Modulation Of Dopaminergic Transmission Research Articles

The adenosine A2A receptor in the basal ganglia: Expression, heteromerization, functional selectivity and signalling.

Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A1, A2A, A2B and A3, which are widely expressed in cells of the nervous system. The A2A receptor (A2AR), the GPCR with the highest expression in the striatum, has a similar role to that of receptors for dopamine, one of the main neurotransmitters. Neuronal and glial A2ARs participate in the modulation of dopaminergic transmission and act in almost any action in which the basal ganglia is involved. This chapter revisits the expression of the A2AR in the basal ganglia in health and disease, and describes the diversity of signalling depending on whether the receptors are expressed as monomer or as heteromer. The A2AR can interact with other receptors as adenosine A1, dopamine D2, or cannabinoid CB1 to form heteromers with relevant functions in the basal ganglia. Heteromerization, with these and other GPCRs, provides diversity to A2AR-mediated signalling and to the modulation of neurotransmission. Thus, selective A2AR antagonists have neuroprotective potential acting directly on neurons, but also through modulation of glial cell activation, for example, by decreasing neuroinflammatory events that accompany neurodegenerative diseases. In fact, A2AR antagonists are safe and their potential in the therapy of Parkinson's disease has already led to the approval of one of them, istradefylline, in Japan and United States. The receptor also has a key role in reward circuits and, again, heteromers with dopamine receptors, but also with cannabinoid CB1 receptors, participate in the events triggered by drugs of abuse.

Expression of Heparan Sulfate Endosulfatases in the Adult Mouse Brain: Co-expression of Sulf1 and Dopamine D1/D2 Receptors.

The heparan sulfate 6-O-endosulfatases, Sulfatase 1 (Sulf1), and Sulfatase 2 (Sulf2), are extracellular enzymes that regulate cellular signaling by removing 6-O-sulfate from the heparan sulfate chain. Although previous studies have revealed that Sulfs are essential for normal development, their functions in the adult brain remain largely unknown. To gain insight into their neural functions, we used in situ hybridization to systematically examine Sulf1/2 mRNA expression in the adult mouse brain. Sulf1 and Sulf2 mRNAs showed distinct expression patterns, which is in contrast to their overlapping expression in the embryonic brain. In addition, we found that Sulf1 was distinctly expressed in the nucleus accumbens shell, the posterior tail of the striatum, layer 6 of the cerebral cortex, and the paraventricular nucleus of the thalamus, all of which are target areas of dopaminergic projections. Using double-labeling techniques, we showed that Sulf1-expressing cells in the above regions coincided with cells expressing the dopamine D1 and/or D2 receptor. These findings implicate possible roles of Sulf1 in modulation of dopaminergic transmission and dopamine-mediated behaviors.

Shati/Nat8l deficiency disrupts adult neurogenesis and causes attentional impairment through dopaminergic neuronal dysfunction in the dentate gyrus.

Successful completion of daily activities relies on the ability to select the relevant features of the environment for memory and recall. Disruption to these processes can lead to various disorders, such as attention-deficit hyperactivity disorder (ADHD). Dopamine is a neurotransmitter implicated in the regulation of several processes, including attention. In addition to the higher-order brain function, dopamine is implicated in the regulation of adult neurogenesis. Previously, we generated mice lacking Shati, an N-acetyltransferase-8-like protein on a C57BL/6J genetic background (Shati/Nat8l-/- ). These mice showed a series of changes in the dopamine system and ADHD-like behavioral phenotypes. Therefore, we hypothesized that deficiency of Shati/Nat8l would affect neurogenesis and attentional behavior in mice. We found aberrant morphology of neurons and impaired neurogenesis in the dentate gyrus of Shati/Nat8l-/- mice. Additionally, research has suggested that impaired neurogenesis might be because of the reduction of dopamine in the hippocampus. Galantamine (GAL) attenuated the attentional impairment observed in the object-based attention test via increasing the dopamine release in the hippocampus of Shati/Nat8l-/- mice. The α7 nicotinic acetylcholine receptor antagonist, methyllycaconitine, and dopamine D1 receptor antagonist, SCH23390, blocked the ameliorating effect of GAL on attentional impairment in Shati/Nat8l-/- mice. These results suggest that the ameliorating effect of GAL on Shati/Nat8l-/- attentional impairment is associated with activation of D1 receptors following increased dopamine release in the hippocampus via α7 nicotinic acetylcholine receptor. In summary, Shati/Nat8l is important in both morphogenesis and neurogenesis in the dentate gyrus and attention, possible via modulation of dopaminergic transmission. Cover Image for this issue: https://doi.org/10.1111/jnc.15061.

Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia

Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post-mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia – even prior to antipsychotic use – seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia.

Different Interactions of Prolyl Oligopeptidase and Neurotensin in Dopaminergic Function of the Rat Nigrostriatal and Mesolimbic Pathways

Prolyl oligopeptidase (PREP) is an intracellular enzyme digesting small proline-containing peptides. Since PREP resides the same brain areas as neurotensin in the nigrostriatal and mesolimbic dopaminergic pathways, we were interested to study if there is an intracellular interaction between them. A colocalization of PREP with neurotensin and neurotensin receptor 1 (NTS1) in the rat striatum, nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) was studied with immunofluorescence. From the same brain areas, the levels of dopamine and its metabolites were measured 1h after the injection of saline, NTS1 ligands (JMV-449; 5μg) or antagonist (SR142948; 5μg) to the rat striatum or NAcc. We also studied whether an intraperitoneal injection of a PREP inhibitor (KYP-2047; 5mg/kg) affects the levels of dopamine and its metabolites alone or modifies the effects of the NTS1 ligands. PREP was highly colocalized with neurotensin and NTS1 in the VTA, and with NTS1 in the SN. Colocalization was moderate or low in other brain areas. When injected to the striatum, JMV-449 had a tendency to increase dopamine (p=0.052) and metabolite levels in the striatum and SN, whereas SR142948 did not. After the injection to the NAcc, JMV-449 but not SR142948, increased dopamine levels in the VTA and dopamine metabolite levels in the NAcc and VTA. KYP-2047 decreased the dopamine levels in the striatum, but increased dopamine metabolite levels in the NAcc and VTA. Our results suggest a novel role for PREP in the modulation of dopaminergic transmission, which may be different in nigrostriatal and mesolimbic pathways.

Abnormal bihemispheric responses in schizophrenia patients following cathodal transcranial direct stimulation

Post-mortem and in vivo studies provide evidence for a link between reduced plasticity and dysconnectivity in schizophrenia patients. It has been suggested that the association between plasticity and connectivity contributes to the pathophysiology and symptomatology of schizophrenia. However, little is known about the impact of glutamate-dependent long-term depression (LTD)-like cortical plasticity on inter-hemispheric connectivity in schizophrenia patients. The aim of the present study was to investigate LTD-like cortical plasticity following excitability-diminishing cathodal transcranial direct current stimulation (tDCS) of the left primary motor cortex (M1) and its effects on the non-stimulated right M1. Eighteen schizophrenia patients and 18 matched (age, gender, handedness, and smoking status) control subjects were investigated in this study. Corticospinal excitability changes following tDCS and intra-cortical inhibitory circuits were monitored with transcranial magnetic stimulation. On the stimulated hemisphere, cathodal tDCS increased resting motor thresholds (RMT) in both groups and decreased motor-evoked potential (MEP) sizes in healthy controls to a greater extent compared to schizophrenia patients. On the non-stimulated hemisphere, RMTs were increased and MEPs were decreased only in the healthy control group. Our results confirm previous findings of reduced LTD-like plasticity in schizophrenia patients and offer hypothetical and indirect in vivo evidence for an association between LTD-like cortical plasticity and inter-hemispheric connectivity in schizophrenia patients. Moreover, our findings highlight the impact of plasticity on connectivity. Dysfunctional N-methyl d-aspartate receptors or modulation of dopaminergic transmission can explain these findings. Nevertheless, the effects of antipsychotic medication still need to be considered.

