Modulatory Effects Of Dopamine Research Articles

The role of dopamine in the modulation of monocyte-induced Th17- and Th1-immune response in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with autoimmune mechanism of development. The investigation of neuroimmune interaction is one of the most developing directions in MS pathogenesis study. Catecholamines are direct mediators of this interaction and can be involved in the pathogenesis of MS by modulating cells of both innate and adaptive immune systems. The aim of this study was to investigate the influence of dopamine and norepinephrine on the ability of monocytes of patients with relapsing-remitting MS, to induce Th17- and Th1-immune response, which play a crucial role in the autoimmunity of the CNS. We found, that both dopamine and norepinephrine modulate the production of Th17- (IL-23, IL-1β, and IL-6) and Th1-promoting (IL-12p70) cytokines by activated peripheral blood mononuclear cells or CD14+ monocytes in patients with MS and in healthy subjects. We also found the inhibitory effect of dopamine and norepinephrine on monocyte-induced production of IL-17 and IFN-γ by autologous CD4+ T-cells in both groups. Finally, the multidirectional role of D1- and D2-like dopaminergic receptors in the modulatory effect of dopamine on the ability of CD14+ monocytes to activate CD4+ T-cells was established, expanding the potential role of dopamine in the neuroimmune interaction.

Spike-Timing-Dependent Plasticity Mediated by Dopamine and its Role in Parkinson's Disease Pathophysiology.

Parkinson's disease (PD) is a multi-systemic neurodegenerative brain disorder. Motor symptoms of PD are linked to the significant dopamine (DA) loss in substantia nigra pars compacta (SNc) followed by basal ganglia (BG) circuit dysfunction. Increasing experimental and computational evidence indicates that (synaptic) plasticity plays a key role in the emergence of PD-related pathological changes following DA loss. Spike-timing-dependent plasticity (STDP) mediated by DA provides a mechanistic model for synaptic plasticity to modify synaptic connections within the BG according to the neuronal activity. To shed light on how DA-mediated STDP can shape neuronal activity and synaptic connectivity in the PD condition, we reviewed experimental and computational findings addressing the modulatory effect of DA on STDP as well as other plasticity mechanisms and discussed their potential role in PD pathophysiology and related network dynamics and connectivity. In particular, reshaping of STDP profiles together with other plasticity-mediated processes following DA loss may abnormally modify synaptic connections in competing pathways of the BG. The cascade of plasticity-induced maladaptive or compensatory changes can impair the excitation-inhibition balance towards the BG output nuclei, leading to the emergence of pathological activity-connectivity patterns in PD. Pre-clinical, clinical as well as computational studies reviewed here provide an understanding of the impact of synaptic plasticity and other plasticity mechanisms on PD pathophysiology, especially PD-related network activity and connectivity, after DA loss. This review may provide further insights into the abnormal structure-function relationship within the BG contributing to the emergence of pathological states in PD. Specifically, this review is intended to provide detailed information for the development of computational network models for PD, serving as testbeds for the development and optimization of invasive and non-invasive brain stimulation techniques. Computationally derived hypotheses may accelerate the development of therapeutic stimulation techniques and potentially reduce the number of related animal experiments.

Involvement of Midbrain Dopamine Neuron Activity in Negative Reinforcement Learning in Mice

The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism's behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.

RETRACTED: l-Tyrosine administration modulates the effect of transcranial direct current stimulation on working memory in healthy humans

Transcranial direct current stimulation (tDCS) is an increasingly popular method of modulating cognitive functions in humans. However, some doubt its efficacy as findings are inconsistent or remain unreplicated. It is speculated dopamine (DA) might play an important role in this inconsistency, by determining the direction and strength of the cognitive-behavioral effects of tDCS. However, so far evidence for this hypothesis has been correlational in nature, precluding definitive conclusions. The present proof-of-principle study aimed at investigating a potentially causal role for DA in the effect of tDCS on cognition in healthy humans. In Experiment 1 we aimed to replicate previous findings showing administration of DA's precursor l-Tyrosine (Tyr), presumably by inducing a modest increase in DA level, can enhance working memory (WM) performance as assessed with a verbal N-back task. In Experiment 2 we investigated the effect of Tyr administration on bilateral tDCS over dorsolateral prefrontal cortex (DLPFC) and WM. Experiment 1 showed Tyr administration enhances performance in a verbal N-back task. Experiment 2 showed Tyr modulates the effect of bilateral tDCS over DLPFC on WM. Specifically, tDCS had opposite effects on performance depending on current direction through the brain and Tyr administration. The present study provides two major findings. First, we replicate Tyr's beneficial effect on verbal WM. Second, our results indicate a causal role for DA in the effect of tDCS on cognition. For this reason, we encourage future studies to consider the modulating effect of DA, as a step towards more consistent and replicable results regarding the efficacy of tDCS.

Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats

The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

Ventral tegmental area inactivation suppresses the expression of CA1 long term potentiation in anesthetized rat.

The hippocampus receives dopaminergic projections from the ventral tegmental area (VTA). Modulatory effect of dopamine on hippocampal long term potentiation (LTP) has been studied before, but there are conflicting results and some limitations in previous reports. Most of these studies show a significant effect of dopamine on the late phase of LTP in CA1 area of the hippocampus, while few reports show an effect on the early phase. Moreover, they generally manipulated dopamine receptors in the hippocampus and there are few studies investigating influence of the VTA neural activity on hippocampal LTP in the intact brain. Besides, VTA neurons contain other neurotransmitters such as glutamate and GABA that may modify the net effect of dopamine. In this study we examined the effect of VTA reversible inactivation on the induction and maintenance of early LTP in the CA1 area of anesthetized rats, and also on different phases of learning of a passive avoidance (PA) task. We found that inactivation of the VTA by lidocaine had no effect on CA1 LTP induction and paired-pulse facilitation, but its inactivation immediately after tetanic stimulation transiently suppressed the expression of LTP. Blockade of the VTA 20 min after tetanic stimulation had no effect on the magnitude of LTP. Moreover, VTA inactivation immediately after training impaired memory in the passive avoidance task, while its blockade before or 20 min after training produced no memory deficit. It can be concluded that VTA activity has no effect on CA1 LTP induction and acquisition of PA task, but involves in the expression of LTP and PA memory consolidation.

Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the neonatal mouse

Monoamines can modulate the output of a variety of invertebrate and vertebrate networks, including the spinal cord networks that control walking. Here we examined the multiple changes in the output of locomotor networks induced by dopamine (DA). We found that DA can depress the activation of locomotor networks in the neonatal mouse spinal cord following ventral root stimulation. By examining disinhibited rhythms, where the Renshaw cell pathway was blocked, we found that DA depresses a putative recurrent excitatory pathway that projects onto rhythm-generating circuitry of the spinal cord. This depression was D(2) but not D(1) receptor dependent and was not due exclusively to depression of excitatory drive to motoneurons. Furthermore, the depression in excitation was not dependent on network activity. We next compared the modulatory effects of DA on network function by focusing on a serotonin and a N-methyl-dl-aspartate-evoked rhythm. In contrast to the depressive effects on a ventral root-evoked rhythm, we found that DA stabilized a drug-evoked rhythm, reduced the frequency of bursting, and increased amplitude. Overall, these data demonstrate that DA can potentiate network activity while at the same time reducing the gain of recurrent excitatory feedback loops from motoneurons onto the network.

Hyperdopaminergic modulation of inhibitory transmission is dependent on GSK‐3β signaling‐mediated trafficking of GABAA receptors

Cortical dopamine (DA) modulation of the gamma-amino butyric acid (GABA) system is closely associated with cognitive function and psychiatric disorders. We recently reported that the glycogen synthase kinase 3β (GSK-3β) pathway is required for hyperdopamine/D2 receptor-mediated inhibition of NMDA receptors in the prefrontal cortex. Here we explore whether or not GSK-3β is also involved in dopaminergic modulation of GABAA receptor-mediated inhibitory transmission. We confirmed that DA induces a dose-dependent, bidirectional regulatory effect on inhibitory postsynaptic currents (IPSCs) in prefrontal neurons. The modulatory effects of DA were differentially affected by co-application of GSK-3β inhibitors and different doses of DA. GSK-3β inhibitors completely blocked high-dose (20 μM) DA-induced depressive effects on IPSCs but exhibited limited effects on the facilitating regulation of IPSC in low-dose DA (200 nM). We also confirmed that surface expressions of GABAA receptor β2/3 subunits were significantly decreased by DA applied in cultured prefrontal neurons and in vivo administration of DA reuptake inhibitor. These effects were blocked by prior administration of GSK-3β inhibitors. We explored DA-mediated regulation of GABAA receptor trafficking and exhibited the participation of brefeldin A-inhibited GDP/GTP exchange factor 2 (BIG2) or dynamin-dependent trafficking of GABAA receptors. Together, these data suggest that DA may act through different signaling pathways to affect synaptic inhibition, depending on the concentration. The GSK-3β signaling pathway is involved in DA-induced decrease in BIG2-dependent insertion and an increase in the dynamin-dependent internalization of GABAA receptors, which results in suppression of inhibitory synaptic transmission.

Peculiarities of dopamine receptors on the membrane of multipolar spinal cord neurons of the brook lamprey Lampetra planeri

On isolated multipolar neurons of spinal cord of amniocoete (larva of the brook lamprey Lampetra planeri) by the patch-clamp method in configuration “the whole cell,” a modulating effect of dopamine on potential-activated Na+ currents was studied. Application of dopamine (10 μM) was shown to produce a complex action on the sodium current amplitude. In some cases a decrease of the amplitude, on average, by 13.5 ± 2.2% was found, while in others—an increase, on average, by 8.6 ± 6.1%. The modulation dopamine effect was not accompanied by any changes either of the threshold of the current appearance or of resistance of neuronal cell membranes. Pharmacological analysis with use of dopamine agonist has shown that the agonist of D1-receptors (−)-SKF-38393 (10 μM) decreases the Na+ current amplitude, whereas the agonist of D2-receptors (−)-quinpirole (10 μM) can produce in different cells both an increase, by 30.7 ± 17.0%, and a decrease, by 13.2 ± 3.1%, of the Na+ current amplitude. The obtained data indicate the existence of D1-and D2-receptors on the membrane of multipolar spinal neurons of the amniocoete (larva of the brook lamprey). Study of action of antagonists has shown that the antagonist of D1-receptors (+)-SCH-23390 (10 μM) does not affect action of the agonist of D1-receptors (−)-SKF-38393 (10 μM); the antagonist of D2-receptors (−)-sulpiride (10 μM) blocks completely effects both of the agonist of D1-receptors (−)-SKF-38393 (10 μM) and of the agonist of D2-receptors (−)-quinpirole (10 μM). The antagonist of D1-receptors (+)-SCH-23390 (10 μM) produced no effect on action of the agonist of D1-receptors (−)-SKF-38393 (10 μM). The obtained data indicate peculiarities of dopamine receptors of Cyclostomata as compared with those in mammals.

Frequency-dependent gating of synaptic transmission and plasticity by dopamine

The neurotransmitter dopamine (DA) plays an important role in learning by enhancing the saliency of behaviorally relevant stimuli. How this stimulus selection is achieved on the cellular level, however, is not known. Here, in recordings from hippocampal slices, we show that DA acts specifically at the direct cortical input to hippocampal area CA1 (the temporoammonic (TA) pathway) to filter the excitatory drive onto pyramidal neurons based on the input frequency. During low-frequency patterns of stimulation, DA depressed excitatory TA inputs to both CA1 pyramidal neurons and local inhibitory GABAergic interneurons via presynaptic inhibition. In contrast, during high-frequency patterns of stimulation, DA potently facilitated the TA excitatory drive onto CA1 pyramidal neurons, owing to diminished feedforward inhibition. Analysis of DA's effects over a broad range of stimulus frequencies indicates that it acts as a high-pass filter, augmenting the response to high-frequency inputs while diminishing the impact of low-frequency inputs. These modulatory effects of DA exert a profound influence on activity-dependent forms of synaptic plasticity at both TA-CA1 and Schaffer-collateral (SC)-CA1 synapses. Taken together, our data demonstrate that DA acts as a gate on the direct cortical input to the hippocampus, modulating information flow and synaptic plasticity in a frequency-dependent manner.

