Regional variations in the physiology of the rat caudate-putamen. 2. Effects of amphetamine and amphetamine induced dopamine release on basal and cortical stimulation evoked multiple unit activity

Summary. Dopaminergic terminals within the caudate-putamen are located in an ideal position to modulate the corticostriatal system. Since this is the major afferent system of the striatum, dopamine has very powerful effects on striatal electrophysiological activity. The striatum is a regionally specialized multifunctional nucleus. It is therefore important to determine if dopamine has the same modulatory effects within different areas of the nucleus. The effects of 2.5 mg/Kg D-amphetamine (IP) on cortical stimulation evoked and basal multiple unit activity (MUA) was measured in 7 dorsal and 7 ventral striatal areas of the urethane anaesthetized rat. In general, amphetamine caused an increase in the basal activity and a decrease in the cortical stimulation evoked activity. However, there were both qualitative and quantitative regionally dependent differences in these responses. The effect on basal MUA was more pronounced in the dorsal and caudal areas whereas the effect on cortical stimulation evoked MUA was more pronounced in the ventral areas. The electrophysiological effects of amphetamine within the striatum were correlated with its regionally dependent effects on extracellular dopamine. This produced a measure of the effects of striatal dopamine on regional electrophysiological activity. This information was also used to determine the mathematical relationship between dopamine concentration change and the change in MUA. These data indicate that the excitatory effects of amphetamine-induced dopamine release on the non-stimulated MUA progressively increase along the rostro-caudal axis of the nucleus. In addition, the effects were more pronounced in the ventromedial as compared to the ventrolateral areas. These effects correlated best with the rate of change in dopamine concentration. In the dorsal striatum amphetamine-induced increases in dopamine had a regionally homogeneous inhibitory effect on the stimulated MUA. In the ventral striatum however, it had a progressively stronger effect along the rostro-caudal axis. These effects correlated best with the absolute change in dopamine concentration. Received April 17, 2002; accepted December 2, 2002 Published online March 5, 2003 Authors' address: Dr. G. Glynn, School of Pharmacy and Allied Health Professions, Creighton University, 2500 California Plaza, Omaha, NE 68178, U.S.A., e-mail: GGlynn@creighton.edu     

Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine

Methamphetamine (m-AMPH) or saline was repeatedly administered to rats. One week later, the caudate-putamen of the m-AMPH-treated rats revealed a decrease in both [3H]mazindol-labeled dopamine uptake sites and tissue dopamine content. Moreover, the resulting pattern of decline in these measures was regionally heterogeneous. The ventral caudate-putamen displayed the greatest decrease in both [3H]mazindol binding and dopamine content while the neighboring nucleus accumbens and the dorsal caudate-putamen remained relatively intact. These results indicate a regional difference in the susceptibility of striatal dopaminergic terminals to the neurotoxic effects of methamphetamine.     

Caudate-putamen and nucleus accumbens extracellular acetylcholine responses to methamphetamine binges

Exposure of experimental animals to an escalating dose, multiple binge pattern of methamphetamine administration results in the progressive emergence of a unique behavioral profile, which includes a significant decrease in the duration of the stereotypy phase as well as a profound increase and qualitative change in the locomotor activation. This behavioral profile is associated with a selective decrease in the caudate-putamen but not nucleus accumbens extracellular dopamine response. Since the acetylcholine interneurons in these regions are partly under the control of the mesostriatal and mesoaccumbens dopamine inputs, changes in the activation of these interneurons should parallel the regionally differential dopamine responses during multiple binge treatment. Therefore, we characterized the caudate-putamen and nucleus accumbens extracellular acetylcholine responses to escalating-dose, multiple binge methamphetamine administration. An acute methamphetamine binge decreased acetylcholine levels in caudate-putamen, but had no effect on levels in nucleus accumbens. Furthermore, corresponding to the selective decrease in the dopamine response, the caudate-putamen but not nucleus accumbens extracellular acetylcholine response exhibited tolerance with repeated binge exposures; i.e. the decrease in acetylcholine associated with the acute methamphetamine binge was attenuated with multiple binge exposure. These results are consistent with our hypothesis and suggest that the regionally differential acetylcholine responses reflect one functional consequence of the escalating-dose, multiple binge stimulant treatment.     