Interactions between histamine H 3 and dopamine D 2 receptors and the implications for striatal function

The striatum contains a high density of histamine H 3 receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H 3 and dopamine D 1 receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H 3 and dopamine D 2 receptors. In this study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynaptic interactions between H 3 and D 1 and also between H 3 and dopamine D 2 receptors. The selective H 3 receptor agonist imetit inhibited, while the H 3 receptor antagonist thioperamide potentiated locomotor activation induced by either the D 1 receptor agonist SKF 38393 or the D 2 receptor agonist quinpirole. High scores of locomotor activity were obtained with H 3 receptor blockade plus D 1 and D 2 receptor co-activation, i.e., when thioperamide was co-administered with both SKF 38393 and quinpirole. Radioligand binding experiments in striatal membrane preparations showed the existence of a strong and selective H 3–D 2 receptor interaction at the membrane level. In agonist/antagonist competition experiments, stimulation of H 3 receptors with several H 3 receptor agonists significantly decreased the affinity of D 2 receptors for the agonist. This kind of intramembrane receptor–receptor interactions are a common biochemical property of receptor heteromers. In fact, by using Bioluminescence Resonance Energy Transfer techniques in co-transfected HEK-293 cells, H 3 (but not H 4) receptors were found to form heteromers with D 2 receptors. This study demonstrates an important role of postsynaptic H 3 receptors in the modulation of dopaminergic transmission by means of a negative modulation of D 2 receptor function.

3H]DPDPE binding to δ opioid receptors in the rat mesocorticolimbic and nigrostriatal pathways is transiently increased by acute ethanol administration

Dopaminergic transmission in the mesolimbic and nigrostriatal pathways plays a key role in the reinforcement mechanisms and brain sensitivity to ethanol, respectively. Ethanol reinforcement and high alcohol drinking behaviour have been postulated to be partially mediated by a neurobiological mechanism involving the ethanol-induced activation of the endogenous opioid system. Activation of opioid neural pathways by ethanol may include alterations in the processing, release and/or the receptor binding of opioid peptides. The aim of this work was to investigate the effects of acute ethanol administration on δ opioid receptors in the rat mesocortical, meso-accumbens and nigrostriatal pathways by quantitative receptor autoradiography, using [ 3H] (2- d-penicillamine, 5- d-penicillamine)-enkephalin as radioligand. A significant increase in [ 3H] (2- d-penicillamine, 5- d-penicillamine)-enkephalin binding was observed in the substantia nigra pars reticulata 1 h after ethanol treatment. Two hours after drug exposure, ligand binding was significantly increased in the frontal and prefrontal cortices, the core and shell regions of the nucleus accumbens, and in the anterior-medial and medial-posterior regions of the caudate–putamen. In contrast, ligand binding was significantly decreased in the posterior region of the caudate–putamen 30 min after ethanol administration. The observed effects may reflect ethanol-induced changes in ligand binding affinity and/or in receptor density. Our results suggest that transitory changes in δ opioid receptors with different kinetic patterns may be involved in ethanol reinforcement and brain sensitivity to the drug. Ethanol-induced δ receptor up- and down-regulation mechanisms may participate in modulation of dopaminergic transmission in the mesocorticolimbic and nigrostriatal pathways.

Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum

Striatal glutamatergic inputs are known to participate in the modulation of dopaminergic transmission. Accordingly, the non-competitive N-methyl- d-aspartate receptor antagonists memantine and amantadine increase striatal dopamine levels, the latter being widely used in Parkinson's disease therapy. Based on our previous work revealing increased function of dopamine receptors and dopamine transporter after amantadine treatment, we studied the effects of repeated memantine administration on dopaminergic neurotransmission. On rat striatal membranes, dopamine-stimulated [ 35S]GTPγS binding was significantly reduced (20%) after 2 days injection with memantine (20 mg/kg per day, i.p.) but not after longer treatments (4 or 7 days). Evaluation of [ 3H]SCH 23390 and [ 3H]spiperone specific bindings only revealed a significant increase in D1 receptor density after 4 or 7 days treatment. Finally, none of these treatments were found to change the activity of the neuronal dopamine transporter in striatal synaptosomes. This shows that amantadine and memantine differentially affect striatal dopaminergic transmission, which could indicate that these two related aminoadamantanes display distinct pharmacodynamic properties.

