Glutamate–dopamine–GABA interactions in the aging basal ganglia

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Review

Glutamate–dopamine–GABA interactions in the agingbasal ganglia

Francisco Mora⁎, Gregorio Segovia, Alberto del ArcoDepartment of Physiology, Faculty of Medicine, Universidad Complutense, Ciudad Universitaria, s/n 28040 Madrid, Spain

A R T I C L E I N F O

⁎ Corresponding author. Fax: +34 91 394 1628.E-mail address: francisco-mora@med.ucmAbbreviations: ACPD, (1S,3R)-1-aminocycl

CPP, 3-[R-2-carboxypiperazin-4-yl]-propyl-1-PDC, L-trans-3,4-dicarboxylic acid; VTA, ventr

A B S T R A C T

Article history:Accepted 6 October 2007Available online 26 October 2007

The study of neurotransmitter interactions gives a better understanding of the physiology ofspecific circuits in the brain. In this review we focus mostly on our own results on theinteraction of the neurotransmitters glutamate, dopamine and GABA in the basal gangliaduring the normal process of aging. We review first the studies on the action of endogenousglutamate on the extracellular concentrations of dopamine and GABA in the neostriatumand nucleus accumbens during aging. It was found that there exists an age-related changein the interaction of glutamate, dopamine and GABA and that these effects of aging exhibit adorsal-to-ventral pattern of effects with no changes in the dorsal parts (dorsal striatum) andchanges in themost ventral parts (nucleus accumbens). Secondwe reviewed the data on theeffects of different ionotropic and metabotropic glutamate receptor agonists on theextracellular concentrations of dopamine and GABA in the nucleus accumbens. Theresults obtained clearly show the different contribution of each glutamate receptor subtypein the age-related changes produced on the interaction of glutamate, dopamine and GABAin this area of the brain. Third the effects of an enriched environment on the action of AMPAand NMDA-receptor agonists in the nucleus accumbens of rats during aging are alsoevaluated. Finally, and since the nucleus accumbens has been suggested to play a role inemotion and motivation and also motor behaviour, we speculated on the possibility of aspecific contribution for the different glutamatergic pathways terminating in the nucleusaccumbens and their interaction with a decreased dopamine playing a relevant role inmotor behaviour during aging.

Keywords:AgingBasal gangliaEmotionMotor behaviourDopamineGlutamateGABA

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412. Neuronal substrates for the interactions of glutamate and dopamine in the basal ganglia . . . . . . . . . . . . . . . 3413. “In vivo” release of dopamine and glutamate in the basal ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

.es (F. Mora).opentane-1,3-dicarboxylic acid; AMPA, amino-3-hydroxy-5methylisoxacole-4-propionate;phosphonic acid; DNQX, 6,7-dinitroquinolaxine-2,3-dione; NMDA, N-methyl-D-aspartate;al tegmental area

hed by Elsevier B.V.

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3.1. Glutamate–dopamine–GABA interactions in striatum and nucleus accumbens in young rats . . . . . . . . . 3423.2. Glutamate–dopamine–GABA interactions in striatum and nucleus accumbens during aging . . . . . . . . . . 343

4. Dopamine and GABA release in the nucleus accumbens, as a result of the activation of different glutamatereceptor subtypes, is decreased during aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

5. On the significance of the unbalanced Glu–DA–GABA interactions in the nucleus accumbens . . . . . . . . . . . . 3466. Environmental enrichment, nucleus accumbens and aging of the brain . . . . . . . . . . . . . . . . . . . . . . . . 3477. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

1. Introduction

The concept of neurotransmitter interaction, that is, thecomplex reciprocal modulation of neural transmissionamong a number of neurotransmitters, emerged severalyears ago to give a better understanding of the physiology ofspecific circuits of the brain. In particular, the interactionbetween glutamate, dopamine and GABA in the basal gangliahas been suggested to be an important neuronal substrate forfunctions such as motor activity, emotion and cognition.Although the nature of these reciprocal interactions is not yetwell understood, its dysfunction has been involved in severalneurological disorders such as Parkinson’s disease andschizophrenia. In recent years studies from our laboratoryhave been accumulated providing evidence for changes in theinteraction between glutamate, dopamine and GABA duringthe normal process of aging in the prefrontal cortex (Porras etal., 1997; Segovia and Mora, 2005b) and particularly in theneostriatum (Porras and Mora, 1995) and nucleus accumbens(Segovia et al., 1999; Segovia and Mora, 2005a). Several otherstudies have also reported changes in the interaction betweendopamine and acetylcholine in the striatum of aged rats(Kametani et al., 1995; Kurotani et al., 2003; Schulz et al., 1993;Thompson et al., 1984; Yamagami et al., 1991).

