Influences of neuronal uptake and D2 autoreceptors on regulation of extracellular dopamine in the core, shell and rostral pole of the rat nucleus accumbens

Fast cyclic voltammetry in rat brain slices containing the nucleus accumbens, was used to examine the regulation of the extracellular concentration of electrically stimulated dopamine overflow in the core, shell and rostral pole. One μM (−)-sulpiride, significantly increased dopamine overflow in all 3 regions but only when the duration of stimulation was greater than 500 ms. One μM cocaine, significantly potentiated dopamine overflow in all 3 regions following all patterns of stimulation. In the presence of 1 μM cocaine, superfusion with 1 μM (−)-sulpiride did not result in a further increase in dopamine overflow at any frequency of stimulation in the rostral pole, but significant increases in dopamine overflow were observed after stimulation with 20 pulses at 10 or 20 Hz in the core or shell; the degree of potentiation was greater in the shell than core. Quinpirole inhibited single pulse stimulated dopamine overflow in a concentration dependent manner (maximum inhibition (100%) in all regions) but was significantly less potent in the rostral pole than in the core or shell. Increasing the number of pulses to 2 or 4 pulses at 50 Hz resulted in a shift of the quinpirole dose-response curve to the right in all regions and in the rostral pole, a significant reduction in the maximum inhibition of dopamine overflow to both stimulation parameters. In the shell a significant reduction in maximum inhibition was only seen with 4 pulses at 50 Hz stimulation, whereas in the core there was no change in the maximum inhibitory effect of quinpirole. Neuronal uptake and D₂ autoreceptor activity contribute to regulation of the extracellular concentration of dopamine in core, shell and rostral pole. The relative importance of either uptake or autoreceptor control is region and stimulus dependent.     

Classification of H2O2 as a Neuromodulator that Regulates Striatal Dopamine Release on a Subsecond Time Scale

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Dopamine D2-like receptors and the antidepressant response.

Converging lines of evidence suggest a role for the mesolimbic dopamine system in the response to somatic antidepressant therapies. Here, we review evidence suggesting that antidepressant treatments of different types share the effect of increasing the sensitivity of dopamine D2-like receptors in the nucleus accumbens, clinical studies suggesting that activation of these receptors has antidepressant efficacy, as well as relevant imaging and genetic data on the role of this system in the antidepressant response. We then attempt to reconcile this data with evidence of a common target of antidepressant drugs in the cyclic adenosine monophosphate (cAMP) response element binding protein-brain-derived neurotrophic factor (CREB-BDNF) pathway in a model that suggests potential directions for future inquiry.     

Potentiated Striatal Dopamine Release Leads to Hyperdopaminergia in Female Brain-Derived Neurotrophic Factor Heterozygous Mice

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Dopamine receptors,controlling dopamine levels in rat adrenal glands — comparison with central dopaminergic autoreceptors

Summary Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case /(–)-HW165/. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.     

Dopamine Autoreceptor Sensitivity is Unchanged in Rat Nucleus Accumbens After Chronic Haloperidol Treatment: An In Vivo and In Vitro Voltammetric Study

Fast cyclic voltammetry was used to assess the effects of chronic oral haloperidol treatment (0.7 mg/kg/day for 21 days) on the sensitivity of dopamine autoreceptors in the rat nucleus accumbens both in vivo and in vitro. Evoked dopamine overflow was significantly reduced after chronic haloperidol treatment, but the sensitivity of dopamine overflow to sulpiride, an antagonist at release-inhibiting dopamine autoreceptors, and quinpirole, an agonist at these receptors, was unchanged. The estimated EC₅₀ values for quinpirole and sulpiride (52 and 60 nM respectively) obtained in vitro and the receptor distribution profiles published in the literature suggest that the autoreceptors involved in this modulation are mainly of the D₃ subtype. The finding that the reduced dopamine overflow in the nucleus accumbens observed after chronic treatment with a classical neuroleptic is not due to dopamine autoreceptor supersensitivity may therefore be the first functional evidence for unchanged autoreceptor activity in the nucleus accumbens, supporting biochemical findings of a lack of D₃ autoreceptor up-regulation after chronic haloperidol treatment. It lends further support to the assumption that the long-term changes occurring during chronic neuroleptic treatment may not lie at the level of presynaptic dopamine receptor regulation.     