The actions of dopamine on the airways.

Dopamine exerts inhibitory and excitatory effects on different systems. In the lungs, dopamine modulates respiratory functions through carotid bodies and modulates pulmonary blood vessel tone, alveolar liquids, and bronchial exchange, and possibly participates in the regulation of airways diameter. It has been reported that dopamine has no acute effect on human airways in normal subjects or those with asthma background. However, inhaled or infused dopamine decreased histamine-induced bronchoconstriction in both normal and asthmatic subjects. We have examined the possible modulating effect of dopamine on bronchial diameter by administering inhaled dopamine and the DA2 dopaminergic blocker metoclopramide to subjects with various degrees of bronchial tone. We examined 56 volunteers. Arterial blood pressure and heart rate were determined in every subject. By means of spirometry, we measured forced vital capacity, forced expiratory volume in the first second, maximal forced expiratory flow, and forced expiratory flow at 50% of vital capacity, before and after each treatment. By inhalation with a nebulizer, we administered dopamine (0.5 microg/kg/min) to 10 healthy subjects, 10 subjects with asthma without acute bronchospasm, and 16 subjects with acute asthma attack; intravenous metoclopramide (7 microg/kg/min) was administered to 10 healthy subjects and 10 subjects with asthma without acute bronchospasm. For ethical reasons, metoclopramide was not used in subjects with acute asthma attack. non-parametric Wilcoxon tests for paired samples, ANOVA tests, and Bonferroni multiple comparison tests were performed. Inhaled dopamine increased forced expiratory volume in the first second, forced vital capacity, maximal forced expiratory flow, and forced expiratory flow at 50% of vital capacity in the acute asthma attack group, but there were no modifications in the healthy group or in the asthma without acute bronchospasm group. Metoclopramide did not induce changes in respiratory parameters in healthy individuals or in those with asthma without acute bronchospasm. Inhaled dopamine was able to induce bronchodilatation when the bronchial tone was already increased by acute asthma attack, but it did not modify the resting bronchial tone in normals or in asthmatics without acute bronchospasm. DA2 blockade with metoclopramide did not modify resting bronchial tone either. We suggest that dopamine exerts a modulatory effect on bronchial tone of human airways depending on the degree of existing basal tone.

Dopamine modulation of neuronal function in the monkey prefrontal cortex

We developed a brain slice preparation that allowed us to apply whole-cell recordings to examine the electrophysiological properties of identified synapses, neurons, and local circuits in the dorsolateral prefrontal cortex (DLPFC) of macaque monkeys. In this article, we summarize the results from some of our recent and current in vitro studies in the DLPFC with special emphasis on the modulatory effects of dopamine (DA) receptor activation on pyramidal and nonpyramidal cell function in superficial layers in DLPFC areas 46 and 9.

D1 and D2 receptor-mediated dopaminergic modulation of visual responses in cat dorsal lateral geniculate nucleus.

The modulatory effects of dopamine (DA) on the visual responses of relay cells of the dorsal aspect of cat lateral geniculate nucleus (dLGN) were tested using local micro-iontophoretic application of DA and application of the receptor-specific agonists SKF38393 (SKF, D1/D5) and quinpirole (QUIN, D2/D3/D4) in the anaesthetized alcuronium-treated cat. The effects of DA and QUIN were clearly dose-dependent: small amounts caused a weak and transient facilitation of visual activity (10-30% increase) preferentially in Y-type relay cells, which changed to a moderate reduction of visual responses when the dose was increased (50%, maximal 70%). The effect of SKF was mainly suppressive and increased with the amount of drug applied (up to 90% reduction). The selective antagonists SCH23390 (SCH, D1) and sulpiride (SULP, D2) reduced the effects of co-applied DA agonists. We found little evidence for a specific dopaminergic modulation of the surround inhibition (stimulus-driven lateral inhibition) although DA slightly facilitated the transmission of weak signals (small stimuli). Nevertheless, some dopaminergic effects seem to be mediated via inhibitory interneurons regulating the strength of sustained or recurrent inhibition. Application of DA agonists during blockade of GABA(A) receptors indicates a direct suppression of relay cells via D1 receptors, an excitation of relay cells via D2 receptors and--with increasing amounts of D2 agonist--probably also an excitation of inhibitory interneurons, which results in an indirect inhibition of dLGN relay cells (predominantly of the X-type). The results are discussed in relation to the impairment of visual functions in Parkinson's disease.

Changes of contrast gain in cat dorsal lateral geniculate nucleus by dopamine receptor agonists

The modulatory effects of dopamine (DA) on the contrast gain of retino-geniculate transmission were tested with local micro-iontophoretical application of DA and the DA receptor agonists SKF38393 (SKF, D1/D5) and quinpirole (QUIN, D2/D3/D4) while recording visually induced spike activity of relay cells of the dorsal aspect of cat lateral geniculate nucleus (dLGN) in the anesthetised and paralyzed preparation. DA and QUIN could either facilitate or inhibit visual activity in a dose-dependent fashion: small amounts caused a facilitation while larger quantities resulted in a more (DA) or less (QUIN) strong inhibition. The effect of SKF was almost always suppressive and increased with the amount of drug applied. The absolute change in activity was depending on stimulus contrast and the strength of the elicited response: facilitation and inhibition of activity was proportional to stimulus contrast and response strength and thus resulted in a changed contrast gain. The results indicate that the visual deficits found in Parkinson's disease patients my be not solely related to retinal dysfunctions.

Modulatory Effect of Dopamine on Doxorubicin-induced Myelosuppression

Bone marrow suppression is a dose-limiting toxicity of anticancer drugs. We have investigated in this study whether dopamine (DA), a catecholamine neurotransmitter, could alleviate the haematotoxicity of doxorubicin (DXN), an established anticancer drug having profound myelotoxicity. DA was injected intraperitoneally at a dose of 50 mg/kg/day for five consecutive days in Swiss mice. The animals received a single intravenous injection of DXN (25 mg/kg) 24h after last injection of DA. DXN caused an immediate and sharp fall in total leucocyte, neutrophil, lymphocyte and platelet counts in peripheral blood, and nucleated cells in femur and spleen. DA treatment before DXN substantially reduced the degree and duration of these abnormalities, and also mediated a significant rise in the number of cells of granulocyte and erythroid lineage in the spleen. DA-pretreated mice showed early recovery of megakaryocytes (MK) and their precursors (SAChE+ cells), and stimulation of pulmonary MK. Thrombopoiesis, assessed in terms of incorporation of 35S by platelets, was stimulated in DA-treated mice. Moreover, DA pretreatment partially protected the day 12 colony-forming unit spleen (CFU-S12) from the lethal effects of DXN, and substantially reduced the mortality of the treated animals. The results demonstrate protection by DA against the myelosuppressive effect of DXN.

Dopaminergic Modulation of Human Bronchial Tone

Background Dopamine exerts inhibitory and excitatory effects on different systems. Its effect on human bronchial tone is controversial. It has been reported that dopamine has no acute effect on human airways from normal subjects or those with asthma background. However, inhaled or infused dopamine decreased histamine-induced bronchoconstriction in both normal and asthmatic subjects. We examined the possible modulating effect of dopamine on bronchial diameter by administering inhaled dopamine and the DA 2 dopaminergic blocker metoclopramide (MTC) to subjects with various degrees of bronchial tone. Methods We examined 50 volunteers. Arterial blood pressure and heart rate were determined in each subject. By means of spirometry, we measured forced vital capacity (FVC), forced expiratory volume in the first second (FEV 1), maximal forced expiratory flow (FEF max), and forced expiratory flow at 50% of vital capacity (FEF 50), before and after each treatment. By inhalation with a nebulizer, we administered the following: a) dopamine (0.5 μg/kg/min) to 10 healthy subjects, 10 subjects with asthma without acute bronchospasm (AWAB), and nine subjects with acute asthma attack (AAA), and b) intravenous (i.v.) metoclopramide (7 μg/kg/min) was administered to 10 healthy subjects and 11 subjects with AWAB. For ethical reasons, MTC was not used in subjects with acute asthma attack. Non-parametric Wilcoxon test for paired samples, ANOVA test, and Bonferroni multiple comparison test were performed. Results Inhaled dopamine increased FEV 1 and FVC, FEF max, and FEF 50 in the AAA group, but there were no modifications in the healthy group or in the AWAB group. Metoclopramide did not induce changes in respiratory parameters in healthy individuals or in those with AWAB. Conclusions Inhaled dopamine is able to induce bronchodilatation when the bronchial tone is already increased by acute asthma attack but did not modify the resting bronchial tone in normal subjects or in asthmatics without acute bronchospasm. Additionally, DA 2 blockade with metoclopramide did not modify resting bronchial tone. Dopamine exerts a modulatory effect on the bronchial tone of human airways depending on the degree of preexisting tone.