Persistence of the releasable pool of CCK in the rat nucleus accumbens and caudate-putamen following lesions of the midbrain

Previous studies have identified populations of dopamine neurons in the midbrain that colocalize cholecystokinin some of which project to the nucleus accumbens and caudate-putamen. The contribution of dopamine-colocalized peptide to the total releasable pool of cholecystokinin in these brain regions was investigated using microdialysis. Dopamine, dihydroxyphenylacetic acid and cholecystokinin immunoreactive levels in dialysates of the posterior medial nucleus accumbens and medial caudate-putamen were determined following 6-hydroxydopamine lesions of the ventral tegmental area and substantia nigra or transection of the medial forebrain bundle. An 89–99% depletion in basal extracellular dihydroxyphenylacetic acid and an 87–99% decrease in veratridine-evoked extracellular dopamine levels was observed in the nucleus accumbens and caudate-putamen, 4 weeks after 6-hydroxydopamine lesion. No statistically significant difference was observed between lesioned and control animals in the basal or veratridine-evoked extracellular level of cholecystokinin immunoreactivity in either region. Similarly, transection of the medial forebrain bundle failed to significantly deplete the releasable pool of cholecystokinin immunoreactivity in the nucleus accumbens or caudate nucleus despite 89–99% depletions of dopamine and its metabolite. These data suggest that midbrain dopamine or non-dopaminergic cells are not the primary source of releasable cholecystokinin in the posterior medial nucleus accumbens and medial caudate-putamen measured by microdialysis.     

Effects of hypoxic-ischemic brain damage on dopaminergic markers in the neonatal rat: a regional autoradiographic analysis.

Dopamine has been implicated as an endogenous substance that may mediate neuronal death after hypoxic-ischemic insult. Using semiquantitative autoradiography, we studied the effect of perinatal hypoxic-ischemic injury on dopamine binding sites in rat brain. Experimental injury resulted in a substantial decrease in dopamine type-1 (D1) and forskolin (adenylate cyclase) binding sites. In contrast, markers for dopamine type-2 (D2) sites and for dopamine uptake were unaffected in lesioned animals. Changes within dopaminergic pathways were variable, with reduction in binding being encountered mainly in components of the extrapyramidal motor system: caudate-putamen, -61%; globus pallidus, -64%; entopeduncular nucleus, -60%; and substantia nigra, -69%. Furthermore, the topography of D1 receptor loss within the caudate-putamen was not uniform, with the greatest decrement in dorsolateral regions. Reduced D1 versus D2 receptor activation may underlie extrapyramidal movement disorders that appear as a consequence of perinatal hypoxic-ischemic insult.     

A comparative study of the dopamine-acetylcholine interaction in telencephalic structures of the rat and of a reptile, the lizard Gekko gecko

The present study describes an investigation in which the dopamine-acetylcholine interaction in the caudate-putamen of the rat was compared with that in other telencephalic regions of the rat and in telencephalic regions of the Gekko gecko. For the rat these regions included the nucleus accumbens and the entorhinal and parietal cortices, for the gekko the striatum, the dorsal ventricular ridge and the cortex. All investigated brain regions in the rat and the gekko receive dopaminergic projections from the ventral mesencephalon. The cholinergic fibers in the rat caudate-putamen and nucleus accumbens are mainly from intrinsic origin, whereas these fibers in the cortex of the rat and in the striatum and the cortex of the gekko predominantly originate from extrinsic sources. The dopamine-acetylcholine interaction was studied at the level of dopamine receptor-mediated inhibition of the depolarization-induced release of radiolabeled acetylcholine in vitro. It appeared that in the caudate-putamen and nucleus accumbens but not in the entorhinal and parietal cortices of the rat stimulation of D2 receptors inhibits the release of acetylcholine. Although we could demonstrate the presence of D2 dopamine receptor binding in all studied telencephalic structures of the gekko, D2 receptor agonists were unable to inhibit the release of radiolabeled acetylcholine in these regions.     

Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase.

A hitherto unsuspected degree of regional topographic organization in the noradrenergic nucleus, locus coeruleus, was revealed by the use of retrograde transport of horseradish peroxidase (HRP) from terminal areas receiving noradrenergic innervation. HRP was injected into hippocampus, hypothalamus, thalamus, caudate-putamen, septum, amygdala-piriform cortex, cerebellum and cortex. Successful transport was obtained from all areas, including the caudate-putamen and cerebral cortex. The pattern of HRP positive cells in the ipsilateral locus coeruleus was markedly different depending on the location of the HRP injection. Thus, hippocampal injections labeled cells in the dorsal locus coeruleus but not at all in the ventral tip. Injections of HRP into caudate-putamen or cerebellum labeled the ventral tip along with the rest of the dorsal portion. HRP injections into the septum labeled cells only in the dorsal half of the dorsal locus coeruleus. There thus exists a three tier division of locus coeruleus into the ventral one third, dorsal one third and intermediate one third. A further division was seen in the anterior-posterior plane with HRP injections into the thalamus labeling the posterior pole of locus very intensely but with little transport to more anterior levels; conversely HRP injection into the hypothalamus resulted in intense labeling only in the anterior pole of locus coeruleus. Amygdala-piriform cortex HRP injections revealed a further pattern with very intensely reactive cells scattered sparsely throughout the nucleus. Cortical HRP injections yielded weaker labeling also in occasional, scattered cells. All HRP transport to locus coeruleus was shown to be noradrenergic by degeneration with 6-hydroxydopamine and due to terminal, rather than fiber of passage, uptake by control injection into the dorsal NA bundle. It is concluded that the locus coeruleus is not an homogenous nucleus with respect to the origin of the noradrenergic projections to sundry forebrain, spinal and cerebellar areas but is comprised of distinct subdivisions of noradrenergic neurons.     

Adrenalectomy decreases corticotropin-releasing hormone gene expression and increases noradrenaline and dopamine extracellular levels in the rat lateral bed nucleus of the stria terminalis

The bed nucleus of the stria terminalis (BNST) has a high density of corticotropin-releasing hormone (CRH)-containing neurons that are significantly innervated by noradrenergic and dopaminergic nerve terminals. This limbic structure is involved in the extrahypothalamic response to stress. The purpose of the present work is to study whether the absence of glucocorticoids, induced by a long-term adrenalectomy, regulates CRH gene expression and noradrenaline and dopamine extracellular levels in the rat BNST. The results showed that adrenalectomy decreases CRH mRNA in the dorsal lateral BNST but not in the ventral lateral BNST. Adrenalectomy also decreases CRH-like immunoreactivity both in BNST subnuclei and in the central nucleus of the amygdala. In addition, adrenalectomy significantly increases noradrenaline and dopamine extracellular levels in the lateral BNST. The present results suggest that adrenalectomy regulates CRH gene expression and noradrenaline and dopamine extracellular levels in the BNST in an opposite way. Thus, the present study adds novel evidence further supporting that the BNST and the central nucleus of the amygdala form part of an adrenal steroid-sensitive extrahypothalamic circuit that has been involved in fear and anxiety responses and in clinical syndromes such as melancholic depression, posttraumatic stress disorders, and addiction.     