Dopamine reward prediction error coding

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.     

Low affinity binding of the classical D1 antagonist SCH23390 in rodent brain: potential interaction with A2A and D2-like receptors

Whereas structurally dissimilar D(1) antagonists competing for [(3)H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is similar in both of these regions, with the high affinity site (K(D) approximately 0.4 nM) consistent with D(1)/D(5) receptors. The appearance of the low affinity site (K(D) approximately 300 nM) is dependent upon the absence of MgCl(2), but independent of D(1) expression (i.e., still present in D(1) knockout mice). Although the density of high affinity state receptor is lower in hippocampus or amygdala of D(1) knockout mice, some residual binding remains, consistent with the known expression of D(5) receptors in these regions. Remarkably, in hippocampus, the affinity of the low affinity site is shifted rightward in the presence of the D(2) antagonist domperidone and is largely absent in the hippocampus of D(2) knockout animals. Additionally, this site is also shifted rightward in the presence of the A(2A) ligands SCH58261, CSC, or NECA, or in the absence of A(2A) receptors. The affinity of SCH23390 for this low affinity site is greater than seen for SCH23390 binding to D(2) receptors in heterologous expression systems, consistent with the hypothesis that both D(2) and A(2A) receptors are involved in the low affinity binding site. Therefore, we suggest that the heteromerization of D(2) and A(2A) receptors reported previously in vitro also may occur in the brain of both rats and mice.     

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

Blockade of dopamine D₂ receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus α-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus α-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D₂ receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D₂ receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.     

Dopamine D2-receptor gene polymorphisms in scandinavian chronic alcoholics

Alterations in the dopamine system have been hypothesized as a predisposing factor in alcoholism. The presence of the TaqI A1 and B1 alleles adjacent to the dopamine D₂-receptor gene (DRD2) was studied in Scandinavian alcoholic inpatients (n=74), alcoholics autopsied at a forensic clinic (n=19) and controls (n=81). There were no significant differences between controls and the alcoholics, but a tendecy of increased DRD2 TaqI A1 or B1 allele frequencies in alcoholic groups selected for severity (i.e. severity according to DSM-III-R criteria, early onset or severe medical complications due to alcohol abuse) and decreased frequencies in the corresponding less severe alcoholic group. The present study does not yield evidence for the hypothesis of an association between the DRD2 TaqI A1 or B1 alleles and alcoholism.     

Increased throughput assays of locomotor dysfunction in Drosophila larvae

Larval locomotion is a sensitive readout of a range of nervous system deficits in Drosophila, and has been utilised to quantify modulation of the disease phenotype in models of human disease. Single larvae are typically analysed in series using manual quantification of parameters such as contraction rate, or grouped together and studied en-masse. Here, we describe the development of tests for the analysis of several spatially isolated third instar larvae in parallel. We rapidly quantify larval turning rate and velocity during wandering behaviour in a 4 plate assay. In a second test, larvae are recorded as they race along five parallel lanes towards a yeast stimulus. This allows increased throughput analysis of comparative genotypes simultaneously, video archiving, and detection of exacerbation or rescue of defective locomotion in a Drosophila model of tauopathy, as we demonstrate genetically and through delivery of candidate therapeutic chemicals in fly food. The tests are well-suited for rapid comparison of locomotion capability in Drosophila mutants or candidate modulation screens in Drosophila models of human disease.     