The effect of ibogaine on κ-opioid- and 5-HT 3-induced changes in stimulation-evoked dopamine release in vitro from striatum of C57BL/6BY mice

Ibogaine is an kndole alkaloid that has bean suggested to have potential efficacy for internrpdng dependermy on stimulant drugs. The κ-opiold and serotonkr 5-HT 3 systems may be involved in the action of Ibogaine, related to their modulation of dopaminergic transmission. The κ-opioid agonist U 62066 attenuated the in vitrostimulation-evoked efflux of tritium label from striatal tissue prelabeled with ( 3H)dopamine. In mice protreated with Ibogaine·HCl (40 mg/kg IP given 2 h prior or 2 × 40 mg/kg and animals killed 18 h later), the Inhibitory effect of U 62066 on stimulation-evoked release of tritium was eliminated. The 5-HT 3 agonist phernylbiguanide had a biphasic effect on stimulation-evoked release of tritium; at 10 −6 M phenylbiguanide, stimulation-evoked release was attenuated. At 10 −5 M the basal outflow of tritium was increased. Ibogaine pretreatment had no effect on basal or stimulation-evokedrelease in the presence of 10 −6 M phenylbiguanide, but increased the stimulation-evoked outflow of bftkan in the presence of 10 −5 M phenylbiguanide. Cocaine (10 −6 M), a dopanlne uptake blocker, increased the electrically-evoked release of dopamine; ibogaine pretreatment did not affect the enhanced electrically-induced release of ( 3H]dopamine by in vitro cocalne. The effects of ibogaine on the κ-opioid and 5-HT 3 receptors, located presynaptically on stristal dopamine terminals, modulating dopamine release may partly underlie its putative antiaddictive properties.

The modulation of dopaminergic transmission in the striatum by MK-801 is independent of presynaptic mechanisms.

This paper reports biochemical and behavioural experiments, planned to obtain a deeper knowledge on the mechanisms of the facilitating action of dopaminergic transmission, induced by the NMDA-sensitive glutamate receptor antagonist, dizocilpine (MK-801). Single or repeated administrations of MK-801 (0.25 mg/kg, i.p., daily for 21 consecutive days) failed to change levels of either dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the striatum of the rat or the haloperidol-induced (0.125 mg/kg, i.p.) accumulation of DOPAC. Consistently, the NMDA antagonist, given at a dose which did not affect the spontaneous motility of the animal (0.125 mg/kg, i.p.), failed to potentiate the behavioural stimulatory effect, induced by the dopaminomimetic agents, methamphetamine or nomifensine. All these results, taken together, exclude a facilitating action of MK-801 on dopaminergic neurotransmission. The possibility that the stimulatory effect of MK-801 on dopaminergic neurones is indirect and independent of presynaptic mechanisms is discussed.

Participation of prostaglandin E2 in dopamine D2 receptor-dependent potentiation of arachidonic acid release.

Stimulation of dopamine D2 receptors potentiates Ca2+ ionophore- or ATP-induced arachidonic acid (AA) release in D2 receptor cDNA-transfected Chinese hamster ovary (CHO) cells [CHO(D2)]. By using a combination of chromatographic, biochemical, and radioimmunochemical techniques, we show here that prostaglandin (PG) E2 is a major product of AA metabolism in CHO(D2) cells stimulated with the Ca2+ ionophore A23187. Formation of this PG was markedly increased by the concomitant application of quinpirole, a D2 receptor agonist. In addition, PGE2 enhanced D2-dependent amplification of AA release, either when it was added (EC50 = 100 nM) or when it was produced endogenously, as shown by experiments carried out with the cyclooxygenase inhibitor indomethacin. The results suggest that PGE2 may participate in D2 receptor-mediated potentiation of AA release in CHO(D2) cells. They also support a functional role for this PG in the modulation of dopaminergic transmission in areas of the CNS, such as amygdala and hypothalamus, where high levels of both PGE2 and dopamine D2 receptors are found.

Dopaminergic transmission and the sleep-wakefulness continuum in man

Modulation of dopaminergic transmission on daytime alertness and performance and on nocturnal sleep were studied in man using 30, 60 and 90 mg pemoline, a dopamimetic drug, and 2, 4 and 6 mg pimozide, a dopamine receptor antagonist. Pemoline lengthened daytime sleep latencies and improved attention, and increased wakefulness during nocturnal sleep. Rapid eye movement (REM) sleep was reduced with 90 mg pemoline, but this was due entirely to increased wakefulness. Pimozide had little effect on overnight sleep, but increased the tendency to fall asleep and impaired performance during the day. These studies suggest that the effects of certain drugs which modulate the activity of neurotransmitters, involved in the control of sleep and wakefulness, may be related to the inherent level of activity of the central nervous system. Modulation of the dopaminergic system can have a profound influence on the manifestation of wakefulness and vigilance, but is unlikely to modify directly the elaboration of REM sleep in man.

