Dopamine Release and Uptake Dynamics within Nonhuman Primate StriatumIn Vitro

Abstract

The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration ([DA] o ) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro in striatal sections from the common marmoset (Callithrix jacchus).[DA] o released by a single stimulus pulse varied threefold along a ventromedial-dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis-Menten kinetics, rate maximum, V max , varied with region: both [DA] o and V max were greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. [DA] o , V max , and regional variation were two-to threefold greater than in rodent caudatoputamen.In addition, steady-state [DA] o at physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of [DA] o by these mechanisms differed significantly between limbic-and motor-associated domains.These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.Key words: Parkinson's disease; basal ganglia; DA transporter; DA uptake; autoreceptor; cocaine The putamen of the primate striatum performs major sensorimotor, cognitive, and emotive functions. A central component of the basal ganglia, the putamen receives the main corticostriatal inputs from the motor, premotor, supplementary motor, and sensorimotor cortices (Kunzle, 1975(Kunzle, , 1977(Kunzle, , 1978Jones et al., 1977;Selemon and Goldman-Rakic, 1985). In turn, loss of dopaminergic innervation underlies the motor dysfunctions of Parkinson's disease (PD) (Hornykiewicz, 1966;Kish et al., 1988). Furthermore, studies using [18 F]-dopa positron emission tomography imaging, HPLC, and [ 3 H]-mazindol binding in PD and in intermediate primate 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-parkinsonism indicate that dopamine (DA) deinnervation follows a regionspecific pattern of vulnerability, beginning in dorsolateral putamen (Elsworth et al., 1987;Kish et al., 1988;Moratella et al., 1992;Antonini et al., 1995). The functions of the intact putamen are topographically compartmentalized along a dorsolateral-ventromedial axis (Haber and McFarland, 1999) with respect to corticostriatal (Kunzle, 1975(Kunzle, , 1977Selemon and Goldman-Rakic, 1985...

Prominent Role of α3/α6β2*nAChRs in Regulating Evoked Dopamine Release in Primate Putamen: Effect of Long-Term Nicotine Treatment

“…Although previous work had shown that dopamine release and uptake share many characteristics in the putamen and caudate, there seems to be a continuum of distinct functional domains from ventral to dorsal areas within these two brain regions, with dopamine release and uptake being significantly greater in the dorsal compared with the ventral regions (Cragg et al, 2000(Cragg et al, , 2002. We therefore investigated ␣3/␣6␤2* and ␣4␤2* nAChR-modulated functional properties in the ventral and dorsal striatal areas, with a focus on the putamen because it is more vulnerable in Parkinson's disease (Hornykiewicz, 2001).…”

“…Moreover, this anatomical diversity is associated with heterogeneity in striatal dopamine function (Cragg et al, 2000;McCallum et al, 2006b). The heterogeneous nature of the putamen is further illustrated by findings that there is a clear ventral-to-dorsal gradient in striatal dopaminergic cell loss with denervation (Song and Haber, 2000;McCallum et al, 2006b).…”

Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins

“…[60][61][62] The dynamics of dopamine release, uptake kinetics, regulation by firing frequency and presynaptic autoreceptor function in the human striatum, which consists of a distinct caudate nucleus and putamen, also differs considerably from rodent striatum. 63,64 Hence, the pharmacological response in cortical or striatal sites to antipsychotic drugs may be different in primate brain than in mouse brain resulting in potentially different transcriptome profiles.…”

Decrease in α3*/α6*Nicotinic Receptors but Not Nicotine-Evoked Dopamine Release in Monkey Brain after Nigrostriatal Damage

“…Although stimulation-evoked release has been measured from monkey striatum in vitro using voltammetry (Cragg et al, 2000) and, more recently, nicotine-stimulated release has been measured in vivo with positron emission tomography (Marenco et al, 2004), nicotine-evoked [ 3 H]dopamine release from synaptosomes has not previously been studied using monkey brain, although this approach is widely used with rodent preparations (Wonnacott, 1997;Grady et al, 2001;Champtiaux et al, 2003;Quik et al, 2003). Because this technique offers the advantage that it allows for the quantitative determination of evoked-release under well defined experimental conditions, we conducted experiments to establish its feasibility using monkey synaptosomes.…”

“…Stimulation-evoked release has previously been measured from control monkey striatum in vitro using voltammetry (Cragg et al, 2000); nicotine-stimulated release has been measured in vivo with positron emission tomography (Marenco et al, 2004). However, nicotine-evoked […”