In this review we will focus mostly on our own results onthe interaction of glutamate and dopamine and also GABA inaging of the basal ganglia. Specifically we will review first ourresults on the action of endogenous glutamate on dopamineandGABA extracellular concentrations in the neostriatum andnucleus accumbens of young rats. Then, the action ofglutamate on dopamine and GABA in those same twostructures during the normal process of aging will be evaluat-ed. Third, we will review the action of ionotropic andmetabotropic glutamate receptor agonists on the extracellularconcentrations of dopamine and GABA in the nucleus accum-bens. Finally our most recent experiments on the influence ofan enriched environment on the action of ionotropic, amino-3-hydroxy-5methylisoxacole-4-propionate (AMPA) and N-meth-yl-D-aspartate (NMDA) receptors on the release of dopamine inthe nucleus accumbens will be briefly evaluated.

2. Neuronal substrates for the interactions ofglutamate and dopamine in the basal ganglia

In recent years, the interaction of glutamate, dopamine andGABA in striatum and nucleus accumbens has received

much attention due, at least in part, to our present know-ledge of the connectivity of these areas of the brain (Fig. 1)(Groenewegen et al., 1991; Meredith, 1999; Sesack et al.,2003; Smith and Bolam, 1990; Smith et al., 2004). Theprincipal neurons in both the striatum and nucleus accum-bens are medium-sized spiny GABA projection neurons(medium spiny neurons) that receive convergent synapticinputs from glutamate and dopamine afferences. In dorsalstriatum, glutamatergic inputs from the sensorimotor cortexbut also from the thalamus (midline and intralaminarthalamic nuclei) synapse on medium spiny GABA neurons.Also synaptic dopaminergic inputs from the substantianigra impinge upon GABA neurons in this area of thebrain. In the nucleus accumbens, however, the glutamater-gic terminals arise from many different sources. Thus,glutamatergic inputs to the nucleus accumbens arise fromcell bodies located not only in amygdala, hippocampus andprefrontal cortex but also from the thalamus (the para-ventricular nucleus among other nuclei) while dopamineinputs arise from the ventral tegmental area (VTA) of themesencephalon.

There are important common features of the glutamateand dopamine afferences to the striatum and nucleusaccumbens (Fig. 1) (David et al., 2005; Groenewegen et al.,1991; Meredith, 1999; Sesack et al., 2003; Smith and Bolam,1990). First, glutamatergic axons synapse mostly onto theheads of the spines of the medium spiny GABA neurons,while the midbrain dopaminergic axons mainly terminateonto the dendritic shafts or the neck of the spines of thesesame GABA neurons. Second, although no direct axoaxonicconnections seem to exist between glutamate and dopamineterminals, a great proportion of spines of the medium spinyGABA neurons receive convergent contacts from theseterminals, a synaptic arrangement referred as “triad”. Andthird, glutamatergic receptors are located on dopaminergicterminals and dopamine receptors on glutamatergic presyn-aptic endings suggesting that presynaptic interactions shouldoccur through extrasynaptic mechanisms of the volumetrictype between dopamine and glutamate within striatum andnucleus accumbens (Del Arco et al., 2003). Therefore, thesynaptic arrangement of both the striatum and nucleusaccumbens gives support to the existence of interactionsbetween glutamate and dopamine afferences and GABAneurons in these areas of the brain. As it will be discussedin the following sections, these interactions include thereciprocal regulation of the release of glutamate, dopamineand GABA.

Fig. 1 – Schematic diagram of the synaptic inputs to themedium spiny neurons in striatum and nucleus accumbens.Glutamatergic axons synapse onto the heads of the spines ofthe medium spiny neurons, while the midbraindopaminergic axons mainly terminate onto the dendriticshafts or the neck of the spines of GABA neurons. Althoughno direct axoaxonic connections seem to exist betweenglutamate and dopamine terminals, a great proportion ofspines of the medium spiny GABA neurons receiveconvergent contacts from these terminals, a synapticarrangement referred as “triad”. Inputs from local neurons(acetylcholine and GABA interneurons) terminate onproximal parts of the dendritic shaft and on the cell body.Ach, acetylcholine; DA, dopamine; Glu, glutamate; SN,substantia nigra; VTA, ventral tegmental area. Modified fromSmith and Bolam (1990) and Groenewegen et al. (1991).

