Modulatory Actions Of Dopamine Research Articles

Dopamine regulation of striatal inhibitory transmission and plasticity: dopamine, low or high?

Basal ganglia are known for their involvement in motor control. This function is accomplished via the modulatory actions of different signalling molecules; one of these is dopamine (DA), which, besides regulating cognition and reward mechanisms, participates in the organization of motor programmes by filtering and selecting cortical commands on striatal synapses (Bromberg-Martin et al., 2010). Modulatory actions of DA in the striatum are very well described in relation to corticostriatal inputs and glutamatergic release on GABAergic medium spiny neurons (MSNs), the projection cells of the nucleus (Cepeda et al., 1993). However, the nigrostriatal pathway's DA also ends at the striatal local GABAergic circuits made by synaptic inputs on MSNs, which come from axonal collaterals of other MSNs, as well as from GABAergic interneurons (Koos et al., 2004). These inhibitory influences shape MSNs activity, both of which DA modulates (Guzman et al., 2003). We recently reported that DA decreases the effect of inhibitory synapses between GABAergic interneurons on MSNs (Nieto-Mendoza and Hernandez-Echeagaray, 2015); however, DA's effects on long-term synaptic plasticity induced in these synapses (GABAergic interneurons-MSNs) depend on the DA concentration and DA receptor subtype activation. High frequency stimulation at low DA concentrations produced mostly long-term depression (LTD), which was also favored in the presence of a D2 agonist, whereas a high concentration of DA favored the generation of long-term potentiation (LTP), which was associated with D1 receptor activation. DA neurons normally display a tonic and slow-firing frequency that is correlated to low rates of DA release; however, high frequency firing of nigrostriatal cells is associated with increases in DA release in the striatum (Cachope and Cheer, 2014). Alterations in striatal DA physiological levels are associated with some neurodegenerative diseases. Low DA levels lead to motor impairments, such as tremors, stiffness or slowing of movement characteristics of Parkinson's disease (PD). On the other hand, increased DA levels have been observed in Huntington's disease (HD), which, besides movement alterations, is also associated with cognitive and psychiatric disorders (Cepeda et al., 2014). We evaluated how the synaptic plasticity between GABAergic interneurons and MSNs was modified in mice treated with non-toxic doses of the mitochondrial inhibitor 3-nitropropionic acid (3-NP), a toxin used as a pharmacological model of striatal degeneration because it mimics some of the features of early stages of HD. The plasticity produced in slices from 3-NP-treated mice in vivo was similar to the LTP triggered under high levels of DA in healthy tissue slices. The D2 antagonist did not affect the LTP, but in the presence of the PKA inhibitor, it prevented LTP induction and generated LTD, suggesting that in a damaged striatum, D1/PKA signalling pathway play a preponderant role in the generation of LTP. Sustained elevation of DA in the striatum causes motor dysfunction, as well as the selective degeneration of MSN (Cyr et al., 2002; Chen et al., 2013). It is known that 3-NP treatment increases DA levels in the striatum (Johnson et al., 2000), and therefore, LTP produced in the inhibitory synapses on MSN, which express D1 receptors, may result from an increase of DA levels in the striatum, modulating inputs of interneurons that largely project to the perisomatic area of MSNs. This occurs because 3-NP treatment reduces the number of spines and the thickness of the dendrites (Mendoza et al., 2014). The interneurons responsible for inhibition in the perisomatic area of MSNs are known to have a synaptic impact, mainly on MSNs expressing D1 receptors (Gustafson et al., 2006). This inhibition is important because GABAergic LTP in MSNs that express D1 receptors may protect them from excitatory inputs from the cortex, and perhaps this is one of the reasons why these neurons are less damaged than are D2 expressing cells in the early stages of striatal degeneration. What can we learn from this? Similar to with excitatory synaptic plasticity in the striatum, DA modulates inhibitory long-term synaptic plasticity. In addition, activation of D1 or D2 DA receptors favors LTP or LTD expression, respectively, while low DA concentration favors LTD through D2 receptor activation. Likewise, increments of DA levels or striatal degeneration promote LTP associated with D1 receptor activation. LTP in the inhibitory synapses on MSN expressing D1 receptors may prevent exacerbated activity of the direct pathway (D1), and perhaps, may also prevent uncontrolled movement in the early stages of striatal degeneration, while LTD in the inhibitory synapses will also disinhibit the indirect pathway (D2), promoting movement. This work was supported by Consejo Nacional de Ciencia y Tecnologia, CONACYT-81062.

