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Dopamine neurons are thought to facilitate learning by comparing actual and expected reward (1, 2). Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area while mice engaged in classical conditioning. Here we demonstrate, by manipulating the temporal expectation of reward, that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA (γ-aminobutyric acid) neurons in the ventral tegmental area reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction-error calculations. Finally, bilaterally stimulating ventral tegmental area GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors., Associative learning depends on comparing predictions with outcomes (3, 4). When outcomes match predictions, learning is not required. When outcomes violate predictions, animals must update their predictions to reflect experience. [...]

Author(s): David R. Sibley; Lei Shi Schizophrenia is a disorder that involves hallucinations, delusions and cognitive impairment, and that affects nearly 1% of the global population. The mainstays of therapy [...]

The DRD4 variable number of tandem repeats (VNTR) allele distribution of 172 Guarani (Kaiowa and Nandeva subgroups) and Kaingang Brazilian Amerindians is reported. These results are integrated with those previously obtained for this ethnic group. Allele frequencies for the three populations are within the interval observed for 15 other Native American populations and show intermediate values between those observed in Amazonia and Patagonia. Significant differences in allele distribution between recent past hunter-gatherer and agriculturalist populations are observed, with an increase of the 7R allele among hunter--gatherers (P < 0.001). Analysis of molecular variance (AMOVA) and pairwise FST data suggest three distinct sectors for the genetic landscape of Native South America: Andes, Center/Southeast region, and Amazonia. Common traits among hunter-gatherers such as novelty-seeking temperament, hyperactivity, and impulsivity could have been important and advantageous in new environments during America's prehistoric colonization. Am J Phys Anthropol 143:458-464, 2010. [c] 2010 Wiley-Liss, Inc. KEY WORDS DRD4; VNTR; Amerindian populations; selection; genetic structure DOI 10.1002/ajpa.21358

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1467-8624.2008.01194.x Abstract: This study investigated dopamine receptor genes (DRD2 and DRD4) and maternal sensitivity as predictors of infant respiratory sinus arrhythmia (RSA) and RSA reactivity, purported indices of vagal tone and vagal regulation, in a challenge task at 3, 6, and 12 months in 173 infant-mother dyads. Hierarchical linear modeling (HLM) revealed that at 3 and 6 months, RSA withdrawal in response to maternal separation was greater (suggesting expected physiological regulation) in infants without the DRD2 risk allele than those with the risk allele. At 12 months, infants with the risk allele who were also exposed to maternal sensitivity showed levels of RSA withdrawal comparable to infants who were not at genetic risk. Findings demonstrate the importance of developmental analysis of gene-environment interaction. Author Affiliation: (1)University of North Carolina-Chapel Hill (2)Pennsylvania State University (3)University of North Carolina-Chapel Hill (4)University of North Carolina-Greensboro (5)North Carolina State University (6)University of North Carolina-Chapel Hill Article note: Correspondence concerning this article should be addressed to Cathi Propper, Center for Developmental Science, University of North Carolina at Chapel Hill, 100 East Franklin Street, CB# 8115, Chapel Hill, NC 27599-8115. Electronic mail may be sent to propper@email.unc.edu.

We have developed a nonparametric approach to the analysis of dynamic positron emission tomography (PET) data for extracting temporal characteristics of the change in endogenous neurotransmitter concentration in the brain. An algebraic method based on singular value decomposition (SVD) was applied to simulated data under both rest (neurotransmitter at baseline) and activated (transient neurotransmitter release) conditions. The resulting signals are related to the integral of the change in free neurotransmitter concentration in the tissue. Therefore, a specially designed minimum mean-square error (MMSE) filter must be applied to the signals to recover the desired temporal pattern of neurotransmitter change. To test the method, we simulated sets of realistic time activity curves representing uptake of [11C]raclopride, a dopamine (DA) receptor antagonist, in brain regions, under baseline and dopamine-release conditions. Our tests considered two scenarios: 1) a spatially homogeneous pattern with all voxels in the activated state presenting an identical DA signal; 2) a spatially heterogeneous pattern in which different DA signals were contained in different families of voxels. In the first case, we demonstrated that the timing of a single DA peak can be accurately identified to within 1 min and that two distinct neurotransmitter peaks can be distinguished. In the second case, separate peaks of activation separated by as little as 5 min can be distinguished. A decrease in blood flow during activation could not account for our findings. We applied the method to human PET data acquired with [11C]raclopride in the presence of transiently elevated DA due to intravenous (IV) alcohol. Our results for an area of the nucleus accumbens--a region relevant to alcohol consumption--agreed with a model-based method for estimating the DA response. SVD-based analysis of dynamic PET data promises a completely noninvasive and model-independent technique for determining the dynamics of a neurotransmitter response to cognitive or pharmacological stimuli. Our results indicate that the method is robust enough for application to voxel-by-voxel data. Index Terms--Dopamine, positron emission tomography, singular value decomposition.