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3. “In vivo” release of dopamine andglutamate in the basal ganglia

A growing body of neurochemical and electrophysiologicalresearch has firmly established the existence of an interactionbetween glutamate, dopamine and GABA in the basal ganglia(Cepeda and Levine, 1998; David et al., 2005; Morari et al., 1998;Surmeier et al., 2007; West et al., 2003). Specifically, localinfusions of the glutamate agonist NMDA increase extracel-lular concentrations of dopamine and GABA in the striatumand nucleus accumbens (Cano-Cebrián et al., 2003; Hernándezet al., 2003; Imperato et al., 1990; Kendrick et al., 1996; Morari etal., 1993; Segovia and Mora, 1998). Also infusions of an AMPA/kainate-receptor agonist increase extracellular dopamine andGABA in these same areas of the brain (Hernández et al., 2003;Kendrick et al., 1996; Patel et al., 2001). In striatum we showedthat the activation of both AMPA and NMDA receptors pro-duced a dose-related increase of dopamine and GABA and thatthe perfusion of AMPA–kainate and NMDA antagonistsblocked or significantly reduced the effects of AMPA andNMDA (Hernández et al., 2003). Also, the release of dopamineproduced by the perfusion of NMDA in striatum was modu-lated by nitric oxide, since the inhibition of the synthesis ofnitric oxide enhanced the release of dopamine (Segovia andMora, 1998).

Several studies have also shown that the dopaminergicinput to the striatum and nucleus accumbens plays a role re-gulating glutamate and GABA neurotransmission (Kalivas andDuffy, 1997; Morari et al., 1994). In fact we have investigatedthe effects of a dopamine receptor (D1–D2) agonist, apomor-phine, and found that it produces a dose–response increase inthe extracellular concentrations of glutamate in striatum andthat these effects were significantly attenuated by blockingthe dopamine receptors (D1–D2) with haloperidol (Expósito etal., 1994). These studies on the actions of dopamine instriatum and nucleus accumbens are in line with electrophys-iological recordings showing that dopamine modulates theexcitatory glutamate corticostriatal transmission to GABAneurons (Bamford et al., 2004; Cepeda et al., 1993; Surmeieret al., 2007; West et al., 2003; West and Grace, 2002).

The reports reviewedhere on the interactions of glutamate,dopamine and GABA in the basal ganglia are supported by theexistence of glutamate receptors on GABA neurons and dopa-mine terminals (Chen et al., 1996; Desce et al., 1992; Gracy andPickel, 1996; Lu et al., 1999; Tarazi and Baldessarini, 1999) andof dopamine receptors on GABA neurons and glutamateterminals (Lu et al., 1998; Maura et al., 1988; Tarazi andBaldessarini, 1999; Wang and Pickel, 2002).

3.1. Glutamate–dopamine–GABA interactions in striatumand nucleus accumbens in young rats

We developed a novel approach to study the effects of endo-genous glutamate on different neurotransmitters in the brainof awake rats (Del Arco and Mora, 1999; Del Arco and Mora,2000; Segovia et al., 1999; Segovia et al., 1997; Segovia andMora, 2001). This approach consisted in increasing the endo-genous concentrations of glutamate (to non-toxic levels) andsee whether such an increase produced any effect on the

extracellular concentrations of dopamine and GABA. For that,endogenous extracellular glutamate was selectively increasedin striatum and nucleus accumbens by perfusing locally,through themicrodialysis probe, the selective uptake inhibitorL-trans-3,4-dicarboxylic acid (PDC) (Segovia et al., 1997; Segoviaet al., 1999; Segovia and Mora, 2001). PDC is a transportableglutamate analogue that produces a selective and potent inhi-bition of glutamate uptake without interfering with ionotropicor metabotropic glutamate receptor binding (Bridges et al.,1991; Thomsen et al., 1994) or producing damage “in vivo” upto very high doses (Massieu et al., 1995; Obrenovitch et al.,1996). Using PDC, it was found a positive significant correla-tion between increases of glutamate and increases of dopa-mine and GABA in both striatum and nucleus accumbens (seeFig. 2).

The responses of dopamine and GABA to the increasedendogenous concentrations of glutamate was partially medi-ated by the ionotropic glutamate NMDA and AMPA/kainatereceptors (Segovia et al., 1997; Segovia and Mora, 2001). Thiswas shown by perfusing specific glutamate receptor blockers,the NMDA-receptor antagonist 3-[R-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) and the AMPA/kainate-recep-tor antagonist 6,7-dinitroquinolaxine-2,3-dione (DNQX). Bothglutamate antagonists reduced the increases of dopamine andGABA produced by endogenous glutamate in striatum. In thenucleus accumbens however only dopamine but not GABAwas attenuated by CPP or DNQX. Actually, CPP potentiated theincreases of GABA produced by endogenous glutamate. There-fore, other type of glutamate receptors (metabotropic) or in-teractions of receptors were mediating the effects of gluta-mate on GABA (Segovia et al., 1997; Segovia and Mora, 2001).