Modulation of dopaminergic transmission in rat cortex by excitatory amino acids : Giovanni Selvaggi o, Paolo Bongioanni, Emilio Fiore, Scuola Superiore di Studi Universitari e di Perfezionamento (S.S.S.U.P.)-S. Anna, Pisa; oUniversity of Turin, ITALY

Modulation of dopaminergic transmission in rat cortex by excitatory amino acids : Giovanni Selvaggi o, Paolo Bongioanni, Emilio Fiore, Scuola Superiore di Studi Universitari e di Perfezionamento (S.S.S.U.P.)-S. Anna, Pisa; oUniversity of Turin, ITALY

Opposite influences of dopaminergic pathways to the prefrontal cortex or the septum on the dopaminergic transmission in the nucleus accumbens. An in vivo voltammetric study

Modulation of dopaminergic transmission in the nucleus accumbens by the dopaminergic pathways reaching the prefrontal cortex (anteromedian and the suprarhinal parts) and the lateral septum was investigated. Changes in dopaminergic transmission in the nucleus accumbens were assessed by in vivo voltammetry using pretreated carbon fiber electrodes. This technique allows the selective detection of 3,4-dihydroxyphenylacetic acid, the main presynaptic metabolite of dopamine. Dopaminergic transmission in the prefrontal cortex (anteromedian and suprarhinal parts) and the lateral septum was altered by local injection of the dopaminergic agonist ( d-amphetamine) and the dopaminergic antagonists (α-flupenthixol and sulpiride). Pharmacological interventions, either stimulation or blockade, in the anteromedian and suprarhinal parts of the prefrontal cortex induced, respectively, a decrease or an increase in extracellular 3,4-dihydroxyphenylacetic acid in the nucleus accumbens. The same pharmacological interventions in the lateral septum had exactly opposite effects in the nucleus accumbens. The inhibitory action of the mesocortical and mesorhinal dopaminergic projections and the facilitatory action of the mesoseptal dopaminergic projection on dopaminergic input in the nucleus accumbens were shown to rely on the activity of inhibitory fugal pathways which could be blocked by local injection of tetrodotoxin in the three structures. In a previous work, it was demonstrated that dopaminergic projections in the amygdala exert an inhibitory influence on dopaminergic transmission in the nucleus accumbens. Thus the present results suggest that functional interdependence between the different dopaminergic pathways arising in the ventral mesencephalon is a general property of this neuronal group. Data obtained after manipulation of dopaminergic transmission in these various projection areas may need to be interpreted in a different light. Similarly, neurological and psychiatric observations may need to be reconsidered in view of the interdependence of the dopaminergic mesencephalic pathways.

Functional and biochemical characteristics of a putative quisqualate-type receptor in rat striatum: effect of brain lesions.

Excitatory amino acids such as L-glutamate (Glu) and quisqualate (QUIS) markedly potentiated K+-evoked release of exogenous [3H]dopamine (DA) from rat striatal slices. Intrastriatal kainic acid injections resulted in a total disappearance of the stimulatory effects of Glu on evoked-release of [3H]DA as well as in a parallel reduction in the maximal number (Bmax) of a D-aspartate-insensitive L-[3H]Glu binding site in striatal particulate fractions. Following cortical ablation, the potentiating effect of Glu on [3H]DA release in decorticated striatal slices lasted longer, compared to normal slices, and occurred during the 2nd min following K+-depolarization. However, the extent (%) of Glu stimulation on [3H]DA release remained the same in decorticated and normal striatal slices. Cortical ablation produced also a significant decrease in the Bmax and in the KD' of the D-aspartate-insensitive binding site towards L-[3H]Glu. These results support the proposal that the D-aspartate-insensitive Glu binding site is somehow related to an amino acid receptor-mediated modulation of dopaminergic transmission in the rat corpus striatum.

Modulation of dopaminergic transmission by alpha-noradrenergic agonists and antagonists: evidence for antidopaminergic properties of some alpha antagonists.

The effects on dopamine (DA) metabolism, on3H-spiperone binding and on amphetamine-induced stereotypies of a variety of drugs with different actions on alpha1-and alpha2-noradrenergic (NA) receptors have been investigated.