.2.1, no data are available concerning specific changes of limbic DA D3 and D4 receptors in the elderly. Future studies on this topic may clarify the role of these receptor subtypes in behavioural disorders of the elderly, probably consequential to dopaminergic neurotransmission impairment.

5.2.3. Alzheimer’s disease and related disorders A significant reduction of DA D1-like receptors was found in the hippocampus of AD patients (Cortes et al., 1988) (Table 4). In SDAT, a marked decrease of D1-like receptors was found in the CA1 and CA3 subfields of the hippocampus and in the molecular layer of the dentate gyrus (Cortes et al., 1988). Binding of the D2 receptor antagonist [125I]epidepride was reduced in several brain areas of AD patients. In the hippocampal complex, which was an area particularly affected,

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receptor loss occurred with a rostro-caudal gradient and involved specific cytoarchitectonic and laminar areas (Ryoo and Joyce, 1994). D2 receptor density decreased primarily in the molecular layer of the dentate gyrus but not in granular or plexiform layers. CA3 – CA4 subfields were affected at all levels and the subiculum at rostral and middle levels only (Ryoo and Joyce, 1994). The entorhinal cortex, which showed a scanty density of binding sites in control individuals, did not undergo changes of D2 receptors in AD. The rostral perirhinal cortex was affected primarily at the middle level (Ryoo and Joyce, 1994). The number of DA D2 receptors in the hippocampus and amygdala decreased in AD patients with or without concomitant Parkinson’s disease (Joyce et al., 1993; Ryoo and Joyce, 1994). The occurrence of changes of dopamine D2-like receptor expression in portions of hippocampal formation involved in processing inputs in AD suggests that this deficit may contribute to a disrupted information flow into the hippocampus. The loss of DA D2-like receptors in the subiculum, the major source of hippocampal efferents (Rosene and Van Hoesen, 1987), could impair dopaminergic neurotransmission in the hippocampus (Ryoo and Joyce, 1994). The presence of DA D2 receptors in the glomerular layer of the human olfactory bulb was suggested (Loopuijt and Sebens, 1990). In the majority of cases, these receptors are lost as a consequence of the remarkable decrease of mitral cells in AD (Loopuijt and Sebens, 1990). Several lines of evidence suggest possible involvement of the DA D2 receptor gene (located in 11q23) in AD (Joyce et al., 1993; Ryoo and Joyce, 1994).

5.2.4. Parkinson’s disease Only a few data are available concerning changes of limbic DA receptors in Parkinson’s disease. A detailed autoradiographic study did not observe changes in the distribution or density of brain D1 receptors (labelled with the D1-like receptor antagonist [3H]SCH 23390) and D2 receptors (labelled with the D2-like receptor agonist [3H]CV 205-502) in patients suffering from idiopathic Parkinson’s disease (Cortes et al., 1989a). Although, in general, [3H]CV 205-502 binding was somewhat higher in Parkinson’s disease than in control individuals, differences in the density of D2 receptors were statistically significant only in the CA3 layer of the hippocampus and in the deep layers of the occipital cortex (Cortes et al., 1989a). The lack of important involvement of limbic DA receptors in Parkinson’s disease is also suggested by more recent investigations indicating that the expression of neostriatal and limbic (nucleus accumbens) D3 receptors is unaltered (Hurley et al., 1996) in Parkinson’s disease.

6. Psychotic behaviour of the elderly Evaluation of behavioural aspects of old age requires a multidimensional research approach, taking into account the personal history of life, dynamics of life in ageing as well as cognitive development and structure of intelligence (Seitelberger, 1992). Cognition involves processes and contents of acquisition of knowl-