Research elucidates the zinc binding sites in the 'transmembrane segments (TM) 7 and 8 microdomain' of the human dopamine transporter by histidine substitutions in the TM 7. Results from a constructed structural model of the TM 7/8 microdomain predicts the structural features in the functional region of the human dopamine transporter.

Antipsychotic drugs used in the treatment of schizophrenia have in common the property of being dopamine-receptor antagonists. However, the rapid timecourse of receptor blockade produced upon drug administration does not correlate with the emergence of clinical actions, which typically require weeks of treatment to become manifest. Studies in rats have shown that repeated antipsychotic drug treatment results in a delayed inactivation of dopamine-neuron firing in the midbrain due to depolarization block. Furthermore, the therapeutic efficacy of antipsychotic drugs in humans correlates with their ability to induce depolarization block of mesolimbic dopamine neurons, whereas their potential to produce extrapyramidal side effects correlates with their propensity for inducing depolarization block in the nigrostriatal dopamine system. Therefore, dopamine-cell depolarization block is an effective model for evaluating antipsychotic drug efficacy, and provides a potential mechanism to account for their therapeutic impact on a dysregulated dopamine system.

The fifth membrane-spanning segment and its surroundings of the dopamine D2 receptor have 25 consecutive residues in the binding-site crevice. 13 side chain residues are exposed in the binding-site crevice. The 10 consecutive exposed residues are between Phe189 and Phe198. A side of the alpha-helix formed by the fifth membrane-spanning segment is exposed in the binding-site crevice.

The regulation of the dopamine D1 receptor was investigated by using c-myc epitope-tagged D1 receptors expressed in Sf9 (fall armyworm ovary) cells. Treatment of D1 receptors with 10 [mu]M dopamine for 15 min led to a loss of the dopamine-detected high-affinity state of the receptor accompanying a 40% reduction in the ability of the receptor to mediate maximal dopamine stimulation of adenylyl cyclase activity. After 60 min of agonist exposure, 45 min after the occurrence of desensitization, 28% of the cell surface receptors were internalized into an intracellular light vesicular membrane fraction as determined by radioligand binding and supported by photoaffinity labeling, immunocytochemical staining, and immunoblot analysis. Pretreatment of cells with concanavalin A or sucrose completely blocked agonist-induced D1 receptor internalization without preventing agonist-induced desensitization, indicating a biochemical separation of these processes. Collectively, these findings indicate that the desensitization of D1 receptor-coupled adenylyl cyclase activity and D1 receptor internalization are temporally and biochemically distinct mechanisms regulating D1 receptor function following agonist activation.

The binding affinity of the ligands to the D2 dopamine receptors in bovine caudate nucleus and recombinant CHO cells that express the receptor is proportional to pH, but the highest number of D2 receptor binding sites is independent of pH. Protonation of one ionizing group affects the binding process for dopamine antagonists such as spiperone and haloperidol but protonation of two ionizing groups modulates the process for antagonist receptors. N,N'-dicyclohexylcarbodiimide inhibits the binding of (3H)YM and (3H)spiperone to D2 receptors indicating that the carboxyl terminal of the ligand is involved in the binding process.

Analysis of the expression and physical properties of D5 dopamine receptors in transfected mammalian cells and brain shows that the D5 receptor is preferentially present in the pyramidal neurons in the primate prefrontal cortex thereby emphasizing the role of D1-like receptors in cortical processes. The D1 receptors are present in dendrite spines of pyramidal cells. Immunoblot analysis shows that the antibodies are specific for the D5 receptor and do not react with other G proteins-coupled receptors.