Dopaminergic Innervation of the Monkey Caudal Nucleus Accumbens

Previous studies have shown that the monkey (Macaca fuscata) caudal nucleus accumbens is neurochemically subdivided into three subdivisions, the medial, dorsolateral, and ventral subdivisions. In this study, dopaminergic innervation of these three subdivisions was studied in detail for the first time by light microscopic immunocytochemistry using a monoclonal antibody against dopamine. The patterns of dopamine fiber distribution were heterogeneous even within each subdivision. The medial subdivision showed extremely dense accumulation of thick dopamine-immunoreactive varicose fibers. Some areas with densely packed cells in Nissl-stained sections corresponded to dopamine-poor areas, while another area with concentrated cells corresponded to a dopamine-rich area. There were also areas with sparse cells that contained a few dopamine-immunoreactive fibers. In the dorsolateral subdivision thick dopamine-immunoreactive varicose fibers were found sparsely among diffuse puncta. The ventral subdivision exhibited similar profiles to those in the dorsolateral one, and there were also many characteristic spiral dopamine-immunoreactive fibers of passage. The present study indicates that the dopaminergic structures of the monkey nucleus accumbens differ according to the subterritories, and are morphologically different from those in the caudate-putamen.     

Chronic neuroleptic administration decreases extracellular GABA in the nucleus accumbens but not in the caudate-putamen of rats.

The extracellular levels of gamma-aminobutyric acid (GABA) in the caudate-putamen and the nucleus accumbens of rats following administration of haloperidol decanoate, fluphenazine decanoate, or vehicle for 8 months were assessed using intracranial microdialysis. Basal levels of extracellular GABA were significantly decreased in the nucleus accumbens of both neuroleptic-treated groups while levels of GABA in the caudate-putamen were not significantly different between groups. These results provide evidence for selective chronic neuroleptic-induced effects on in vivo GABA function in different terminal regions containing dopamine receptors.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390

The regional distribution of D1 dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D1 antagonist [3H]SCH 23390 as a ligand. The binding of [3H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (Kd = 2.05 nM); it occurred at a single population of sites and possessed the pharmacological features of the D1 DA receptor. The highest densities of [3H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA1 and dentate gyrus). In the anteromedial and suprarhinal cortices, [3H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [3H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [3H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [3H]SCH 23390 has also been studied in detail in striatal subregions. The density of D1 receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D1 sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.     

Regional localization of dopamine and ionotropic glutamate receptor subtypes in striatolimbic brain regions

Localization of dopamine (D(1)-, D(2)-like, and D(4)) and ionotropic glutamate (NMDA, AMPA, and KA) receptor subtypes within the striatolimbic forebrain remains incomplete, but basic to understanding the functional organization of this important brain region. We found that frontal cortical ablation supported colocalization of D(4) and NMDA receptors on corticostriatal afferents to caudate-putamen and nucleus accumbens in rat forebrain. Local injection of kainic acid into caudate-putamen, nucleus accumbens, or hippocampus produced massive local postsynaptic losses of D(1)- and D(2)-like, as well as NMDA, AMPA, and KA receptors, and kainic acid ablation of hippocampal-striatal projections indicated the selective expression of presynaptic NMDA and KA autoreceptors. Degeneration of nigrostriatal dopamine projections with 6-hydroxydopamine showed that all three glutamatergic subtypes exist as heteroceptors on nigrostriatal dopaminergic terminals. Our findings suggest common interactions between excitatory glutamatergic and inhibitory dopaminergic receptors in rat forebrain. Further localization of these receptor subtypes in striatolimbic forebrain should help to clarify their contributions to the pathophysiology of neuropsychiatric disorders and their treatment.     

C-type natriuretic peptide (CNP) regulates cocaine-induced dopamine increase and immediate early gene expression in rat brain

The neuropeptide C-type natriuretic peptide (CNP) is the primary biologically active natriuretic peptide in brain. Using in situ hybridization, the present report demonstrates that CNP regulates egr-1, c-fos and junB immediate early gene expression in rat brain. In the frontal cortex, CNP induced immediate early gene expression whereas it inhibited dose-dependently the cocaine-induced early gene expression in the dopaminergic projection fields nucleus accumbens and caudate-putamen. CNP may produce its effect directly on dopaminergic neurons because we found that its receptor, guanylyl cyclase GC-B, was expressed in the mesencephalon where dopaminergic neurons originate, as well as in their projection fields. The inhibition by CNP of the early gene expression elicited by cocaine in the caudate-putamen is correlated with a CNP-evoked decrease in cocaine-induced rise in extracellular dopamine, measured by in vivo microdialysis experiments. The significance of the inhibition of cocaine-induced dopamine release and early gene induction by the endogenous peptide CNP is demonstrated by data indicating that CNP reduced the cocaine-induced spontaneous locomotor activation. By inhibiting dopaminergic neuronal activity, CNP represents a potential negative regulator of related behavioural effects of cocaine.     

Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat

Striatal cholinergic interneurons located in the dorsal striatum and nucleus accumbens are amenable to influences of the dopaminergic mesolimbic pathway, which is a pathway involved in reward and reinforcement and targeted by several drugs of abuse. Dopamine and acetylcholine neurotransmission and their interactions are essential to striatal function, and disruptions to these systems lead to a variety of clinical disorders. Dopamine regulates acetylcholine release through dopamine receptors that are localized directly on striatal cholinergic interneurons. The dopamine D2 receptor, which attenuates acetylcholine release, has been implicated in drug relapse and is targeted by therapeutic drugs that are used to treat a variety of neurological disorders including Tourette Syndrome, Parkinson's disease and schizophrenia. The present study provides the first direct evidence for the localization of dopamine D2 receptors on striatal cholinergic interneurons of the rat brain using dual labeling immunocytochemistry procedures. Using light microscopy, dopamine D2 receptors were localized on the cell somata and dendritic and axonal processes of striatal cholinergic interneurons in the dorsal striatum and nucleus accumbens of the rat brain. These findings provide a foundation for understanding the specific roles that cholinergic neuronal network systems and interacting dopaminergic signaling pathways play in striatal function and in a variety of clinical disorders including drug abuse and addiction.     

Interactions between imidazoline binding sites and dopamine levels in the rat nucleus accumbens

Imidazoline binding sites are present in the striatal complex and in the extended amygdala and have been implicated in mood disorders. In this report we analysed the influence of these sites on the functional activity of the mesolimbic dopaminergic transmission, one of the major brain systems involved in the regulation of motivation and reward. We studied the effects of two imidazoline ligands, S23229 and S23230 (respectively S(+) and R(-) enantiomers of the S22687 or (5-[2-methyl phenoxy methyl] 1,3-oxazolin-2-yl) amine), on extracellular dopamine in the nucleus accumbens using microdialysis in freely moving rats. We compared these imidazoline ligands to cocaine, a dopamine uptake blocker known to increase extracellular dopamine concentrations. S23229 dose-dependently increased extracellular dopamine and locomotor activity. S23230 dose-dependently increased extracellular dopamine and produced a near-significant dose-effect on locomotor activity. S23229 had a stronger efficacy than S23230 and increased dopamine levels in the nucleus accumbens at an extent similar to the one of cocaine. These results suggest that central imidazoline binding sites could contribute to the functional regulation of the mesolimbic dopaminergic system.     

Altered dopaminergic function in the prefrontal cortex, nucleus accumbens and caudate-putamen of an animal model of attention-deficit hyperactivity disorder — the spontaneously hypertensive rat

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for Attention-Deficit Hyperactivity Disorder (ADHD). The behavioural problems of ADHD have been suggested to be secondary to altered reinforcement mechanisms resulting from dysfunction of the mesolimbic and mesocortical dopaminergic systems. The present study therefore investigated whether there are regional differences in dopamine (DA) and acetylcholine (ACh) release and DA D₂-receptor function in SHR compared to their normotensive Wistar-Kyoto (WKY) controls. The DA D₂-receptor agonist, quinpirole, caused significantly greater inhibition of DA release from caudate-putamen but not from nucleus accumbens or prefrontal cortex slices of SHR relative to WKY. DA D₂-receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in DA release from nucleus accumbens slices of SHR compared to WKY suggesting increased efficacy of DA autoreceptors at low endogenous agonist concentrations in the nucleus accumbens of SHR. The electrically-stimulated release of DA was significantly lower in caudate-putamen and prefrontal cortex slices of SHR than in slices of WKY. This could be attributed to increased autoreceptor-mediated inhibition of DA release in caudate-putamen slices but not in the prefrontal cortex. No difference was observed between SHR and WKY with respect to DA D₂-receptor-mediated inhibition of ACh release from caudate-putamen or nucleus accumbens slices, suggesting that postsynaptic DA D₂-receptor function is not altered in SHR relative to WKY.     