Moderate Alcohol Exposure during the Rat Equivalent to the Third Trimester of Human Pregnancy Alters Regulation of GABAA Receptor-Mediated Synaptic Transmission by Dopamine in the Basolateral Amygdala

Fetal ethanol (EtOH) exposure leads to a range of neurobehavioral alterations, including deficits in emotional processing. The basolateral amygdala (BLA) plays a critical role in modulating emotional processing, in part, via dopamine (DA) regulation of GABA transmission. This BLA modulatory system is acquired during the first 2 weeks of postnatal life in rodents (equivalent to the third trimester of human pregnancy) and we hypothesized that it could be altered by EtOH exposure during this period. We found that exposure of rats to moderate levels of EtOH vapor during the third trimester-equivalent [postnatal days (P) 2–12] alters DA modulation of GABAergic transmission in BLA pyramidal neurons during periadolescence. Specifically, D1R-mediated potentiation of spontaneous inhibitory postsynaptic currents (IPSCs) was significantly attenuated in EtOH-exposed animals. However, this was associated with a compensatory decrease in D3R-mediated suppression of miniature IPSCs. Western blot analysis revealed that these effects were not a result of altered D1R or D3R levels. BLA samples from EtOH-exposed animals also had significantly lower levels of the DA precursor (L-3,4-dihydroxyphenylalanine) but DA levels were not affected. This is likely a consequence of reduced catabolism of DA, as indicated by reduced levels of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the BLA samples. Anxiety-like behavior was not altered in EtOH-exposed animals. This is the first study to demonstrate that the modulatory actions of DA in the BLA are altered by developmental EtOH exposure. Although compensatory adaptations were engaged in our moderate EtOH exposure paradigm, it is possible that these are not able to restore homeostasis and correct anxiety-like behaviors under conditions of heavier EtOH exposure. Therefore, future studies should investigate the potential role of alterations in the modulatory actions of DA in the pathophysiology of fetal alcohol spectrum disorders.

Dampened dopamine‐mediated neuromodulation in prefrontal cortex of fragile X mice

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

Modulatory actions of dopamine and serotonin on insect antennal lobe neurons: insights from studies in vitro

Biogenic amines play diverse roles in the development and modulation of invertebrate neurons and ultimately also, in the regulation of animal behaviour. Here we examine the contribution that analyses of antennal lobe neurons in vitro have made towards our understanding of the mechanisms through which dopamine and serotonin operate in primary olfactory centres of the brain of the moth, Manduca sexta and the honey bee, Apis mellifera. This chapter reviews evidence suggesting that these biogenic amines function as regulators of neuronal development and as mediators of cellular and behavioural plasticity, in part at least, through the modulation of K(+) conductances in the cells. Insect neurons in vitro provide an excellent model for exploring basic principles of amine function and their impact on neuronal excitability.

Dopamine presynaptically and heterogeneously modulates nucleus accumbens medium-spiny neuron GABA synapses in vitro.

BackgroundThe striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections.ResultsWe examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABAA, GABAB, norepinephrine and serotonin modulation, revealing a multiplicity of modulatory autoreceptors and heteroreceptors on individual varicosities. In some instances, autaptic connections had two components that were differentially modulated by dopamine agonists, suggesting that dopamine receptors could be distributed heterogeneously on the presynaptic varicosities making up a single synaptic (i.e. autaptic) connection.ConclusionDifferential trafficking of dopamine receptors to different presynaptic varicosities could explain the many controversial studies reporting widely varying degrees of dopamine receptor colocalization in medium-spiny neurons, as well as more generally the diversity of dopamine actions in target areas. Longer-term changes in the modulatory actions of dopamine in the striatal complex could be due to plasticity in the presynaptic distribution of dopamine receptors on medium-spiny neuron varicosities.