Modulatory effects of dopamine D3/2 agonists on kappa opioid-induced antinociception and diuresis in the rat.

The dopamine (DA) D3/2 agonist 7-OH-DPAT has been shown to attenuate the behavioral effects of the mu agonist morphine as well as the development of morphine tolerance. To evaluate the effects of DA D3/2 agonists [7-OH-DPAT, (+)-PD128,907, quinelorane, (-)-quinpirole], a D1 agonist (SKF38393), a D1 antagonist [(+)-SCH23390], a DA antagonist (spiperone), and an indirect DA agonist (cocaine) on the antinociceptive effects of kappa agonists (spiradoline, U69,593, bremazocine) as well as the effects of D3/2 agonists on the diuretic effects of spiradoline. Antinociception was determined using a warm water (50-55 degrees C) tail-withdrawal procedure and urine output was collected over a 2-h interval. The antinociceptive effects produced by the kappa agonists varied with the intensity of the nociceptive stimulus (water), as maximal or near maximal effects were obtained with spiradoline at 55 degrees C, U69,593 at 52 degrees C, and bremazocine at 50 degrees C water. 7-OH-DPAT produced a dose-dependent attenuation of the antinociceptive effects of spiradoline, U69,593, and bremazocine. Spiperone completely reversed the effects of 7-OH-DPAT on spiradoline antinociception. (+)-PD128,907 and quinelorane, but not (-)-quinpirole or the other DAergic agents examined, attenuated the antinociceptive effects of spiradoline in a dose- and time-dependent manner. The diuretic effects of spiradoline were attenuated by 7-OH-DPAT, (+)-PD128,907, quinelorane, and (-)-quinpirole, and this attenuation was reversed by spiperone. The present study demonstrated that some D3/2 agonists can modulate both the antinociceptive and diuretic effects of kappa agonists. These modulatory actions are similar to those obtained against the effects of mu agonists.

Calcium currents in turtle retinal ganglion cells. II. Dopamine modulation via a cyclic AMP-dependent mechanism.

1. Voltage-activated calcium currents participate in shaping the firing pattern of neurons. Calcium currents also have a role in signal transduction. In the retina, little is known of the regulation of calcium entry into neurons via voltage-activated channels. In the present series of experiments we used standard whole cell and perforated patch clamp techniques to study the ability of the neurotransmitter dopamine (DA) to modulate voltage-dependent calcium currents in isolated turtle retinal ganglion cells. 2. Two types of calcium current have been described in these cells, one transient and the other sustained. Here we focused our studies primarily on the sustained current (ICa). Exogenous DA reduced ICa in some cells (59%), facilitated ICa in others (17%), or had no effect on the remainder (24%). Regardless of the action of DA, there was no effect on the voltage dependence of ICa. In addition, the effects were all reversible. The average magnitude of decrease was 43%, whereas that of increase was 75%. 3. The application of a specific D1 receptor agonist, SKF38393, mimicked the effect of DA. This was also true for a membrane permeable cyclic AMP (cAMP) analogue (8-CPT-cAMP). Inhibition of protein kinase A (PKA) activity by a specific inhibitor, IP20-amide, injected into cells prevented the modulatory effects of DA on ICa. 4. Immunocytochemical studies demonstrated that DA stimulation of the retina significantly increased the level of cAMP immunoreactivity in peripheral ganglion cells, whereas those cells in central retina were less affected. Forskolin induced a general elevation of cytoplasmic cAMP staining in all ganglion cells. 5. Current clamp experiments were carried out to determine the role of the calcium currents in action potential generation. Both the sustained and transient currents participated in the shaping of current-induced firing patterns of isolated cells. Depolarizing current-induced spiking of ganglion cells was found to be highly modified by dopamine. 6. These results support the notion that endogenous DA modulates the conductance of voltage-dependent calcium channels in turtle retinal ganglion cells and that this modulation is mediated by a D1 dopamine receptor-cAMP-PKA pathway. The direct result of this modulation is an alteration in the signaling properties of certain cells.

