Dopamine-rich Brain Areas Research Articles

Expected value and prediction error abnormalities in depression and schizophrenia

The dopamine system has been linked to anhedonia in depression and both the positive and negative symptoms of schizophrenia, but it remains unclear how dopamine dysfunction could mechanistically relate to observed symptoms. There is considerable evidence that phasic dopamine signals encode prediction error (differences between expected and actual outcomes), with reinforcement learning theories being based on prediction error-mediated learning of associations. It has been hypothesized that abnormal encoding of neural prediction error signals could underlie anhedonia in depression and negative symptoms in schizophrenia by disrupting learning and blunting the salience of rewarding events, and contribute to psychotic symptoms by promoting aberrant perceptions and the formation of delusions. To test this, we used model based functional magnetic resonance imaging and an instrumental reward-learning task to investigate the neural correlates of prediction errors and expected-reward values in patients with depression (n=15), patients with schizophrenia (n=14) and healthy controls (n=17). Both patient groups exhibited abnormalities in neural prediction errors, but the spatial pattern of abnormality differed, with the degree of abnormality correlating with syndrome severity. Specifically, reduced prediction errors in the striatum and midbrain were found in depression, with the extent of signal reduction in the bilateral caudate, nucleus accumbens and midbrain correlating with increased anhedonia severity. In schizophrenia, reduced prediction error signals were observed in the caudate, thalamus, insula and amygdala-hippocampal complex, with a trend for reduced prediction errors in the midbrain, and the degree of blunting in the encoding of prediction errors in the insula, amygdala-hippocampal complex and midbrain correlating with increased severity of psychotic symptoms. Schizophrenia was also associated with disruption in the encoding of expected-reward values in the bilateral amygdala-hippocampal complex and parahippocampal gyrus, with the degree of disruption correlating with psychotic symptom severity. Neural signal abnormalities did not correlate with negative symptom severity in schizophrenia. These findings support the suggestion that a disruption in the encoding of prediction error signals contributes to anhedonia symptoms in depression. In schizophrenia, the findings support the postulate of an abnormality in error-dependent updating of inferences and beliefs driving psychotic symptoms. Phasic dopamine abnormalities in depression and schizophrenia are suggested by our observation of prediction error abnormalities in dopamine-rich brain areas, given the evidence for dopamine encoding prediction errors. The findings are consistent with proposals that psychiatric syndromes reflect different disorders of neural valuation and incentive salience formation, which helps bridge the gap between biological and phenomenological levels of understanding.

Caffeine modulates attention network function

The present work investigated the effects of caffeine (0 mg, 100 mg, 200 mg, 400 mg) on a flanker task designed to test Posner’s three visual attention network functions: alerting, orienting, and executive control [Posner, M. I. (2004). Cognitive neuroscience of attention. New York, NY: Guilford Press]. In a placebo-controlled, double-blind study using a repeated-measures design, we found that the effects of caffeine on visual attention vary as a function of dose and the attention network under examination. Caffeine improved alerting and executive control function in a dose–response manner, asymptoting at 200 mg; this effect is congruent with caffeine’s adenosine-mediated effects on dopamine-rich areas of brain, and the involvement of these areas in alerting and the executive control of visual attention. Higher doses of caffeine also led to a marginally less efficient allocation of visual attention towards cued regions during task performance (i.e., orienting). Taken together, results of this study demonstrate that caffeine has differential effects on visual attention networks as a function of dose, and such effects have implications for hypothesized interactions of caffeine, adenosine and dopamine in brain areas mediating visual attention.

Cortical dopaminergic neurotransmission in rats intoxicated with lead during pregnancy. Nitric oxide and hydroxyl radicals formation involvement

It is well established that low level Pb-exposure is associated with a wide range of cognitive and neurobehavioral dysfunctions in children. In fact, Pb-induced damage occurs preferentially in the prefrontal cerebral cortex, hippocampus and cerebellum — the anatomical sites which are crucial in modulating emotional response, memory and learning. Previously it was also shown that nitric oxide (NO) signaling pathway as well as glutamatergic neurotransmission are both involved in brain development, neurotoxicity and neurodegeneration processes whereas Pb 2+ interfere with both. For this reason we investigated the effect of ontogenetic Pb 2+ exposure on dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) of rats after amphetamine (AMPH) and/or 7-nitroindazole (7-NI) administration. Furthermore, the possible role of oxidative stress in Pb 2+-induced neurotoxicity in prenatally Pb 2+-treated rats was explored in the content of hydroxyl radical (HO •) species in mPFC after AMPH and/or 7-NI injection, assessed by HPLC analysis of 2.3-dihydroxybenzoic acid (2.3-DHBA) — spin trap product of salicylate. As shown, the results of this study suggest that Pb 2+ exposure during intrauterine life did not substantially affect cortical dopaminergic neurotransmission in adult offspring rats evaluated by means of microdialysis of mPFC and the content of the cortical HO •. It is likely that striatum, nucleus accumbens or other dopamine rich brain areas are more intricately associated with Pb 2+ precipitated behavioral, dopamine — dependent impairments observed in mammalians.