Differential visualization of dopamine and norepinephrine uptake sites in rat brain using [3H]mazindol autoradiography

Mazindol is a potent inhibitor of neuronal dopamine (DA) and norepinephrine (NE) uptake. DA and NE uptake sites in rat brain have been differentially visualized using [3H]mazindol autoradiography. At appropriate concentrations, desipramine (DMI) selectively inhibits [3H]mazindol binding to NE uptake sites without significantly affecting binding to DA uptake sites. The localization of DMI-insensitive specific [3H] mazindol binding, reflecting DA uptake sites, is densest in the caudate-putamen, the nucleus accumbens, the olfactory tubercle, the subthalamic nucleus, the ventral tegmental area, the substantia nigra (SN) pars compacta, and the anterior olfactory nuclei. In contrast, the localization of DMI-sensitive specific [3H]mazindol binding, representing NE uptake sites, is densest in the locus coeruleus, the nucleus of the solitary tract, the bed nucleus of the stria terminalis, the paraventricular and periventricular nuclei of the hypothalamus, and the anteroventral thalamus. The distribution of DMI-insensitive specific [3H]mazindol binding closely parallels that of dopaminergic terminal and somatodendritic regions, while the distribution of DMI-sensitive specific [3H]mazindol binding correlates well with the regional localization of noradrenergic terminals and cell bodies. Injection of 6-hydroxydopamine, ibotenic acid, or colchicine into the SN decreases [3H]mazindol binding to DA uptake sites in the ipsilateral caudate-putamen by 85%. In contrast, ibotenic acid lesions of the caudate-putamen do not reduce [3H]mazindol binding to either the ipsilateral or contralateral caudate-putamen. Thus, the DA uptake sites in the caudate-putamen are located on the presynaptic terminals of dopaminergic axons originating from the SN.     

Distinct pharmacological regulation of evoked dopamine efflux in the amygdala and striatum of the rat in vivo

The pharmacological regulation of evoked extracellular dopamine was compared in the basolateral amygdaloid nucleus (BAN) and caudate-putamen (CP) of the urethane-anesthetized rat. The effects of drugs, which alter dopamine uptake, release or degradation, were examined. Dopamine efflux was elicited by electrical stimulation of ascending dopamine fibers and was monitored by fast-scan cyclic voltammetry at Nafioncoated, carbon-fiber microelectrodes. Dopamine uptake inhibitors, nomifensine (25 mg/kg) and cocaine (20 mg/kg), and the dopamine receptor antagonist, haloperidol (0.5 mg/kg), robustly increased evoked extracellular dopamine in the CP. In sharp contrast, these drugs were much less effective in the BAN. The relative potencies of the uptake inhibitors varied between the two regions. Nomifensine was more potent than cocaine in the CP, whereas cocaine was more potent that nomifensine in the BAN. The monoamine oxidase inhibitor, pargyline (75 mg/kg), and the catechol-O-methyltransferase (COMT) inhibitor, Ro 40-7592 (40 mg/kg), had small or negligible effects in either region. No electrochemical evidence was found for the formation of 3-methoxytyramine, the dopamine metabolite formed by the action of COMT on released dopamine, on the time scale of the measurements in control or after pharmacological manipulation of the degradative enzymes for dopamine. The conclusions reached are: (1) potent mechanisms for uptake and autoreceptor inhibition of release, which exist in the CP to tightly control the concentration of extracellular dopamine, are considerably weaker in the BAN; (2) the extracellular clearance of evoked dopamine in the BAN and CP is the result of cellular uptake and not degradation; and (3) these results support the view that the pharmacological regulation of extracellular dopamine is regionally distinct in the brain. © 1995 Wiley-Liss, Inc.     