Evaluation of HCN2 abnormalities as a cause of juvenile audiogenic seizures in Black Swiss mice

Epilepsy is an often-debilitating disease with many etiologies. Genetic predisposition is common for many of the generalized epilepsy syndromes, and mutations in genes encoding neuronal ion channels are causative in many cases. We previously identified a locus for juvenile audiogenic monogenic seizures (jams1) in the Black Swiss mouse strain, delimited by the gene basigin (Bsg) and the marker D10Mit140. This region includes Hcn2, the gene encoding the hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), an ion channel implicated in epilepsy. By sequencing genomic DNA, we found that Black Swiss mice have a single polymorphism in exon 2 within the Hcn2 gene. This single G/C to A/T base change alters the third position of a codon specifying alanine residue 293, without changing the predicted amino acid sequence. Furthermore, we found no detectable differences in HCN2 protein expression in the brains of Black Swiss mice, compared to control mice. We therefore reason that juvenile audiogenic seizures in Black Swiss mice are unlikely to be due to abnormalities of HCN2 channel function.     

Rapid desensitization of presynaptic dopamine autoreceptors during exposure to exogenous dopamine

When nomifensine is employed to inhibit neuronal uptake, exposure to dopamine (DA) (0.1–0.3 μM) or apomorphine (0.01–0.1 μM) inhibited, in a concentration-dependent manner, the electrically evoked release of [³H]dopamine from slices of the rabbit caudate nucleus. Apomorphine inhibited transmitter release independently of the time of exposure to the drug (6–32 min). On the other hand, the inhibitory effect of exogenous dopamine occurred only if a short period (4–12 min) of exposure was employed. In studies on the electrically evoked release of [³H]acetylcholine in slices of the rabbit caudate nucleus there was no evidence for desensitization to apomorphine or exogenous dopamine at the level of the dopamine receptors that inhibit [³H]acetylcholine release. These results indicate that the dopamine autoreceptors modulating [³H]dopamine release in the caudate nucleus become subsensitive after a few minutes of exposure to exogenous dopamine. This effect does not occur at the level of the dopamine receptors which inhibit the release of [³H]acetylcholine.     

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

Blockade of dopamine D₂ receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus -methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus -methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D₂ receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D₂ receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.     

Dopamine in the history of the schizophrenic brain: recent contributions of brain-imaging studies

Recent developments in positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have enabled functional measurements of dopamine (DA) transmission at dopamine D(2) receptors in the living human brain. Studies using these techniques have demonstrated that, in schizophrenia, increased DA stimulation of striatal D(2) receptors is associated with the first episode of illness and subsequent episodes of illness exacerbation. While this dysregulation of DA function is not associated with the severity of positive symptoms per se, increased synaptic DA activity is predictive of good therapeutic response to antipsychotic treatment. Abnormalities of DA function were not detected during periods of illness remission. These findings are integrated into a clinical model proposing that, in schizophrenia, neurodevelopmental abnormalities of cortico-subcortical connectivity result in a vulnerability of the mesolimbic DA system to the development of a process of endogenous sensitization, and that the resulting sustained hyperstimulation of D(2) receptors induces neuroplastic changes within corticostriatal-thalamocortical loops, perturbing information processing and underlying the psychotic experience.     

The clock gene Per2 is required for normal platelet formation and function

Introduction

Apoptotic cell death is a highly regulated genetic program, which has been observed in mature megakaryocytes fragmenting into platelets. The clock gene Per2, a key component of core clock oscillator, was involved in affecting both cell cycle control and apoptosis. Thus, loss of Per2 function may be considered potential influence of platelet formation and function.

Methods

Per2-null mice and C57BL/6 mice were used in the study. Bleeding time, platelet count, megakaryocyte count, megakaryocyte ploidy, megakaryocyte apoptosis, rate of proplatelet formation, clot retraction, platelet aggregation and secretion were performed to evaluate thrombopoiesis and hemostasis. Quantitative RT-PCR was employed to analyze genes expression in liver, bone marrow and enriched megakaryocytes.

Results

The Per2-null mice had nearly 50% platelet counts in peripheral blood. Per2-null platelets were compromised in their ability to aggregate and secretion, consistent with a marked reduction in the number of dense and a-granules. Megakaryocytes from Per2-null mice showed no significant variation in number but increased in ploidy. Ultrastructural examination of Per2-null megakaryocytes revealed many vacuoles in demarcation membranes and reduction in platelet granules. Megakaryocytes from Per2-null bone marrow decreased the rate of proplatelet formation and impaired apoptosis. Per2-null mice showed increased both in Tpo in livers and its receptors C-mpl in bone marrow, and the megakaryocytes from these mice decreased P53 expression, consequently increased Bcl-xl and Bcl-2 level.

