Elsevier

Brain Research

Volume 936, Issues 1–2, 17 May 2002, Pages 58-67
Brain Research

Research report
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat

https://doi.org/10.1016/S0006-8993(02)02542-8Get rights and content

Abstract

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.

Introduction

The medial prefrontal cortex (mPFC) has been implicated in the regulation of cognition and emotion in rats, monkeys and humans. Additionally, it has been suggested that this structure plays a role in nearly every major mental disorder in humans. The mPFC is heterogeneous and consists of several subregions in the rat: the dorsally localized anterior cingulate cortex and the more ventrally localized prelimbic and infralimbic cortices [9]. The patterns of afferent and efferent projections differ between each of these subregions [9], [32] and prior research indicates that these subdivisions are associated with different behavioral functions [9], [29].

The mesocortical dopaminergic projection to the mPFC has been linked to stress, drug abuse, and schizophrenia [1], [15], [37]. This pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to the mPFC [11]. However, the dopaminergic afferent input to the mPFC is not homogenous, rather, innervation density varies by subregion [8]. The dopaminergic innervation is particularly dense in the prelimbic/infralimbic areas but is much sparser in the anterior cingulate subregion [38]. In addition to differences in innervation densities, there are differences in dopamine transporter (DAT) densities between these subregions [33]. The DAT is a critical protein for DA regulation as it is responsible for the reuptake of DA from the synapse.

It has been demonstrated that blockade of the norepinephrine transporter (NET) increases extracellular DA levels in the mPFC, providing evidence that NET is also involved in clearing DA in the mPFC of the rat [3], [17], [30]. The ability of NET to clear DA is significant, as there is an increased innervation of NE terminals compared to DA terminals in the mPFC and this NE innervation is relatively homogenous [34]. It has been suggested that increases in synaptic DA concentrations in the mPFC may be due largely to blockade of the more prevalent NET, rather than of DAT [3], [30]. NET actually possesses a slightly higher affinity for DA than for NE [31]. However, previous microdialysis studies have not distinguished between the mPFC subregions in the regulation of DA release by NET. This raises the possibility of subregional variation in the relative importance of NET versus DAT in the clearance of extracellular DA.

Despite these neuroanatomical findings, few functional, in vivo, neurochemical studies have distinguished between the subregions of the mPFC. Thus, the principal aim of the present study was to examine the subregional effects of DAT and NET blockers on in vivo DA release in the rat mPFC. In order to determine the relative functional contributions of DA and NE systems in the regulation of DA levels within mPFC subregions, ligands that vary in selectivity for DAT versus NET blockade were perfused directly into either the dorsal (anterior cingulate/frontal cortices) or ventral (prelimbic/infralimbic cortices) mPFC. These drugs included the DA, NE, and serotonin (5-HT) uptake blocker/releaser amphetamine (AMPH), the DAT/NET blocker nomifensine (NOM), the selective DAT blocker GBR 12909, and the selective NET blocker desmethylimipramine (DMI). In vivo microdialysis was used to examine extracellular DA concentrations before, during, and after drug administration.

These results were contrasted with the effects of AMPH and NOM infusions in the anterodorsolateral caudate-putamen (CP). This structure is innervated by the nigrostriatal DA system but receives no noradrenergic input [11]. Numerous studies have identified differences between the regulation of the nigrostriatal and mesocortical DA systems [2], [7].

Section snippets

Animals and surgery

Male Sprague–Dawley rats (250–350 g) were housed in group cages in a 12:12 h light/dark environment. Food and water were available ad libitum. Animals were anesthetized intramuscularly with a mixture of ketamine (70 mg/kg) and xylazine (6 mg/kg) prior to surgery. Rats were fixed in a stereotaxic apparatus and burr holes were drilled above either the mPFC (AP +3.2, ML ±0.8) or the anterior CP (AP +1.2, ML ±3.4) [27]. Dura was removed carefully and stainless steel guide cannulae (21 ga) were

Baseline dopamine

Baseline concentrations of extracellular dopamine in experiments 1–3 are shown in Table 1. The anterior cingulate subregion of the mPFC exhibited the lowest concentration of dopamine, 0.40±0.02 pg/20 μl dialysate (equivalent to 2.64 fmol/20 μl; n=109). The prelimbic/infralimbic subregion had a higher baseline concentration, 0.80±0.04 pg/20 μl dialysate (equivalent to 5.28 fmol/20 μl; n=113), while the mean concentration in the anterodorsolateral CP was approximately 10-fold higher: 5.44±0.40

Discussion

The results of the present study demonstrate that intracortical administration of the biogenic amine releaser AMPH produces differential increases in extracellular DA between the dorsal (frontal/anterior cingulate) and ventral (prelimbic/infralimbic) subregions of the mPFC. At the highest concentration employed, 100 μM, AMPH-induced DA efflux was significantly greater in the prelimbic, relative to the anterior cingulate, cortex. At this concentration, AMPH infusions also produced a

Acknowledgements

This study was supported by the Department of Veterans Affairs Medical Center and grant MH 52220 to E.A.P. We wish to thank Dr Bryan Yamamoto for use of his histological equipment. We would also like to thank Sam Crish and Betty Raker for their technical assistance and Murali Jatla and Chris Masters for their help in probe assembly.

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