Of interest is the fact that despite of a lack of direct glu-tamate–dopamine synapses in striatum and nucleus accum-

Fig. 2 – Correlation between increases of dopamine (A and C) andof glutamate extracellular concentrations after local perfusion (minhibitor PDC (1, 2 and 4 mM) in striatum (A and B) and nucleusSegovia et al. (1999).

bens a significant correlation between increases of endo-genous glutamate and endogenous dopaminewas found. Thiswould be indicative of a physiological role for local glutamateregulating positively the release of dopamine in these areasof the brain (Cano-Cebrián et al., 2003; Hernández et al., 2003;Imperato et al., 1990; Kendrick et al., 1996; Morari et al., 1993;Segovia and Mora, 1998 but see Taber et al., 1996). Interest-ingly, one of the possible mechanisms of this glutamatergicregulation of dopamine release (see Section 4) is through anextrasynaptic interaction, that is, synaptically releasedglutamate diffusing through the extracellular space andinteracting with receptors located on dopamine terminals(Scanziani et al., 1997; Szapiro and Barbour, 2007). Anotherpossible source of extracellular glutamate may be astrocytes(Araque et al., 1999; Volterra and Meldolesi, 2005) or, morespecifically, the neuron-astrocyte unit (Del Arco et al., 2003).In fact, we have recently suggested that under specific con-ditions glutamate released from astrocytes (monitored withmicrodialysis) would act as an extrasynaptic (volume trans-mission) signal in specific circuits of the brain (Del Arco et al.,2003).

3.2. Glutamate–dopamine–GABA interactions in striatumand nucleus accumbens during aging

As an extension of the findings reviewed in the previoussection,we investigated the effects of aging [rats of 2–3months(young), 12–14 months (middle age), 27–32 months (aged) and37 months (very aged)] on the actions of increasing concen-trations of endogenous glutamate on the extracellular con-centrations of dopamine and GABA in striatum and nucleusaccumbens of the awake rat usingmicrodialysis (Segovia et al.,1999). Our study showed an age-related change in the effects

GABA (B andD) extracellular concentrations and the increasesicrodialysis) of a range of doses of the glutamate uptakeaccumbens (C and D) of young (2–4 months) rats. Taken from

of endogenous glutamate on extracellular dopamine andGABA in the nucleus accumbens (see below).

In striatum there were no differences in dopamine/glu-tamate and GABA/glutamate ratios (the ratio of the increasesof DA and GABA to the maximal increases of glutamate)between middle-aged, aged and very aged rats when com-pared to young rats (see Fig. 3). In contrast, in the nucleusaccumbens, the increases of extracellular concentrations ofdopamine produced by glutamate were lower in middle-aged,aged and very aged rats compared to young rats. Moreover asignificant negative correlation was found between the dopa-mine/glutamate ratio and age (see Fig. 3). In contrast, nosignificant changes were found for the GABA/glutamate ratioand age except for a small positive significant correlation ofthis ratio with age.

These findings suggest that the changes in the glutamate–dopamine interactions during the normal process of aging areregionally specific and that these effects of aging in the basalganglia exhibits a dorsal-to-ventral pattern of effects with nochanges in the dorsal parts (dorsal striatum) and changes inthe most ventral parts (nucleus accumbens). Several otherreports have indicated a similar dorsal-to-ventral gradients ofeffects produced by aging in the basal ganglia (Crawford andLevine, 1997; Friedemann and Gerhardt, 1992). Thus, it hasbeen reported that the effects of amphetamine or a D2receptor agonist, quinpirole, on c-Fos expression in the basalganglia exhibit a dorsal-to-ventral pattern, with changes innucleus accumbens and no changes in dorsal striatum (Craw-ford and Levine, 1997). Also, the release of dopamine after highpotassium stimulation was reduced in both the striatum andnucleus accumbens compared with young rats but the de-creases were larger and appeared earlier (18 months rats) in

Fig. 3 – Effects of aging on the ratio of increases of dopamine (Aincreases of glutamate extracellular concentrations after local pePDC (4 mM) in striatum (A and B) and nucleus accumbens (C and(27–32months) and very aged (37months) rats. *p<0.05 comparedModified from Segovia et al. (1999).