Conclusions

The clock gene Per2 modulating the apoptosis of megakaryocytes was required for platelet formation and function.     

Dopamine transporter regulates the enhancement of novelty processing by a negative emotional context

The dopaminergic (DA) system has been recently related the emotional modulation of cognitive processes. Moreover, patients with midbrain DA depletion, such as Parkinson's Disease (PD), have shown diminished reactivity during unpleasant events. Here, we examined the role of DA in the enhancement of novelty processing during negative emotion. Forty healthy volunteers were genotyped for the dopamine transporter (DAT) gene SLC6A3 or DAT1 and performed an auditory-visual distraction paradigm in negative and neutral emotional context conditions. 9R− individuals, associated to a lesser striatal DA display, failed to show increased distraction during negative emotion, but experienced an enhancement of the early phase of the novelty-P3 brain response, associated to the evaluation of novel events, in the negative relative to the neutral context. However, 9R+ individuals (associated to larger striatal DA display) showed larger distraction during negative emotion and larger amplitudes of the novelty-P3, irrespective of the condition. These results suggest a blunted reactivity to novelty during negative emotion in 9R− individuals due to a lesser DA display and stronger activation of the representation of novel events in the 9R+ group, due to a larger DA availability, thus reaching a ceiling effect in the neutral context condition with no further enhancement during negative emotion. The present results might help to understand the functional implications of dopamine in some neuropsychiatric disorders.     

Dopamine receptors mediate drug-induced but not Pavlovian conditioned contralateral rotation in the unilateral 6-OHDA animal model

Following Pavlovian conditioning treatment sessions with apomorphine, animals receiving the paired treatment showed substantial contralateral rotation when placed without drug into the test environment previously paired to the apomorphine (0.5 mg/kg) injection while animals in the unpaired control treatment showed only ipsilateral rotation. Subsequent tests with the D1 antagonist (SCH 23390), or the D2 antagonist (haloperidol) partially suppressed and the combined D1-D2 antagonists completely suppressed the apomorphine-induced response of contralateral rotation. The identical contralateral rotation response occurring as a Pavlovian conditioned response in the paired apomorphine treatment group was not attenuated by dopamine receptor blockade. In both paired and unpaired groups, the spontaneous ipsilateral rotation response was completely blocked. Thus, non-dopaminergic mechanisms mediate conditioned rotation whereas the drug-induced as well as the spontaneous rotation responses require stimulation of striatal dopamine receptors.     

Gender-specific expression of the DRD4 gene on adolescent delinquency,anger and thrill seeking

The present study investigated gender differences in the associations between the DRD4 variable number tandem repeat (VNTR) polymorphism and adolescent delinquency, short temper and thrill seeking. We also explored whether the gender-specific expression of the DRD4 can be explained by gender differences in the exposure to psychosocial risks, such as poor parent–child relationship. Participants were 263 14- to 17-year olds (50% males) living in Russia. DNA was extracted from saliva samples and the VNTR DRD4 polymorphisms were genotyped using polymerase chain reaction. Participants reported on the extent of their delinquent behaviour, short temper, thrill seeking and exposure to psychosocial risk (i.e. poor parental monitoring of adolescent behaviour, exposure to violence and peer delinquency). Compared to individuals with the 4/4 genotype, males, but not females, with the 7-repeat allele (7R) had significantly higher delinquency, short temper and thrill seeking. This interaction effect, however, was completely explained by males’ higher exposure to psychosocial risk factors. When parental monitoring of youths’ activities and youth exposure to violence were included in the model, the 7R × gender interaction was no longer significant. Thus, social context plays an important role in explaining gender-specific phenotypic expression of the DRD4 gene.     

NMDA receptors and fear extinction: implications for cognitive behavioral therapy

Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyi-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy.