Dopamine and semantic activation: An investigation of masked direct and indirect priming

To investigate the effects of dopamine on the dynamics of semantic activation, 39 healthy volunteers were randomly assigned to ingest either a placebo (n = 24) or a levodopa (it = 16) capsule. Participants then performed a lexical decision task that implemented a masked priming paradigm. Direct and indirect semantic priming was measured across stimulus onset asynchronies (SOAs) of 250, 500 and 1200 ms. The results revealed significant direct and indirect semantic priming effects for the placebo group at SOAs of 250 ms and 500 ms, but no significant direct or indirect priming effects at the 1200 ms SOA. In contrast, the levodopa group showed significant direct and indirect semantic priming effects at the 250 ms SOA, while no significant direct or indirect priming effects were evident at the SOAs of 500 ins or 1200 ms. These results suggest that dopamine has a role in modulating both automatic and attentional aspects of semantic activation according to a specific time course. The implications of these results for current theories of dopaminergic modulation of semantic activation are discussed.

Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic-pituitary-adrenal axis responses to different stressors

Recent investigations have implicated the medial prefrontal cortex (mPFC) in modulation of subcortical pathways that contribute to the generation of behavioural, autonomic and endocrine responses to stress. However, little is known of the mechanisms involved. One of the key neurotransmitters involved in mPFC function is dopamine, and we therefore aimed, in this investigation, to examine the role of mPFC dopamine in response to stress in Wistar rats. In this regard, we infused dopamine antagonists SCH23390 or sulpiride into the mPFC via retrodialysis. We then examined changes in numbers of cells expressing the c-fos immediate-early gene protein product, Fos, in subcortical neuronal populations associated with regulation of hypothalamic-pituitary-adrenal (HPA) axis stress responses in response to either of two stressors; systemic injection of interleukin-1beta, or air puff. The D-1 antagonist, SCH23390, and the D-2 antagonist, sulpiride, both attenuated expression of Fos in the medial parvocellular hypothalamic paraventricular nucleus (mpPVN) corticotropin-releasing factor cells at the apex of the HPA axis, as well as in most extra-hypothalamic brain regions examined in response to interleukin-1beta. By contrast, SCH23390 failed to affect Fos expression in response to air puff in any brain region examined, while sulpiride resulted in an attenuation of the air puff-induced response in only the mpPVN and the bed nucleus of the stria terminalis. These results indicate that the mPFC differentially processes the response to different stressors and that the two types of dopamine receptor may have different roles.

Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents

DCC (deleted in colorectal cancer)-the receptor of the netrin-1 neuronal guidance factor-is expressed and is active in the central nervous system (CNS) during development, but is down-regulated during maturation. The substantia nigra contains the highest level of netrin-1 mRNA in the adult rodent brain, and corresponding mRNA for DCC has also been detected in this region but has not been localized to any particular neuron type. In this study, an antibody raised against DCC was used to determine if the protein was expressed by adult dopamine neurons, and identify their distribution and projections. Significant DCC-immunoreactivity was detected in midbrain, where it was localized to ventrally displaced A9 dopamine neurons in the substantia nigra, and ventromedial A10 dopamine neurons predominantly situated in and around the interfascicular nucleus. Strong immunoreactivity was not detected in dopamine neurons found elsewhere, or in non-dopamine-containing neurons in the midbrain. Terminal fields selectively labeled with DCC antibody corresponded to known nigrostriatal projections to the dorsolateral striatal patches and dorsomedial shell of the accumbens, and were also detected in prefrontal cortex, septum, lateral habenular and ventral pallidum. The unique distribution of DCC-immunoreactivity in adult ventral midbrain dopamine neurons suggests that netrin-1/DCC signaling could function in plasticity and remodeling previously identified in dopamine projection pathways. In particular, a recent report that DCC is regulated through the ubiquitin-proteosome system via Siah/Sina proteins, is consistent with a potential involvement in genetic and sporadic forms of Parkinson's disease. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.

Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D-2-receptor occupancy method in the rat

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal doparnine D-2-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/ day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D2-receptor occupancies were determined using H-3-raclopride. The doses required to achieve dopamine D-2-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day. (c) 2006 Elsevier B.V All rights reserved.