the nucleus accumbens (Friedemann and Gerhardt, 1992).Other studies using microdialysis have reported a lack ofeffects of aging on the chemically stimulated release of dopa-mine in dorsal striatum (Gerhardt and Maloney, 1999; Kame-tani et al., 1995; Santiago et al., 1993). However, it has beensuggested that during aging, the decrease of dopamine releasecould be compensated for by a longer inactivation of theextracellular dopamine due to a decrease of dopamine uptake(Friedemann and Gerhardt, 1992; Gerhardt and Maloney, 1999;Hebert and Gerhardt, 1999). Therefore, the lack of changes inthe release of dopamine in the striatum of aged rats may bethe result of an enhanced diffusion of dopamine from releasesites which, as a consequence, would maintain extracellulardopamine increased for longer periods of time (Stanford et al.,2001). Finally, the findings reviewed in this section are ingeneral agreement with a recent detailed analysis of theeffects of aging on the nigrostriatal andmesolimbic dopaminesystems (Cruz-Muros et al., 2007). In fact, the mesolimbic sys-tem seems to be more vulnerable to aging than the nigros-triatal system (Cruz-Muros et al., 2007).

4. Dopamine and GABA release in the nucleusaccumbens, as a result of the activation of differentglutamate receptor subtypes, is decreased duringaging

Our results shown in the previous section clearly indicatesthat the interaction glutamate–dopamine, expressed as thecapacity of glutamate to release dopamine is decreased duringaging in the nucleus accumbens. As discussed, this finding isin line with the reported vulnerability of the mesolimbic

and C) and GABA (B and D) extracellular concentrations torfusion (microdialysis) of the glutamate uptake inhibitorD) of young (2–4 months), middle-aged (12–14 months), agedto young rats (one-way ANOVA followed by Dunnett's t test).

dopamine systems to the normal process of aging (Barili et al.,1998; Cruz-Muros et al., 2007; Del Arco et al., 2001). Alterna-tively, the effects of aging on the actions of endogenousglutamate on extracellular dopamine in the nucleus accum-bens may be, at least in part, a consequence of a specificdecrease in the number or in the activity of the glutamatergicreceptors that mediate the effects of glutamate. In fact, dif-ferent studies have shown a decrease in the density of gluta-mate receptors in striatumand nucleus accumbens (Ossowskaet al., 2001; Segovia et al., 2001), and also a reduction of theresponses mediated by these receptors in striatum (Akopianand Walsh, 2006; Cepeda et al., 1989; Cepeda et al., 1996;Gonzales et al., 1991; Lin, 2006). In view of these changes it wasof interest to investigate whether the activation of glutama-tergic receptors, both ionotropic and metabotropic, producedany changes on the extracellular concentrations of dopamineand GABA and whether these changes are modified as a resultof aging (Segovia and Mora, 2005a). In accordance we in-vestigated the effects of a dose-related perfusion of NMDA,AMPA and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid(ACPD; group I and IImetabotropic glutamate receptor agonist)on the release of dopamine and GABA in the nucleus accum-bens of young (2–4 months) middle-aged (10–14 months) andaged (24–32 months). It was found (see Fig. 4) that NMDA andAMPA agonist but not ACPD agonists produced an increase of

Fig. 4 – Effects of aging on the increases of dopamine and GABA(microdialysis) of the glutamate agonists NMDA (500 μM), AMPAyoung (2–4 months), middle-aged (9–14 months) and aged (24–32(planned comparisons in a three-way ANOVA with repeated me

dopamine in the young rat. These increases were significantlydecreased in middle-aged and aged rats. Interestingly, theperfusion of the three glutamate agonists NMDA, AMPA andACPD produced an increase in the extracellular concentra-tions of GABA which were also significantly reduced in agedrats compared to young rat (see Fig. 4). These results provide afurther understanding of the actions of endogenous glutamateon the extracellular concentrations of dopamine and GABA inthe nucleus accumbens, indicating clearly the differentcontribution of each glutamate receptor subtype involved inthe responses found.