Brain levels of neuropeptides in human chronic methamphetamine users

Animal data show that neuropeptide systems in the dopamine-rich brain areas of the striatum (caudate, putamen, and nucleus accumbens) are influenced by exposure to psychostimulants, suggesting that neuropeptides are involved in mediating aspects of behavioral responses to drugs of abuse. To establish in an exploratory study whether levels of neuropeptides are altered in brain of human methamphetamine users, we measured tissue concentrations of dynorphin, metenkephalin, neuropeptide Y, neurotensin, and substance P in autopsied brains of 16 chronic methamphetamine users and 17 matched control subjects. As expected, levels of most neuropeptides were enriched in dopamine-linked brain regions such as the nucleus accumbens and striatum of normal human brain. In contrast to animal findings of increased neuropeptide levels following short-term methamphetamine exposure, striatal neuropeptide concentrations were either normal or moderately decreased in the methamphetamine users. In other examined dopamine-poor cortical and subcortical brain areas, neuropeptide levels were generally either normal or variably reduced. Although the neuropeptide differences might be explained by methamphetamine-induced damage to neuropeptide-containing neurons, our human data are consistent with the possibility that, at least in the human striatum, long-term methamphetamine exposure leads to an adaptive process that is distinct from that which increases neuropeptide levels after acute methamphetamine exposure.

Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine

Phospholipids are essential components of cell membranes which may also function to mediate some of the behavioural effects of dopamine receptor stimulation caused by psychostimulant drugs. Neuroimaging and pharmacological data suggest that abnormal brain metabolism of phospholipids might explain some of the consequences of chronic exposure to drugs of abuse including drug craving. We previously reported decreased activity of calcium-stimulated phospholipase A 2 (Ca-PLA 2) in autopsied putamen of human cocaine users. To establish the specificity of this change in phospholipid metabolism and whether decreased Ca-PLA 2 might be a general feature of all abused drugs which enhance dopaminergic neurotransmission, we measured activity of 11 major phospholipid metabolic enzymes in dopamine-rich (putamen) and poor brain areas of chronic users of cocaine and of methamphetamine. Enzyme changes were restricted to the putamen which showed decreased (−21%, as compared with the control subjects) Ca-PLA 2 activity in users of methamphetamine and reduced (−31%) activity of phosphocholine cytidylyltransferase (PCCT), the rate-limiting enzyme of phosphatidylcholine synthesis, in the cocaine users. We suggest that chronic exposure to psychostimulant drugs might cause a compensatory downregulation of Ca-PLA 2 in dopamine-rich brain areas due to excessive dopamine-related stimulation of the enzyme. Decreased striatal Ca-PLA 2 and/or PCCT activity in cocaine users might also help to explain why CDP choline, which enhances phospholipid synthesis, reduces craving in some users of the drug cocaine.

Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users

We measured levels of methamphetamine and those of its metabolite amphetamine in 15 autopsied brain regions of 14 human methamphetamine users. Only slight regional differences were observed in drug concentrations among the brain areas. Although, some redistribution of the drugs probably occurred postmortem, these data suggest that methamphetamine might not be preferentially retained in dopamine-rich brain areas but is heterogenously distributed in brain of chronic human users of the drug. The possible pharmacological actions of methamphetamine in both dopamine-rich and poor brain areas of chronic drug users need to be considered.

An Improved HPLC‐Electrochemical Detection Method for Measuring Brain Levels of 5‐S‐Cysteinyldopamine, 5‐S‐Cysteinyl‐3,4‐Dihydroxyphenylalanine, and 5‐S‐Cysteinyl‐3,4‐Dihydroxyphenylacetic Acid

Brain levels of the 5-S-cysteinyl adducts of 3,4-dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylacetic acid (DOPAC), and dopamine were determined in several mammalian species. The low levels of the compounds and the risk of artifacts during sample preparation necessitated rather profound modifications of the assaying method. The refined method has made it possible to present more accurate data than those previously reported from this laboratory. The occurrence of low levels of the 5-S-cysteinyl adducts in dopamine-rich brain areas, but not in cerebellum, is indirect evidence of in vivo autoxidation of DOPA, DOPAC, and dopamine. The products generated during catechol autoxidation, including quinones and reduced forms of oxygen, are known to be potentially cytotoxic.