The DVD animal model of schizophrenia: Effects of low maternal vitamin D on brain dopamine

Background: We have previously shown that the offspring of vitamin D3 depleted rats have enlarged ventricles and altered neurotrophin profiles (reduced NGF and GDNF). These findings enhance the biological plausibility that low prenatal vitamin D may be a risk factor for schizophrenia. Our recent behavioural studies have found that adult rats with developmental vitamin D deficiency (DVD) have a subtle increase in baseline locomotor activity and a heightened response to dopamine (DA) antagonists. The aim of this study was to investigate brain DA neurochemistry in the DVD model. Methods: We examined cerebrums and striatal tissue from neonates and a variety of brain tissues from the remaining littermates at adulthood. DA, DOPAC, HVA, serotonin and 5HIAA were analysed by HPLC. Single point comparisons for DA1, DA2 and NMDA receptors were also assessed in these tissues. Results: Significant increases in DA and HVA were found in brains from DVD deplete neonates (P=0.01). However, DA and its metabolites were not increased in either the neonate or adult striatum, however there was a trend towards increased DA and its metabolites in the accumbens (P=0.1). Receptor densities were unaffected by prenatal vitamin D levels. Conclusions: Although the effect of maternal diet appears to increase DA production and turnover in neonatal brain, this does not persist into adulthood. Thus other factors must underlie the increased locomotor activity noted in these animals. Future experiments will concentrate on monitoring accumbens and striatal DA release and turnover using microdialysis in pharmacologically challenged behavioural paradigms. References: Eyles D, Brown J; Mackay-Sim A, McGrath J, Feron F. (2003) Vitamin D3 and brain development. Neuroscience 118 (3) 641–653. Burne T, McGrath J, Eyles D, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. (2005) Behavioural Brain Res: 157 299–308.

The influence of dopamine on semantic activation in Parkinson's disease: Evidence from a multipriming task

Research has suggested that semantic processing deficits in Parkinson's disease (PD) are related to striatal dopamine deficiency. As an investigation of the influence of dopamine on semantic activation in PD, 7 participants with PD performed a lexical-decision task when on and off levodopa medication. Seven healthy controls matched to the participants with PD in terms of sex, age, and education also participated in the study. By use of a multipriming paradigm, whereby 2 prime words were presented prior to the target word, semantic priming effects were measured across stimulus onset asynchronies (SOAs) of 250 Ins and 1,200 Ins. The results revealed a similar pattern of priming across SOAs for the control group and the PD participants on medication. In contrast, within-group comparisons revealed that automatic semantic activation was compromised in PD participants when off medication. The implications of these results for the neuromodulatory influence of dopamine on semantic processing in PD are discussed.

Dopamine, empathy and the neurobiology of leadership

Objectives: Organisational Psychologists have long sought after methods by which to train individuals to become more effective leaders. Indeed considerable sums of money are spent on the design of such training programs. Yet it is not clear whether or not leadership skills can be taught or whether they are innate. Social leadership is a varied construct consisting of many diverse aspects, yet the ability to empathise with subordinates is a core skill that underpins effective transformational leadership. This type of leadership consists of four characteristics which are labelled ‘idealized influence’, ‘inspirational motivation’, ‘intellectual stimulation’ and ‘individualized consideration’. This is distinct from the transactional style of leadership, which is based on offering contingent rewards for completion of specific tasks. By identifying a specific gene that mediates distinct leadership traits, more effective training regimes can be designed. Design: There are two likely candidate genes that may mediate empathic leadership. The first is catechol-O-methyltransferase (COMT) which is involved with dopamine synthesis, and the second is the serotonin transporter promoter gene (5-HTTLPR). Both these genes mostly appear in the general population in their heterozygotic form. Thus by comparing phenotypes in leadership traits a measure of base line differences can be examined. Methods: 115 volunteers completed the Multifactor Leadership questionnaire (MLQ), which is a standard 12-item leadership psychometric scale and also underwent buccal swab for subsequent genotyping. Results: Of the 115 subjects 37 were heterozygotic for the COMT gene and 47 heterozygotic for 5-HTTLPR. Of the 12 MLQ subscales, the scores for two of the subscales only differed between the two participant groups. Individuals who were heterozygotic for the COMT gene scored higher on the ‘Inspirational motivation’ t(84)=1.99, p=0.05 and ‘Intellectual stimulation’ t(82)=1.94, p=0.05 scales compared to the carriers for the heterozygotic 5HTPP gene. Conclusions: Given that the behaviours described by these two MLQ subscales require leaders to empathise with subordinates, the current results suggest that dopamine may play a role in this important social task. The fact that both heterozygotic carriers for COMT and 5HTPP were compared allows a comparison to be made between the genotypes most prevalent in the general population.