Several mechanisms have been suggested to exist for theregulation of dopamine release through the different gluta-matergic inputs to the nucleus accumbens (Fig. 5) (Grace et al.,2007; Pralong et al., 2002). For instance, a direct extrasynapticaction of glutamate released from terminals arising in thethalamus and amygdala releasing dopamine has been re-ported (Howland et al., 2002; Jackson and Moghaddam, 2001;Parsons et al., 2007). On the contrary, the prefrontal cortexglutamatergic input to the nucleus accumbens seems to in-hibit the release of dopamine through the activation of GABAprojection neurons to the VTA (Jackson et al., 2001; Kalivaset al., 1993; Yim and Mogenson, 1980). It has also been shownthat stimulation of prefrontal cortex increases dopamine inthe nucleus accumbens through an indirect activation of do-

extracellular concentrations induced by local perfusion(100 μM) and ACPD (1000 μM) in the nucleus accumbens ofmonths) rats. **p<0.01, *p<0.05 compared to young rats

asures design). Modified from Segovia and Mora (2005a,b).

Fig. 5 – Diagram showing the suggested mechanisms through which dopamine release is regulated by the differentglutamatergic inputs to the nucleus accumbens (Grace et al., 2007; Pralong et al., 2002). (1) The perfusion of glutamate agonistslocally into the nucleus accumbens would result in a balanced activation of these different mechanisms regulating dopaminerelease. (2) A direct extrasynaptic action of glutamate, released from the thalamic and amygdalar afferences, releases dopamine(Howland et al., 2002; Jackson and Moghaddam, 2001; Parsons et al., 2007). (3) The prefrontal cortex input to the nucleusaccumbens seems to inhibit the release of dopamine through the activation of GABA projection neurons to the VTA (Jacksonet al., 2001; Kalivas et al., 1993; Yim and Mogenson, 1980). (4) Stimulation of the ventral hippocampus afference to the nucleusaccumbens increases dopamine release through a loop involving the activation of the accumbal GABA output to ventralpallidum which in turn would inhibit the pallidal GABA projection to the VTA (Blaha et al., 1997; Floresco et al., 2001; Florescoet al., 2003; Taepavarapruk et al., 2000). DA, dopamine.

pamine neurons in the VTA (for the sake of clarity this hasbeen omitted fromFig. 5) (Jackson et al., 2001; Taber et al., 1995;Taber and Fibiger, 1995; You et al., 1998). Furthermore, it hasbeen established that stimulation of the ventral hippocampusafference to the nucleus accumbens increases dopaminerelease through a loop involving the activation of theaccumbal GABA output to ventral pallidum which in turnwould inhibit the pallidal GABA projections to the VTA (Blahaet al., 1997; Floresco et al., 2003; Floresco et al., 2001; Taepa-varapruk et al., 2000 but see Legault et al., 2000). Thus, theperfusion of glutamate agonists into the nucleus accumbenswould result in a balanced activation of these differentmecha-nisms regulating dopamine release in this area of the brain.Changes in this balance may underlie the reduction of dopa-mine release observed during the normal process of aging.

5. On the significance of the unbalancedGlu–DA–GABA interactions in the nucleusaccumbens

The age-related changes of the interaction of glutamate, dopa-mine and GABA found in our studies could be relevant in orderto understand the changes in motor behaviour that occur

during the normal process of aging. Thus, during aging, ratsdisplay a reduction in spontaneous locomotor activity that hasbeen suggested to be analogous to the bradykinesia observedin elderly humans (Fig. 6) (Crawford and Levine, 1997; Emerichet al., 1993; Hebert and Gerhardt, 1998; Hebert and Gerhardt,1997; Huang et al., 1995; Nyakas et al., 1992).

This reduction, originally attributed mostly to changes ofdopamine in the nucleus accumbens (Hebert and Gerhardt,1998; Hebert and Gerhardt, 1997; Huang et al., 1995; Nyakas etal., 1992) receives now a more complementary view based onthe unbalanced interactions between dopamine, glutamateandGABA. The nucleus accumbens has been suggested to playa role in emotion and motivation, and more generally, inlimbic-motor integration, that is, the translation in neuronalcoding from motivational to purposeful motor behaviour(Mogenson et al., 1980). This hypothesis has been based onthe anatomical organization of the nucleus accumbens whichsuggests that this nucleus is an interface throughwhich limbicglutamatergic structures influence motor activity, and thatthese limbic influences on behaviour could in part be con-trolled by themesolimbic dopaminergic system (Willner et al.,1991). Indeed, it has been shown that local administration ofglutamatergic agonists into the nucleus accumbens has im-portant effects in locomotor activity which seem to be media-

Fig. 6 – Effects of aging on the spontaneous locomotoractivity in an open-field arena of young (6 months),middle-aged (15 months) and aged (24 months) rats.***p<0.001, **p<0.01 compared to young rats (plannedcomparisons in a three-way ANOVAwith repeatedmeasuresdesign). Modified from Mora et al. (2007).

ted by dopamine (David et al., 2005; Svensson et al., 1994;Vezina and Kim, 1999). Moreover, activation of glutamatergicafferents to the nucleus accumbens increases both the re-lease of dopamine and locomotor activity (Brudzynski andGibson, 1997; Taepavarapruk et al., 2000; Zornoza-Sabina et al.,2005).