Autoradiographic distribution of the D 1 agonist [ 3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D 2 dopamine receptors

The regional distribution of the specific D 1 agonist [ 3H]SKF 38393 (SKF 38393, 2,3,4,5-tetra-hydro-7, 8-dihydroxy-1-phenyl-1H-3-benzazepine) has been studied autoradiographically in the rat CNS. The binding of [ 3H]SKF 38393 to striatal sections was saturable, stereospecific, reversible, of high affinity (K d = 9.9 nM) and partly sodium sensitive; it occurred at a single population of sites and possessed the pharmacological characteristics of the dopamine D 1 receptor. The highest levels of [ 3H]SKF 38393 binding sites were found in the caudate-putamen, nucleus accumbens, olfactory tubercle and substantia nigra. Moderately high concentrations of the [ 3H]ligand were observed in the amygdala, endopyriform nucleus, nucleus olfactorius anterior, lateral septum, primary olfactory cortex, cerebellum (molecular layer) and spinal cord. An intermediate labelling was found in the thalamus, habenula, subthalamic nucleus, hypothalamus, ventral tegmental area, superior colliculus, hippocampus and cerebral cortex. Moderate levels of [ 3H]SKF 38393 binding were observed in the globus pallidus and arcuate nucleus. The autoradiographic distribution of [ 3H]SKF 38393 overlapped with that of [ 3H]N,n-propylnorapomorphine, a radioligand which labels the D 2 dopamine receptors, in a number of dopamine-rich brain areas but there were several areas which exhibited a high density of [ 3H]SKF 38393 binding sites but undetectable concentrations of [ 3H]N,n-propylnorapomorphine. Moreover, in the spinal cord, the subregional localization of these [ 3H]ligands clearly differed. Intrastriatal injection of ibotenic acid caused a large decrease in [ 3H]SKF 38393 and [ 3H]N,n-propylnorapomorphine binding in the striatum and provoked a reduction of [ 3H]SKF 38393 but not [ 3H]N,n-propylnorapomorphine binding in the substantia nigra confirming the view that nigral D 1 but not D 2 receptors are located on striatonigral fibres.

Regional in vivo binding of the substituted benzamide [ 3H]eticlopride in the rat brain: Evidence for selective labelling of dopamine receptors

The novel substituted benzamide eticlopride, (S)-(−)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxy salicylamide hydrochloride (A38503; FLB 131), was radiolabelled to high specific activity and used for in vivo receptor binding studies in the rat brain. Intravenous injections of [ 3H]eticlopride resulted in a rapid accumulation of radioactivity in several brain regions: striatum > olfactory tubercle > septum > substantia nigra > frontal cortex > cerebellum. Approximately 95% of the radioactivity recovered from the striatum was in the form of authentic eticlopride, as determined by thin-layer chromatography. Two hours after injection, the ratio between the amount of radioactivity present in the striatum and in the cerebellum was approximately 10:1. The in vivo binding of [ 3H]eticlopride was saturable in all dopamine-rich areas, with a very low proportion of non-specific binding. The specific in vivo binding of [ 3H]eticlopride was blocked by several dopamine antagonists, including haloperidol, (+)-butaclamol, spiperone, d, l-sulpiride and remoxipride. The dopamine agonist N-n-propylnorapomorphine, but not apomorphine, was found to be a potent blocker of in vivo [ 3H]eticlopride binding. Serotonin and noradrenaline receptor antagonists did not prevent the in vivo binding of [ 3H]eticlopride. Autoradiographic analysis of the in vivo [ 3H]eticlopride binding showed a high density of binding sites in the striatum, nucleus accumbens and the olfactory tubercle. Moderate binding was found in the hippocampal formation and in the entorhinal area, but little or no binding was detected in other cortical regions. [ 3H]Eticlopride binding in all these areas was blocked by pretreatment with (+)-butaclamol. Taken together, these findings show that the substituted benzamide compound [ 3H]eticlopride passes readily into the brain and binds with high specificity to dopamine or neuroleptic receptors in dopamine-rich brain areas. Thus, eticlopride may be a useful tool in studies of dopamine D-2 receptors in vivo.