Variability and selectivity of anterior pituitary response to dopamine agonists throughout the normal menstrual cycle

To clarify whether there is a variation of dopamine effect throughout the normal menstrual cycle, 24 studies were performed during the follicular, periovulatory, and luteal phase in seven ovulatory women. The subjects were studied for 24 hours after receiving two different dopamine agonists, 2.5 mg of bromocriptine in one cycle and 50 μg of pergolide in a subsequent cycle. Baseline plasma luteinizing hormone, follicle-stimulating hormone, prolactin, and thyrotropin were followed through time, and the dynamic responses to gonadotropin-releasing hormone and thyrotropin-releasing hormone before and at 6 and 22 hours after medication were studied. Since the results obtained with both agonists were similar, the data have been combined in a single group. Baseline luteinizing hormone levels (but not follicle-stimulating hormone) were significantly suppressed (p < 0.01) during the follicular phase only, and the plasma luteinizing hormone and follicle-stimulating hormone response to gonadotropin-releasing hormone was not affected by the agonists in any of the three cycle phases. Baseline plasma prolactin was suppressed equally (p < 0.005) in all phases of the cycle, and the response to thyrotropin-releasing hormone was similarly suppressed in all phases only at 6 hours (p < 0.002). Baseline thyrotropin also was suppressed (p < 0.01) in all phases but the degree of inhibition was greater in the luteal than in the follicular phase (p < 0.05). The response to thyrotropin-releasing hormone was inhibited, with the smallest response seen at 22 hours (p < 0.01). In conclusion, these results suggest that the modulatory effect of dopamine on pituitary hormone secretion is variable and selective throughout the normal menstrual cycle. The greatest inhibition is on prolactin release, which is similar in all phases, followed by thyrotropin, which is greater in the luteal phase, and then by luteinizing hormone in the follicular phase only; it has no effect on follicle-stimulating hormone release.

Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization

Intracellular recordings were obtained from directly identified rat nigral dopamine cells in vivo. This identification was based on an increase in glyoxylic acid-induced catecholamine fluorescence in the impaled dopamine neurons. One of three compounds was injected intracellularly into each cell to produce the heightened fluorescence: (1) l-DOPA, to increase the intracellular dopamine content by precursor loading; (2) tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, to increase intracellular dopamine concentration through activation of the rate-limiting enzyme for dopamine synthesis and (3) colchicine, to arrest intraneuronal transport and thus allow the build-up of dopamine synthesizing enzymes and dopamine in the soma. In addition, dopamine cells were antidromically activated from the caudate nucleus and collision with a directly elicited action potential was demonstrated. Identified dopamine neurons were shown to possess an input resistance of 31.2 ± 7.4 MΩ (means ± SD) and a time constant of 12.1 ± 3.2 ms. The action potentials were of long duration (2.75 ± 0.5 ms) with a marked break between the initial segment and the somatodendritic spike components. The initial segment was the only component commonly elicited during antidromic activation. Spontaneously occurring action potentials were usually preceded by a slow, pacemaker-like depolarization. Burst firing by summation of depolarizing afterpotentials was observed to occur spontaneously, but could not be triggered by short depolarizing current pulses. Intravenously administered apomorphine demonstrated the same inhibitory effect on cell firing that was previously reported to occur when recording extracellularly from identified dopaminergic neurons. The determination of the electrophysiological characteristics of a population of cells directly identified as containing a specific neurotransmitter (in this case, dopamine) may allow one to construct better models of a system's functioning. Thus, the high input resistance and long time constant of dopamine-containing cells, combined with their burst/pause firing mode, may be important functionally with respect to a possible modulatory effect of dopamine in postsynaptic target areas.