As already mentioned, previous studies have shown thatspontaneous locomotor activity is decrease in aged ratscompared to young rats (see Fig. 6). Based on our own resultsshowing an age-related alteration in the interaction ofglutamate, dopamine and GABA in the nucleus accumbens,we reasoned the possibility of this neurochemical alterationbeing of relevance to understand these motor deficits. Sinceglutamate and dopamine inputs to the nucleus accumbensconverge onmedium spiny GABA neurons, our findings wouldbe indicative of a disruption of the balanced regulation ofglutamate and dopamine on the activity of GABA projectionneurons. As a consequence, aging would be associated with adysfunctional accumbal output to several motor circuits(through ventral pallidum and VTA/substantia nigra), whichwould be expressed as a reduction of spontaneous locomotoractivity (Fig. 7). Among the possible motor circuits affected bythe age-related change in the activity of the nucleus accum-bens output are the ventral pallidum projection to themediodorsal thalamus, which in turn projects to prefrontalcortex, and the direct and indirect projections to the sub-stantia nigra pars reticulata and hence the motor loops to the

dorsal striatum (Heimer et al., 1997; Hooks and Kalivas, 1995;Nicola, 2007).

The findings reported in this review raise the question onwhether the changes in glutamate–dopamine interactionoccurring during aging are the result of a differential alterationof the specific glutamatergic inputs to the nucleus accumbensregulating dopamine release (see Fig. 5). The specificity ofthese changeswould be relevant to understand the behaviourscoded in the nucleus accumbens since it has been proposedthat the activity of functional neuronal ensembles in thisarea of the brain is dependent on the integration of thedifferent glutamatergic (and dopaminergic) inputs it receives(Groenewegen et al., 1999; O’Donnell, 1999; West et al.,2003). Further studies will be needed to elucidate the effectsof aging on the specific glutamate afferences to the nucleusaccumbens.

6. Environmental enrichment, nucleusaccumbens and aging of the brain

Research from previous decades have provided an increasingbody of evidence supporting the existence of an environmen-tal dependent plasticity of the brain and its relevance for agingand neurodegenerative diseases (Mattson and Magnus, 2006;Nithianantharajah and Hannan, 2006; van Praag et al., 2000).In fact, we coined the term “ambiome” (ambiens-ambientis =environment) for that set of physical, psychological and cultu-ral factors that changes the biochemistry, anatomy and phy-siology of the brain or could determine the clinical expressionof a disease (Mora and Sanguinetti, 2004). The experimentalsetting mainly used in these studies is referred as “environ-mental enrichment” in which groups of animals are kept inlarge cages containing tunnels, platforms, toys, runningwheels and that potentiates social interactions, learning andmemory and sensory and motor stimulation (Mohammed etal., 2002; Mora et al., 2007; Rosenzweig and Bennett, 1996; vanPraag et al., 2000). Specifically, both young and aged animals(rodents), housed in these conditions, improved learning andmemory, enhanced neurogenesis in the dentate gyrus of thehippocampus, increased brain weight and size and enhanceddendritic branching and new synapse formation in thecerebral cortex (Bennett et al., 2006; Mirmiran et al., 1986;Mohammed et al., 2002; Mora et al., 2007; Olson et al., 2006;Rosenzweig and Bennett, 1996; Segovia et al., 2006; van Praaget al., 2000). Moreover, we have recently shown that animalsundergo changes in different neurotransmitter systems in theprefrontal cortex and hippocampus as a consequence of livingin an enriched environment, e.g. cholinergic (Del Arco et al.,2007b; Del Arco et al., 2007a; Segovia et al., submitted forpublication), dopaminergic (Del Arco et al., 2007a; Segovia etal., 2007), and glutamatergic (Segovia et al., 2006). Thesefindings in the prefrontal cortex and hippocampus raise thequestion on whether an enriched environment would alsomodify the effects of aging on the interaction of neurotrans-mitters in the basal ganglia.