Dopamine Modulation of Honey Bee (Apis mellifera) Antennal-Lobe Neurons

Primary olfactory centers [antennal lobes (ALs)] of the honey bee brain are invaded by dopamine (DA)-immunoreactive neurons early in development (pupal stage 3), immediately before a period of rapid growth and compartmentalization of the AL neuropil. Here we examine the modulatory actions of DA on honey bee AL neurons during this period. Voltage-clamp recordings in whole cell configuration were used to determine the effects of DA on ionic currents in AL neurons in vitro from pupal bees at stages 4-6 of the nine stages of metamorphic adult development. In approximately 45% of the neurons tested, DA (5-50 x 10(-5) M) reduced the amplitude of outward currents in the cells. In addition to a slowly activating, sustained outward current, DA reduced the amplitude of a rapidly activating, transient outward conductance in some cells. Both of the currents modulated by DA could be abolished by the removal of Ca2+ from the external medium or by treatment of cells with charybdotoxin (2 x 10(-8) M), a blocker of Ca2+-dependent K+ currents in the cells. Ca2+ currents were not affected by DA, nor were A-type K+ currents (I(A)). Results suggest that the delayed rectifier-like current (I(KV)) also remains intact in the presence of DA. Taken together, our data indicate that Ca2+-dependent K+ currents are targets of DA modulation in honey bee AL neurons. This study lends support to the hypothesis that DA plays a role in the developing brain of the bee.

The modulatory actions of dopamine D2/3 agonists and antagonists on the locomotor-activating effects of morphine and caffeine in mice

Morphine produces robust increases in locomotor activity in mice. Recent data indicate that dopamine (DA) D2/3 agonists attenuate the discriminative stimulus and antinociceptive effects of mu opioid agonists such as morphine. The present study was designed to determine the extent to which D2/3 receptor activation and blockade can modulate morphine-induced locomotion using a novel cumulative dosing procedure in Swiss–Webster mice. The results indicate that morphine-induced locomotion is nonsignificantly attenuated by the D2/3 agonists quinelorane and quinpirole, whereas the D2/3 antagonists eticlopride and nafadotride, as well as the partial D2/3 agonist BP897, significantly reduced morphine-induced locomotion. To determine the specificity of this modulation, these agonists and antagonists were examined in combination with caffeine, a drug that also indirectly alters DAergic activity. Unlike the effects on morphine, caffeine-induced locomotion was unaltered by eticlopride, nafadotride and BP897, but was attenuated by quinelorane and quinpirole. These results indicate that modulation of D2/3 receptors can, in turn, alter the locomotor-activating effects of morphine.

Dopamine Modulation of Responses Mediated by Excitatory Amino Acids in the Neostriatum

This chapter summarizes several studies that have been designed to examine the electrophysiological interactions that occur when subtypes of dopamine (DA) and excitatory amino acid (EAA) receptors are activated simultaneously and to test the hypothesis that the direction of DA modulation is a function of both the subtype of EAA receptor and the subtype of DA receptor activated. The present findings demonstrate that the complex modulatory actions of DA are dependent on combinations of coactivation of specific subtypes of EAA and DA receptors. The chapter demonstrates that the direction of the modulatory effects of DA receptor agonists can be very predictable if the subtype of receptor activated is controlled. When N-methyl-D-aspartate (NMDA) receptors are activated, D1 DA receptor agonists potentiate excitatory responses. When non-NMDA receptors are activated, D2 DA receptor agonists attenuate excitatory responses. Application of the D2-receptor agonist, quinpirole produced inconsistent effects from cell to cell. Thus responses mediated by NMDA receptors are consistently potentiated by D1 DA agonists, while those mediated by non- NMDA receptors are consistently attenuated by D2 DA agonists. These findings are of clinical relevance since the actions of DA and EAAs have been implicated in neurological and affective disorders.

Dopamine enhancement and depression of glutamate-regulated calcium and electrical activity in hypothalamic neurons.