Dopamine and the diseased brain

Dysfunction of central dopaminergic neurotransmission has been implicated in a series of neuropsychiatric disorders, including Tourette's syndrome, schizophrenia, and drug and alcohol dependence. The behavioral and psychopathological manifestations of central dopaminergic dysfunction differ depending on the site of their neurobiological correlate. These sites may be found in the dorsal or ventral striatum, but also in cortical regions such as the limbic and prefrontal cortex, among other locations. A low basic dopamine turnover and an increase in the availability of dopamine D2 receptors in the caudate body have been associated with the severity of motor tics in Tourette's syndrome. In the ventral striatum and particularly in the nucleus accumbens, different drugs of abuse stimulate dopamine release and thus reinforce drug consumption. The downregulation of dopamine D2 receptors in this area of the brain has been associated with alcohol craving and an increase in the processing of alcohol-related stimuli in the medial prefrontal cortex. Brain imaging studies in which intrasynaptic dopamine release is manipulated in vivo have shown that increased subcortical dopamine release is associated with the pathogenesis of positive symptoms in schizophrenia. This review discusses a broad range of brain imaging and neuroendocrinological studies on dopaminergic dysfunction in neuropsychiatric disorders, including relevant findings on the basis of primate studies. In addition, the hypothesis is examined that phasic dopamine release is associated with salience attribution to external stimuli, insofar as it mediates reward anticipation in the ventral striatum and limbic cortex, habit formation in the dorsal striatum, and working memory function in the prefrontal cortex.     

Autoradiographic localization of D1 dopamine receptors in the rat brain with [H]SCH 23390

The regional distribution of D₁ dopamine (DA) receptors in the rat brain has been studied by quantitative autoradiography using the specific D₁ antagonist [³H]SCH 23390 as a ligand. The binding of [³H]SCH 23390 to striatal sections was saturable, stereospecific, reversible and of high affinity (K_d = 2.05nM); it occurred at single population of sites and possessed the pharmacological features of the D₁ DA receptor. The highest densities of [³H]SCH 23390 binding sites were found in the caudate-putamen, olfactory tubercle, nucleus accumbens and substantia nigra (especially in the pars compacta). High densities were also observed in the nucleus interstitialis striae terminalis, the anterior olfactory nucleus, the entopeduncular nucleus, the subthalamic nucleus, the claustrum and the amygdalohippocampal area. An intermediate labelling was found in the anteromedial and suprarhinal DA terminal fields of the cerebral cortex, the basolateral, medial and lateral amygdaloid nuclei, the endopiriform nucleus, the primary olfactory cortex, the globus pallidus, the superior colliculus (especially the superficial layer), the nucleus amygdaloideus corticalis and the dorsal hippocampus (molecular layer of the CA₁ and dentate gyrus). In the anteromedial and suprarhinal cortices, [³H]SCH 23390 binding was more concentrated in layers V and VI. Moderate levels of [³H]SCH 23390 were found in the thalamus, hypothalamus, the habenula, the ventral tegmental area, the posterior cingulate and entorhinal cortices, the supragenual dopamine terminal system and the cerebellum (molecular layer). This regional distribution of [³H]SCH 23390 closely correlated (except for the cerebellum) with the reported distribution of dopaminergic terminals. The topographical distribution of [³H]SCH 23390 has also been studied in detail in striatal subregions. The density of D₁ receptors was much greater in the ventrolateral sector and medial margin of the striatum than in the ventromedial and dorsolateral sectors. A rostrocaudal decrease in the densities of D₁ sites was also found along the rostrocaudal axis of the caudate-putamen. These lateral to medial and anteroposterior gradients overlapped with the density of the dopaminergic afferents.