Different studies have shown that the basal ganglia issensitive to environmental modulation. In particular, hous-ing rats in an enriched environment enhance dendriticbranching andnewsynapse formation in striatumandnucleus

Fig. 7 – Diagram showing the integration of the different glutamatergic and dopaminergic inputs to the nucleus accumbens(limbic-motor integration). Changes in the interaction between glutamate and dopamine in the nucleus accumbens duringaging would result in a disruption of the balanced regulation of glutamate and dopamine inputs to the nucleus accumbens(activity of GABA projection neurons). Aging is suggested to be associated with a dysfunctional accumbal output to severalmotor circuits, which would be expressed as a reduction of spontaneous locomotor activity. Glu, glutamate; DA, dopamine.

accumbens (Comery et al., 1996; Hamilton and Kolb, 2005; Kolbet al., 2003). Moreover, the reduction in drug-induced locomo-tor sensi isation produced by environmental enrichment hasbeen attributed to changes in the nucleus accumbens (Bardo etal., 1995; Bardo et al., 2001; Green et al., 2003; Xu et al., 2007). Inparticular, it has been shown that environmental enrichmentchanges the expression of glutamate receptors in the nucleusaccumbens (Wood et al., 2005), which is in line with the wellestablished increases in the expression of glutamate receptorsin the hippocampus (Bredy et al., 2004; Foster et al., 1996;Mlynarik et al., 2004; Naka et al., 2005; Olson et al., 2006). Incontrast, some controversy exists with regard to the effects ofan enriched environment on the dopaminergic projections tothe basal ganglia. Thus, some studies have reported nochanges in dopamine content and release and in the ex-pression of dopamine transporters and receptors (Bardo et al.,1995; Bardo andHammer, 1991; Zhu et al., 2005; Zhu et al., 2004)while others have shown decreases/increases in these sameneurochemical parameters (Bardo et al., 1999; Bezard et al.,2003; Bowling et al., 1993; Wagner et al., 2005). Interestingly, awell documented down-regulation of the mesocortical dopa-mine system both in basal conditions and after an stressfulchallenge has been reported (Del Arco et al., 2007a; Segovia etal., 2007; Zhu et al., 2005; Zhu et al., 2004).

In a recent series of experiments we studied the effects ofthe activation of the ionotropic glutamate receptors AMPA andNMDA on the release of dopamine in the nucleus accumbensof rats housed in enriched conditions from 3 to 24 months ofage.

Specifically we evaluated the effects of perfusing theagonist AMPA, and its possible modulation by NMDA, on theextracellular concentrations of dopamine in rats of 6, 15, and24 months of age. The results show that environmental en-richment does not modify the increases of dopamine pro-duced by the perfusion of AMPA nor AMPA plus NMDA.Further experiments will be performed to study the possibleeffects of environmental enrichment on the interactionglutamate–dopamine mediated by different ionotropic gluta-mate receptors such as NMDA.

7. Conclusions

In this review we have focused on the dynamics of threespecific neurotransmitters, namely, glutamate, dopamine andGABA in the basal ganglia and during the normal process ofaging. It was concluded that the interaction between gluta-mate and dopamine in the nucleus accumbens but not indorsal striatum decreases with age. These decreases producedby age were in part a consequence of the reductions in theresponsesmediated by specific glutamate receptors regulatingdopamine release. These data point to the hypothesis thatchanges in the glutamate–dopamine–GABA interactions dur-ing aging are regionally specific and that the effects of aging inthe basal ganglia exhibit a dorsal-to-ventral pattern with nochanges in the dorsal parts (dorsal striatum) and changes inthemost ventral parts (nucleus accumbens). Since the nucleusaccumbens has been suggested to play a role in emotion and

motivation and also motor behaviour through the interactionglutamate–dopamine–GABA, we suggest that changes in thisinteraction would underlay the decrease of spontaneousmotor behaviour found with age. Moreover, we speculatedon the possibility of a specific contribution of each of thedifferent glutamatergic pathways terminating in the nucleusaccumbens, namely hippocampus (memory), amygdala (emo-tion) and prefrontal cortex (cognition), and its interaction witha decreased dopamine, playing a relevant role inmotor behav-iour during aging. Further research should be aimed to deter-mine the emotional and motivational component of thedecreased spontaneous motor activity displayed by animalsand humans during aging.

Acknowledgments

The studies from our own laboratory referred in this articlehave been supported by the Spanish Ministry of Science andTechnology DGICYT (SAF2000-0112, SAF2003-0448 andSAF2006-01554), the Comunidad Autónoma de Madrid (CAM08.5/0020.1/03) and The University Complutense (PR45/05/14199/UCM). The authors thank very much the collaborationof Pedro Garrido and Marta de Blas and the technicalassistance of Angela Amores.

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Glutamate–dopamine–GABA interactions in the aging basal ganglia

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