A study of the interaction of the dopamine receptor D1A and D2 neuronal pathways in the striatum using mutant mice lacking DA receptor reveals that these mice have altered striatal function that give rise to the direct striatal output pathway. These mutants show growth retardation and death after weaning age and also show reduced rearing behavior. The striatal sections of these mutants do not exhibit D1A receptor binding and have decreased levels of substance P mRNA colocalized with D1A receptors.

Experimental studies using selective substitution of (125I)epidepride in D3 receptors by 7-hydroxy-N,N-di(1-propyl)-2-aminotetralin and partial replacement of (125I)epidepride from D2 receptors with domperidone help estimate the localization of (125I)epidepride-bound D2-like and D3-like receptors in the basal ganglia and limbic regions of human brain. Islands of dense binding in the nucleus accumbens and ventral putamen exhibit significant binding of (125I)epidepride to D3-like receptors. Cortex and hippocampus exhibit the binding of (125I)epidepride to D2 receptors but not to D3 receptors.

Dopamine receptors are the primary targets in the treatment of schizophrenia, Parkinson's disease, and Huntington's chorea, and are discussed in this review by Philip Seeman and Hubert Van Tol. Improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. Most antipsychotic drugs block [D.sub.2] receptors in direct correlation to clinical potency, except clozapine, which prefers [D.sub.4] receptors. [D.sub.1] and [D.sub.2] receptors can enhance each other's actions, possibly through subunits of the G proteins. In schizophrenia, the [D.sub.2] and [D.sub.3] receptor density is elevated by 10%, while the [D.sub.4] receptor density is elevated by 600%. Therefore, [D.sub.4] receptors may be a target for future antipsychotic drugs. While antipsychotics originally helped to discover dopamine receptors, the five cloned dopamine receptors are now facilitating the discovery of selective antipsychotic and antiparkinson drugs.

A study of 57 female and 16 male nonalcoholic and nondrug abusing obese subjects reveals that the TaqI A D2 dopamine receptor (DRD2) gene is involved in obesity. Though the DRD2 A1 allele is not associated with the risk of cardiovascular diseases, it is associated with carbohydrate preference, postpuberty initiation and parental history of obesity. DRD2 polymorphism is associated with the initiation of obesity as revealed by progressive enhancement in the presence of A1+ allele in child-adolescent and adult-onset obesity. Those with no parental history of obesity had less A1+ alleles than those with parental history of obesity.

D2 dopamine receptors present in the kidney correspond to those in the brain and a D2 agonist induces a decrease in renal nerve activity, glomerular filtration rate and sodium-water excretion. The actions of dopamine in D2 receptors in the kidney as they are executed at presynaptic or postsynaptic sites.

Phospholipids are crucial for D-1 dopamine receptor preservation during solubilization and reconstitution procedures. Phosphatidylcholine (PC) addition increases receptor yield to 48% plus or minus 5.5% of total. PC is involved in receptor stabilization during the initial solubilization but inhibits the receptor yield during reconstitution. Addition of phosphatidyl ethanolamine reduces the PC inhibitory action, and vesicles yield larger receptor amounts during both solubilization and reconstitution.

An analysis of dopamine D1 receptors reveals that D1 receptors improve midbrain GABA release when stimulated by initially present dopamine, inhibiting midbrain dopamine due to the inhibition of dopamine neurons by GABA. D1 receptors help release other neurotransmitters. GABA enhancing by dopamine modulates GABA synaptic actions as part of the brain's feedback circuit.

The binding of (H)raclopride to D2 receptors during schizophrenia was found to be insensitive to guanine nucleotide, because this link is lowered in schizophrenia tissue. A mere 10% rise in the combined density of D2 and D3 receptors is effected in schizophrenia brain, but a sixfold enhancement in the density of dopamine D4 receptors is observed.

D-2 receptors for dopamine are absent in prolactinomas that are completely resistant to pharmacological therapy, and have very good potential of growing in soft agar and in developing tumors in nude mice. Prolactinoma cells lower their rate of proliferation, because they are incapable of developing colonies in soft agar and forming tumors in nude mice, and are reexpressed in the lactotroph specific D-2 receptor protein inhibiting prolactin secretion, after these cells were exposed to nerve growth factor for four days.

Dopamine is a key neurotransmitter that is important for many physiological functions including motor control, mood and the reward pathway. Two different molecules namely beta-arrestin 2 and Par-4, are identified that unexpectedly are involved in dopamine signaling via dopamine receptor 2.