1. The neurotransmitter dopamine is found throughout the hypothalamus both in cell bodies and in axons originating from intra- and extrahypothalamic sources. To study the mechanisms of action of dopamine on cultured rat hypothalamic neurons, particularly in relation to Ca2+ regulation, we used Ca2+ digital imaging with fura-2 and whole cell patch-clamp recording. We focused on the modulatory actions of dopamine on glutamate. 2. Dopamine administration had little or no independent effect on intracellular Ca2+. However, in the presence of tetrodotoxin to block action potentials and action-potential-dependent transmitter release, dopamine (10 microM for 2-3 min) caused an increase in glutamate-evoked Ca2+ rises in 22% of 64 neurons and depressed glutamate-evoked Ca2+ rises in an equal number of neurons. Shorter exposure to dopamine reduced the number of responding cells. 3. Dopamine application to neurons with an elevated Ca2+ due to synaptic release of glutamate (in the absence of tetrodotoxin) generally caused a decrease in Ca2+ levels (40% of 106 neurons), but sometimes increased cytosolic Ca2+ (10% of 106 neurons). That dopamine influenced cells differently in conditions of spontaneous activity compared with evoked activity may be due to dopamine effects on presynaptic receptors detected under conditions of ongoing synaptic release of glutamate. 4. Dopamine modulation of glutamate responses was detected at early stages of neuronal development (embryonic day 18 after 2 days in vitro) and also after 60 days in vitro. 5. The D1, D2, and D3 dopamine receptor agonists SKF38393, quinpirole, and 7-OH-DPAT (+/- 7 hydroxy-dipropylaminotetralin) caused a reduction in Ca2+ levels raised by endogenous glutamate release or evoked by exogenous glutamate application. 6. To block the actions of dopamine released by hypothalamic neurons, D1 and D2 dopamine receptor antagonists were used. As with dopamine, dopamine antagonists had no effect on intracellular Ca2+ during glutamate receptor blockade. In the absence of glutamate receptor block, the D1 antagonist SCH23390 (1 microM) reduced Ca2+ in responding cells; in contrast, the D2 antagonist eticlopride (1 microM) generated a delayed increase in Ca2+ levels. 7. Dopamine is known to activate second messengers through G proteins independent of changes in membrane potential or input resistance. Whole cell recording was used to demonstrate that, parallel to the modulation of Ca2+, dopamine exerted a dramatic change in glutamate-mediated electrical activity, generally depressing activity and hyperpolarizing the membrane potential (8 of 15 neurons). In a smaller number of neurons (5 of 15), dopamine enhanced glutamate-mediated excitatory activity. 8. Dopamine-evoked changes in membrane potential were in part mediated through modulation of glutamate actions. Dopamine depressed glutamate-evoked currents in a dose-dependent fashion, with Hill slopes in individual neurons ranging from 0.3 to 0.6. Dopamine could also evoke a direct hyperpolarizing action on hypothalamic neurons in the presence of tetrodotoxin or glutamate receptor blockers, at least in part by opening K+ channels. 9. Glutamate plays an important role as a primary excitatory transmitter within the hypothalamus. Our data support the hypothesis that a major mechanism of dopamine's influence on hypothalamic neurons involves the modulation of glutamate's excitatory action, mostly by inhibition. This is consistent with the hypothesis that modulation of glutamate activity may be an important mechanism of dopamine action throughout the nervous system.

Modulatory Actions of Dopamine on NMDA Receptor-Mediated Responses Are Reduced in D1A-Deficient Mutant Mice

The role of D1 dopamine (DA) receptors in mediating the ability of DA to modulate responses attributable to activation of NMDA receptors was examined in mice lacking D1A dopamine receptors. Specifically, experiments were designed to test the hypothesis that the ability of DA to potentiate responses mediated by activation of NMDA receptors was attributable to activation of D1 receptors. Based on this hypothesis, we would predict that in the D1A mutant mouse, either DA would not induce enhancement of NMDA-mediated responses, or the enhancement would be severely attenuated. The results provided evidence to support the hypothesis. In mutant mice, DA and D1 receptor agonists did not potentiate responses mediated by activation of NMDA receptors. In contrast, in control mice, both DA and D1 receptor agonists markedly potentiated responses mediated by activation of NMDA receptors. The effects of DA in attenuating responses mediated by activation of non-NMDA receptors also were altered in the mutant, suggesting that this action of DA may require coupling or interactions between D1 and D2 receptors. The present studies also provided an opportunity to assess some of the basic electrophysiological and morphological properties of neostriatal neurons in mice lacking D1A DA receptors. Resting membrane potential, action potential parameters, input resistance, excitability, somatic size, dendritic extent, and estimates of spine density in mutants and controls were similar, suggesting that these basic neurophysiological and structural properties have not been changed by the loss of the D1A DA receptor.

Immunocytochemical localization of D1 and D2 dopamine receptors in the basal ganglia of the rat: light and electron microscopy.

