Research reportEffects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat
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.
References (40)
- et al.
Regional and laminar density of the dopamine innervation in adult rat cerebral cortex
Neuroscience
(1987) - et al.
The origin and distribution of dopamine-containing afferents to the rat frontal cortex
Brain Res.
(1978) - et al.
Cloning and functional characterization of a cocaine-sensitive dopamine transporter
FEBS Lett.
(1991) - et al.
In vivo electrochemical studies of monoamine release in the medial prefrontal cortex of the rat
Neuroscience
(1989) - et al.
Effect of amphetamine on extracellular acetylcholine and monoamine levels in subterritories of the rat medial prefrontal cortex
Eur. J. Pharmacol.
(2000) - et al.
Evidence for carrier-mediated efflux of dopamine from corpus striatum
Biochem. Pharmacol.
(1982) - et al.
Organization of catecholamine neurons projecting to the frontal cortex in the rat
Brain Res.
(1978) - et al.
Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum
Neuroscience
(1990) - et al.
Effects of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine
Eur. J. Pharmacol.
(1977) - et al.
Regional concentrations of noradrenaline and dopamine in the frontal cortex of the rat: dopaminergic innervation of the prefrontal subareas and lateralization of prefrontal dopamine
Brain Res.
(1982)
Topographical distribution of dopaminergic innervation to dopaminergic receptors of the anterior cingulate cortex of the rat
Brain Res.
Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level
Neuroscience
A neurochemical heterogeneity of the rat striatum as measured by in vivo electrochemistry and microdialysis
Brain Res.
In vivo measurement of extracellular dopamine and DOPAC in rat striatum after various dopamine-releasing drugs; implications for the origin of extracellular DOPAC
Eur. J. Pharmacol.
Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex
J. Neurochem.
Pharmacology of mesocortical dopamine neurons
Pharmacol. Rev.
Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals
J. Neurochem.
In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens
J. Neurochem.
The dopamine transporter: immunochemical characterization and localization in brain
J. Neurosci.
Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum
J. Neurophysiol.
Cited by (128)
Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance
2019, Neurochemistry InternationalCitation Excerpt :Similar interference from reminiscent noradrenergic nerve fibers is not possible, since the striatum is missing noradrenergic innervation. However, noradrenergic nerve fibers may affect clearance of dopamine in the prefrontal cortex (Fuxe, 1965; Mazei et al. 2002; Swanson and Hartman, 1975). Furthermore, the motor behavior was impaired after the DSP4 lesion when the released dopamine levels were enhanced.
A novel dopamine D1 receptor agonist excites delay-dependent working memory-related neuronal firing in primate dorsolateral prefrontal cortex
2019, NeuropharmacologyCitation Excerpt :There has also been suggestive data from in vivo recordings in monkeys where DA application was excitatory (Jacob et al., 2013; Sawaguchi et al., 1988, 1990), but these studies did not utilize a D1R antagonist to test for receptor actions. This is essential, as DA can have excitatory actions via D2R (Ott et al., 2014), or via uptake and rerelease by NE terminals (Lewis et al., 2001; Mazei et al., 2002), e.g. onto postsynaptic alpha-2A-AR (Wang et al., 2007). In vivo recordings have shown a marked reduction in the firing of dlPFC neurons following iontophoresis of high dose D1R antagonist (Williams and Goldman-Rakic, 1995), consistent with endogenous excitatory actions of DA at D1R.
Development of a non-human primate model to support CNS translational research: Demonstration with D-amphetamine exposure and dopamine response
2019, Journal of Neuroscience MethodsDopamine and stress
2019, Stress: Physiology, Biochemistry, and Pathology Handbook of Stress Series, Volume 3