Specific in vitro and in vivo binding of 3H-raclopride a potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain

The substituted benzamide drug raclopride, [((-)-( S)-3,5-dichloro- N-((1-ethyl-2-pyrrolidinyl) methyl)-6-methoxy-salicylamide tartrate; FLA 870(-); A40664] was shown to be a potent and selective antagonist of dopamine D-2 receptors by its high affinity for striatal 3H-spiperone binding sites and low potency to block dopamine stimulated adenylate cyclase in vitro. In vitro studies showed that 3H-raclopride binds with a high affinity ( K D = 1.2 nM) and a low proportion of non-specific binding to rat striatal homogenates. The binding of 3H-raclopride is saturable ( B max = 23.5 pmoles/g wet wt) and reversible (dissociation half-time = 30 min) with a regional distribution of the specifically bound drug showing the following rank-order: striatum > nucleus accumbens > olfactory tubercle > septum > hypothalamus > hippocampus > frontal cortex. After in vivo administration, 3H-raclopride accumulates preferentially in dopamine rich brain areas with approximately 10 times higher levels in the striatum than in the cerebellum, when examined 30 min after injection. The in vivo binding of 3H-raclopride was saturable, reversible and showed a low component of non-specific binding. More than 90% of the drug reached the brain in a non-metabolized form as judged by thin-layer chromatography. Pharmacological analysis of 3H-raclopride binding showed that it could be displaced by dopamine agonists and antagonists but not by serotoninergic or noradrenergic drugs. Taken together, the results suggest that 3H-raclopride labels dopamine D-2 receptors with high specificity in the rat brain both in vitro and in vivo, and thus, that it should be a useful tool in studies of central dopamine D-2 receptors.

The effects of chronic neuroleptic treatment on neurotensin-like immunoreactivity in the rat central nervous system

The dopamine receptor antagonist fluphenazine decanoate, when administered for a total period of 10 months, produced a large increase in neurotensin-like immunoreactivity in dopamine-rich brain areas, such as the nucleus accumbens, the striatum and the frontal cortex. A smaller, non-significant increase was observed in the substantia nigra with no change in either the hypothalamus or the spinal cord. The present results provide further evidence in favour of a functional interaction between neurotensin and dopamine in the central nervous system.

Increased salsolinol levels in rat striatum and limbic forebrain following chronic ethanol treatment.

Endogenous levels of salsolinol and its methylated metabolite were measured by combined gas chromatography and mass spectrometry in rats chronically exposed to ethanol for 150 days. The chronic ethanol administration produced a significant increase of salsolinol concentrations in dopamine-rich brain areas, e.g., the striatum and the limbic forebrain. A negative correlation was observed between plasma ethanol concentration and the level of salsolinol in the brain. A possible role for salsolinol in the regulation of ethanol drinking and/or in the development of ethanol dependence is discussed.

Evidence for in vivo binding of apomorphine and bromocriptine to receptor sites not labelled by 3H-spiperone

The novel substituted benzamide eticlopride, (S)-(−)-5-chloro-3-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxy salicylamide hydrochloride (A38503; FLB 131), was radiolabelled to high specific activity and used for in vivo receptor binding studies in the rat brain. Intravenous injections of [3H]eticlopride resulted in a rapid accumulation of radioactivity in several brain regions: striatum > olfactory tubercle > septum > substantia nigra > frontal cortex > cerebellum. Approximately 95% of the radioactivity recovered from the striatum was in the form of authentic eticlopride, as determined by thin-layer chromatography. Two hours after injection, the ratio between the amount of radioactivity present in the striatum and in the cerebellum was approximately 10:1. The in vivo binding of [3H]eticlopride was saturable in all dopamine-rich areas, with a very low proportion of non-specific binding. The specific in vivo binding of [3H]eticlopride was blocked by several dopamine antagonists, including haloperidol, (+)-butaclamol, spiperone, d, l-sulpiride and remoxipride. The dopamine agonist N-n-propylnorapomorphine, but not apomorphine, was found to be a potent blocker of in vivo [3H]eticlopride binding. Serotonin and noradrenaline receptor antagonists did not prevent the in vivo binding of [3H]eticlopride. Autoradiographic analysis of the in vivo [3H]eticlopride binding showed a high density of binding sites in the striatum, nucleus accumbens and the olfactory tubercle. Moderate binding was found in the hippocampal formation and in the entorhinal area, but little or no binding was detected in other cortical regions. [3H]Eticlopride binding in all these areas was blocked by pretreatment with (+)-butaclamol. Taken together, these findings show that the substituted benzamide compound [3H]eticlopride passes readily into the brain and binds with high specificity to dopamine or neuroleptic receptors in dopamine-rich brain areas. Thus, eticlopride may be a useful tool in studies of dopamine D-2 receptors in vivo.