The modulatory actions of dopamine on the flow of cortical information through the basal ganglia are mediated mainly through two subtypes of receptors, the D1 and D2 receptors. In order to examine the precise cellular and subcellular location of these receptors, immunocytochemistry using subtype specific antibodies was performed on sections of rat basal ganglia at both the light and electron microscopic levels. Both peroxidase and pre-embedding immunogold methods were utilized. Immunoreactivity for both D1 and D2 receptors was most abundant in the neostriatum where it was mainly contained within spiny dendrites and in perikarya. Although some of the immunoreactive perikarya had characteristics of interneurons, most were identified as medium-sized spiny neurons. Immunoreactivity for D1 receptor but not D2 receptor was associated with the axons of the striatonigral pathway and axons and terminals in the substantia nigra pars reticulata and the entopeduncular nucleus. In contrast, D2 immunoreactivity but not D1 immunoreactivity was present in the dopaminergic neurons in the substantia nigra pars compacta and ventral pars reticulata. In the globus pallidus, little immunoreactivity for either D1 or D2 receptor was detected. At the subcellular level, D1 and D2 receptor immunoreactivity was found to be mainly associated with the internal surface of cell membranes. In dendrites and spines immunoreactivity was seen in contact with the membranes postsynaptic to terminals forming symmetrical synapses and less commonly, asymmetrical synapses. The morphological features and membrane specializations of the terminals forming symmetrical synapses are similar to those of dopaminergic terminals previously identified by immunocytochemistry for tyrosine hydroxylase. In addition to immunoreactivity associated with synapses, a high proportion of the immunoreactivity was also on membranes at non-synaptic sites. It is concluded that dopamine receptor immunoreactivity is mainly associated with spiny output neurons of the neostriatum and that there is a selective association of D1 receptors with the so-called direct pathway of information flow through the basal ganglia, i.e. the striatoentopeduncular and striatonigral pathways. Although there is an association of receptor immunoreactivity with afferent synaptic inputs a high proportion is located at extrasynaptic sites.

Differential modulation of striatonigral dynorphin and enkephalin by dopamine receptor subtypes

Previous studies indicate that dopaminergic transmission inhibits the biosynthesis of enkephalin and stimulates that of dynorphin in the striatonigral pathway of intact rat. The purpose of this study was to determine which dopamine (DA) receptor subtype(s) mediate the modulatory actions of DA. We measured striatal and nigral levels of enkephalin and dynorphin in: (1) intact rats repeatedly injected with D 1 (SKF-38393, 5 mg/kg, i.p.) or D 2 (LY-171555, 1 mg/kg, i.p.) agonists, alone or in combination, (2) 6-hydroxydopamine (6-OHDA)-lesioned rats repeatedly injected with the same D 1 or D 2 agonists, and (3) intact rats repeatedly injected with D 1 (SCH-23390, 0.05 mg/kg, s.c.) or D 2 (sulpiride, 100 mg/kg, s.c.) antagonists, given alone or in combination with the mixed D1/D2 agonist apomorphine (5 mg/kg, i.p.). Repeated injections of the D 1 agonist to intact rats (twice daily for 7 days) produced a small but not statistically significant increase in striatal levels of dynorphin; similar treatment with the D 2 agonist did not affect dynorphin levels at all. Combined treatments with D 1 and D 2 agonists did not potentiate the effect of the D 1 agonist. 6-OHDA lesions of the nigrostriatal DA pathway alone decreased the level of dynorphin in both the striatum and substantia nigra. However, repeated D 1 agonist, but not D 2, injections not only reversed the decrease in dynorphin levels, but caused a significant increase above control levels. In intact rats, repeated injections of the D 1 or D 2 antagonist alone failed to alter the levels of dynorphin, but the D 1 antagonist, not the D 2 antagonist, attenuated the apomorphine-induced increase in striatal dynorphin. Regulation of striatal [Met 5]enkephalin (ME) was found to be different from that of dynorphin. While repeated D 1 agonist injections in intact rats had no effect on striatal ME, D 2 agonist treatment caused a modest increase in ME. The effect of the D 2 agonist in intact rats was blocked by co-administration with the D 1 agonist. In addition, 6-OHDA lesions alone increased striatal levels of ME, and this increase was blocked by the D 1 agonist, but not the D 2 agonist. Finally, the D 1 antagonist increased the striatal level of ME in intact rats, whereas the D 2 antagonist had no effect. These data indicate that D 1 receptors mediate excitatory control over the biosynthesis of striatonigral dynorphin and also exert a tonic inhibitory influence on the enkephalin system. Furthermore, stimulation of the D 2 subtype imposes an excitatory stimulus on enkephalin biosynthesis but has no effect on dynorphin.