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edge, i.e. perception and apperception, memory, learning, as well as thinking and purposeful planning of actions and behaviours (Seitelberger, 1992). There are a number of different relationships among ageing, psychosis and movement disorders, most of which have been proposed to involve the dopaminergic system. Disturbances in dopaminergic neurotransmission were implicated in the aetiology of psychotic disorders (Catalano et al., 1993). The majority of antipsychotic agents available block DA D2-like receptors and are quite effective in the treatment of psychotic phenomena of the elderly. However, the use of conventional neuroleptics is not out of risk in aged subjects, due to their higher susceptibility, in comparison with younger individuals, to extrapyramidal side-effects. Age-related physiological changes of several body functions alter pharmacokinetic and pharmacodynamic characteristics of antipsychotic drugs, placing the elderly at heightened risk for adverse drug effects (Zaleon and Guthrie, 1994). The most frequent side-effects of antipsychotic drugs observed in aged subjects are orthostatic hypotension, anticholinergic effects, pseudoparkinsonism, and tardive dyskinesia (Zaleon and Guthrie, 1994). Age-related impairment of DA content and DA receptors may relate to the time of onset of different motor and psychotic disorders, as well as to their appearance (Lohr and Bracha, 1988). Psychotic phenomena of the elderly, characterized by obsessive and compulsive manifestations, may involve dopaminergic dysfunction. There is substantial clinical literature suggesting a link between obsessive–compulsive symptoms and basal ganglia neuropathology. Further work is necessary to ascertain the contribution of the limbic dopaminergic system to the pathophysiology of these disorders. The most common clinical manifestations of obsessive–compulsive phenomena are washing, checking, and counting behaviours (Schwartz, 1997). In general terms, compulsions are repetitive behavioural responses to obsession, which are intrusive anxiety-provoking urges most often related to fears of contamination or of harm coming to oneself or to others (Schwartz, 1997). Connections between the orbitofrontal cortex (including a closely associated structure, the anterior cingulate gyrus) and caudate nucleus probably represent the neuroanatomical substrate of obsessive – compulsive disorders (Schwartz, 1997). Vascular diseases may be involved in the aetiology of psychosis in the elderly. Functional studies have confirmed frontal and medial temporal lobe dysfunction in psychotic manifestations (Brown, 1993). Important neurochemical changes in psychosis include those affecting the dopaminergic system, serine metabolism, and probably neurotensin. Psychosis has been proposed as a dysfunction of the corticostriatal pathways with negative feedback disinhibition of the thalamic filter. This results in sensory flooding, leading to psychotic perception in susceptible subjects (Brown, 1993). In AD patients, psychosis is often associated with increased density of senile plaques and neurofibrillary tangles in the prosubiculum and middle frontal cortex, respectively. This observation is consistent with the increased rate of cognitive decline that accompanies these behavioural disorders (Zubenko et al., 1991). Visual hallucinations were a prominent feature in psychotic patients and the atypical nature of these psychoses might explain why some authors did not find evidence of dopaminergic involvement in their pathophysiology (Mellers et al., 1995)

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7. Concluding remarks and future research directions The role of impaired dopaminergic neurotransmission in the pathogenesis of motor disturbances affecting the elderly is clearly demonstrated (see Amenta et al., 1991). In this paper, we have reviewed the main evidence of the influence of altered limbic dopaminergic neurotransmission on higher cognitive and affective functions as well as on behavioural abnormalities affecting the elderly. Although altered limbic dopaminergic neurotransmission mechanisms are recognized among the causes of psychotic behaviour of old age, the role of this system in the pathogenesis of higher cognitive dysfunction both in physiological ageing and in age-related neurodegenerative disorders is still to be defined. The increasing knowledge on the subtypes of dopamine receptors present in different brain regions, including extrapyramidal nuclei and limbic areas, the availability of more specific drugs acting on these receptors and evaluation of the influence of age-related neurological and psychiatric disorders on the expression of these receptors will probably provide the basis for a better knowledge of the role of limbic dopaminergic system in health and disease. The fact that a large number of investigations have been performed in which DA receptors were thought to belong to two subtypes only, will require further work to assess eventual specific receptor subtype changes in different brain areas and disorders affecting the elderly. Another important challenge of future studies in this area will be to establish if alterations of limbic dopaminergic neurotransmission may represent a cause or merely a consequence of other neurotransmitter system changes occurring in physiological and pathological ageing.

Acknowledgements The present study was supported by grants of Camerino and Genova Universities. PB was the recipient of a fellowship of the Italian National Research Council (Progetto finalizzato invecchiamento). The authors thank Ch. Fringuelli for his invaluable help in figure preparation.

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