Depolarisation and suppression of burst firing activity in the mouse subthalamic nucleus by dopamine D1/D5 receptor activation of a cyclic-nucleotide gated non-specific cation conductance

Neuronal burst firing in the subthalamic nucleus (STN) is one of the hallmarks of dopamine depletion in Parkinson's disease. Here, we have determined the postsynaptic effects of dopamine in the STN and the functional consequences of dopamine receptor modulation on burst firing in vitro. STN cells displayed regular spiking activity at a rate of 7.9 +/- 0.5 Hz. Application of dopamine (30 mu M) induced membrane depolarisations accompanied by an increase in firing rate of mean 12.0 +/- 0.6 Hz in all 69 cells. The dopamine effect was mimicked by the dopamine D1/D5 receptor agonist SKF38393 (10 mu M, 17 cells) and the dopamine D2-like receptor agonist quinpirole (10 mu M, 35 cells), partly reduced by D1/D5 antagonist SCH23390 (2 mu M, seven cells), but unaffected by the D2 antagonists sulpiride (10 mu M, seven cells) or eticlopride (10 mu M, six cells). Using voltage ramps, dopamine induced an inward current of 69 +/- 9.4 pA at a holding potential of -60 mV (n = 17). This current was accompanied by an increase in input conductance of 1.55 +/- 0.35 nS which reversed at -30.6 +/- 2.3 mV, an effect mimicked by SKF38393 (10 AM, nine cells). Similar responses were observed when measuring instantaneous current evoked by voltage steps and in the presence of the I-h blocker, ZD7288, indicating effects independent of I-h. The increase in conductance was blocked by SCH23390 (2 mu M, n = 4), mimicked by the activator of adenylyl cyclase forskolin (10 mu M, n = 7) and blocked by H-89, an inhibitor of cyclic AMP dependent protein kinase A (10 PM, n = 6). These results indicate that the dopamine depolarisation is in part mediated by D1/D5 receptor mediated activation of a cyclic-nucleotide gated (CNG) non-specific cation conductance. This conductance contributes to the membrane depolarisation that changes STN neuronal bursting to more regular activity by significantly increasing burst duration and number of spikes per burst.

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABAA receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity. © 2006 IBRO.

Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

Renal dopamine and salt-retaining states

Although generally regarded as a neurotransmitter, dopamine is also known to be secreted by the kidney whereby it promotes sodium excretion in its role as a natriuretic honnone. Peripheral dopamine may be formed by two alternative pathways; the decarboxylation of circulating L-Dopa by L-aromatic amino acid decarboxylase (LAAAD), and the desulphation of dopamine sulphate by arylsulphatase A (ASA), the latter being poorly represented in the literature. In many conditions and diseases with which sodium retention is associated, a reduced urinary excretion of dopamine has been noted implicating the involvement of dopamine in the maintenance of sodium homeostasis.This study investigates renal dopamine production via the desulphation of dopamine sulphate in a sample cohort during normal unregulated dietary sodium intake and following a low sodium regimen. After dietary salt restriction urinary dopamine sulphate levels were significantly increased, indicating that dopamine sulphate is indeed a physiological reservoir of active free dopamine, the necessity for which is reduced during self depletion. This confirmed the dopamine/dopamine sulphate pathway as one which may be relevant to the maintenance of sodium homeostasis. The activity of urinary ASA was investigated in diabetes mellitus as an example of a sodium-retaining state, and compared with that in a matched normal control group. A decreased ASA activity was anticipated, given the blunted dopamine excretion observed in many sodium-retaining states, however an unexpected increase in activity in the diabetic group was observed. Enzyme kinetic analysis of ASA showed that this was not due to the existence of an isoform having an altered affinity for dopamine sulphate. This rather paradoxical situation, that urinary-dopamine is decreased while ASA activity is increased, may be explained by the sequestering of free dopamine by autoxidation to 6-hydroxydopamine as has been hypothesised recently to occur in diabetes mellitus. To confirm the homogeneity of ASA in the normal and diabetic groups, four amplicons spanning the 3637bp intronic and exonic regions of the gene were generated by PCR. These were sequence utilising a fluorescent-dye terminator reaction using the forward PCR primer as sequencing primer. Although single nucleotide polymorphisms were observed between the two groups these occurred either in intronic regions or, when exonic, generated silent mutations, supporting the enzyme kinetic data. The expression of ASA was investigated to determine the basis of the increased activity observed in diabetes mellitus. Although a validated comparative RT-PCR assay was developed for amplification of arsa transcripts from fresh blood samples, expression analysis from archived paraffin-embedded renal tissue was complicated by the low yield and degradation of unprotected mRNA. Suggestions for the development of this work using renal cell-culture are discussed.