Search

The progressive degeneration of dopamine (DA) neurons in the substantia nigra compacta (SNc) leads to the emergence of motor symptoms in patients with Parkinson's disease (PD). To propose neuroprotective therapies able to slow or halt the progression of the disease, it is necessary to identify cellular alterations that occur before DA neurons degenerate and before the onset of the motor symptoms that characterize PD. Using electrophysiological, histochemical, and biochemical approaches, we have examined if glutamatergic synaptic transmission in DA neurons in the SNc and in the adjacent ventral tegmental area (VTA) was altered in middle‐aged (10–12 months old) mice with the hG2019S point mutation (G2019S) in the leucine‐rich repeat kinase 2 (LRRK2) gene. G2019S mice showed increased locomotion and exploratory behavior compared with wildtype (WT) littermates, and intact DA neuron integrity. The intrinsic membrane properties and action potential characteristics of DA neurons recorded in brain slices were similar in WT and G2019S mice. Initial glutamate release probability onto SNc‐DA neurons, but not VTA‐DA neurons, was reduced in G2019S mice. We also found reduced protein amounts of the presynaptic marker of glutamatergic terminals, VGLUT1, and of the GluA1 and GluN1 subunits of AMPA and NMDA receptors, respectively, in the ventral midbrain of G2019S mice. These results identify alterations in glutamatergic synaptic transmission in DA neurons of the SNc and VTA before the onset of motor impairments in the LRRK2‐G2019S mouse model of PD. [ABSTRACT FROM AUTHOR]

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson’s Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson's Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons. [ABSTRACT FROM AUTHOR]

On the 13 Albino rats in norm, on the model of Parkinson's disease (PD) and on the same model with protection by Naja Naja Oxiana (NOX) venom the analysis of 422 neurons of substantia nigra compacta (SNc) single-unit activity under stimulation of globus pallidus (GP) has been conducted. The frequency of spikes in rotenone treated rats increased because of the excitotoxicity. Under the influence of NOX on the model of PD received a significant reduction the spike frequency of SNc neurons, which is obviously protective impact of venom NOX. [ABSTRACT FROM AUTHOR]

The osmotic stress is a powerful stimulus that elicits profound peripheral and central disturbances. In the mammalian brain, osmotic stress has been associated to several glial and neuronal changes. The lack of data regarding the impact on the dopaminergic system and locomotion led us to investigate the effect of prolonged water deprivation in rat on the midbrain dopaminergic system and locomotor performance by dehydrating rats for one and two weeks. Locomotor activity and tyrosine hydroxylase (TH) expression were assessed using the open field test and immunohistochemistry respectively. Water deprivation was accompanied with a significant increment of TH expression within substantia nigra compacta (SNc) and ventral tegmental area (VTA) gradually as the duration of dehydration increases. While locomotor activity showed the inverse tendency manifested by a drop of crossed boxes number following one and two weeks of water deprivation. Our data suggest a substantial implication of midbrain dopaminergic system in the central response to the osmotic stimuli accompanied with locomotor deficiencies. [ABSTRACT FROM AUTHOR]

The cytology and connections of the lateral habenula (LHb) are reviewed. The habenula is first introduced, after which the cytology of the LHb is discussed mainly with reference to cell types, general topography and descriptions of subnuclei. An overview of LHb afferent connections is given followed by some details about the projections to LHb from a number of structures. An overview of lateral habenula efferent connections is given followed by some details about the projections from LHb to a number of structures. In considering the afferent and efferent connections of the LHb some attention is given to the relative validity of regarding it as a bi-partite structure featuring ‘limbic’ and ‘pallidal’ parts. The paper ends with some concluding remarks about the relative place of the LHb in adaptive behaving. [ABSTRACT FROM AUTHOR]

Dopamine neurons of the substantia nigra pars compacta (SNc) are uniquely sensitive to degeneration in Parkinson’s disease (PD) and its models. Although a variety of molecular characteristics have been proposed to underlie this sensitivity, one possible contributory factor is their massive, unmyelinated, axonal arbor that is orders of magnitude larger than other neuronal types. In our previously published work, we examined the energetic impact imposed on SNc dopamine neurons by their extensive, unmyelinated axonal arbor and attempted to calculate the energy cost of action potential (AP) propagation throughout the axonal arbors. Among our main findings were that a) the energy demand associated with AP conduction is related in a supra-linear manner to the axonal size and complexity and, b) that synaptic stimulation is necessary to ensure reliable propagation throughout the axonal arbors of neurons with higher levels of branching. Indeed, predictions of our biophysical model of SNc dopamine neurons suggest that tonic activity for the reliable propagation of APs throughout the axonal arbour of neurons with small-to-moderate size arbours, whereas synaptic stimulation is required for for reliable propagation in neurons with larger and more complex arbors (Pissadaki and Bolam 2013). SNc dopamine neurons may thus be classified into functionally distinct groups according to the size of their axonal arborisation. Furthermore, SNc dopamine neurons are divided into ventral tier neurons, which are more susceptible in PD and extend their dendrites in both SN pars reticulata (SNr)) and SNc, and dorsal tier neurons that restrict their dendrites within SNc. As SNr dendrites receive proportionally greater inhibitory input than SNc dendrites (Henny et al 2012), we examined the relationship between the dendritic compartmentalisation, synaptic input, burst generation and the extent of axonal arborisation. Because spatiotemporal interplay of synaptic stimulation has been shown to facilitate bursting behaviour, we hypothesise that SNc neurons with dendrites in both compartments are more likely to generate bursts. Preliminary results indicate that the temporal latencies of synaptic stimulation in the two sub-cellular compartments can sculpt the output of the model neuron. These findings may represent a driving mechanism that explains how the local ongoing network activity can modulate the activity of SNc dopamine neurons and underlie changes from autonomous to burst firing.

Early degeneration of pedunculopontine nucleus (PPN) is considered part of changes that characterize premotor stages of Parkinson’s disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length ( p < 0.001) and deviation ( p < 0.001) of the traveled path and also in the time spent ( p < 0.01) in the circular small beam (CBS) ( p < 0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with the control group ( p < 0.05). Biochemical studies revealed that after 48-h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) ( p < 0.05). This significant increase of CAT EA persisted in the nigral tissue ( p < 0.001) and reached the striatal tissue ( p < 0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA ( p < 0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum ) were found. The events associated with the generation of free radicals at nigral and striatal levels, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion. [ABSTRACT FROM AUTHOR]

Neurones in the rat substantia nigra compacta (SNC) are initially resistant to transient forebrain ischaemia in contrast to vulnerable neurones in the striatum that die within 24 h. Animals were exposed to 20 min of four vessel occlusion and killed 1 and 3 weeks after reperfusion. All ischaemic animals had striatal neurone loss. Analysis of the number of tyrosine hydroxylase immunoreactive neurones (THir) in the SNC was comparable between controls and ischaemic animals killed 1 week after reperfusion. However, there was a significant reduction in THir neurone number (24%), SNC volume (17%), and THir dendritic arborization in the substantia nigra reticulata (SNR) that occurred 3 weeks after reperfusion, despite the persistence of THir axons in the striatum. Detailed morphological analysis of areas distant from the initial ischaemic injury suggest delayed degeneration may play an important role in the brain's response to ischaemia, and may provide insights for clinical stroke treatment and management.

Studies have sought to assess various potential neuroprotective therapeutics in Parkinson's disease. The aim of this study was to evaluate the effects of static magnetic field stimulation 14 days after a 6-Hydroxydopamine (6-OHDA) substantia nigra compacta (SNc) lesion on motor behavior, as assessed by the rotarod (RR) test and brain tissue morphology. Forty male Wistar rats were used and were divided into five groups: control group, sham group (SG), lesion group (LG), lesion north pole group (LNPG) and lesion south pole group (LSPG). In groups with magnetic stimulation, a 3200-gauss magnet was fixed to the skull. After the experiments, the animals were anesthetized for brain perfusion. Coronal sections of the SNc were stained with Nissl. The RR test showed a decrease in the time spent on the apparatus in the LG compared with all groups. The LNPG and LSPG had significant increases in the time spent when compared to the LG. A morphometric analysis revealed a significant reduction in the number of neurons in the LG, LNPG and LSPG in relation to the SG. There were a higher number of neurons in the LNPG and LSPG than the LG, and a higher number of neurons in the LSPG than the LNPG. We observed that the LG, LNPG and LSPG showed a higher number of glial cells than the SG, and the LNPG and LSPG showed a lower number of glial cells than the LG. Our results demonstrate a potential therapeutic use of static magnetic fields for the preservation of motor behavior and brain morphology in the SNc after 14 days with 6-OHDA lesion. [ABSTRACT FROM AUTHOR]

Abstract: The mesopontine rostromedial tegmental nucleus (RMTg) is a newly discovered brain structure thought to profoundly influence reward-related pathways. The RMTg is prominently GABAergic, receives dense projections from the lateral habenula and projects strongly to the midbrain ventral tegmental area and substantia nigra compacta. It receives additional afferent connections from widespread brain structures and sends additional strong efferent connections to a number of non-dopaminergic brainstem structures and, to a lesser extent, the forebrain. Projection neurons of the RMTg have been shown to express Fos in response to aversive stimuli and/or reward omission and psychostimulant drug administration. This review will first recount how the RMTg was discovered and then describe in greater detail what is known about its neuroanatomical relationships, including afferent and efferent connections, neurotransmitters, and receptors. Finally, we will focus on what has been reported about its function. [Copyright &y& Elsevier]

Abstract: Tetrahydroberberine (THB) exhibits neuroprotective effects but its targets and underlying mechanisms are largely unknown. Emerging evidence indicates that ATP-sensitive potassium (KATP) channels in the substantia nigra pars compacta (SNc) promote Parkinson disease (PD) pathogenesis, thus blocking KATP channels may protect neurons against neuronal degeneration. In the present study, we tested a hypothesis that THB blocks KATP channels in dopaminergic (DA) neurons acutely dissociated from rat SNc. Using perforated patch-clamp recording in current-clamp mode, the functional KATP channels can be opened by persistent perfusion of rotenone, an inhibitor of complex I of the mitochondrial respiratory chain. Bath-application of THB reversibly blocks opened KATP channels in a concentration-dependent manner, which is comparable to a classical KATP channel blocker, Tol. Compared to THB analogs, l-stepholidine (l-SPD) or l-tetrahydropalmatine (l-THP), THB exhibits more profound blockade in KATP channels. In addition, exposure of THB alone to the recorded neuron increases action potential firing, and THB also restores rotenone-induced membrane hyperpolarization in the presence of dopamine D2 receptor antagonist (sulpiride), suggesting that THB exhibits an excitatory effect on SNc DA neurons through the block of KATP channels. Collectively, the blockade of neuronal KATP channels by THB in SNc DA neurons is a novel pharmacological mechanism of THB, which may contribute to its neuroprotective effects in PD. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1–7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine neurons in the midbrain respond to behavioral events and environmental stimuli. Their different patterns of activation in turn modulate the activity of forebrain regions and modulate the expression of selective behavioral responses. However, their activity is closely dependent on the cholinergic systems in the brainstem. Ascending cholinergic projections from the pedunculopontine and laterodorsal tegmental nuclei target dopaminergic neurons in the substantia nigra compacta and ventral tegmental area following a topographical gradient. These projections, by means of the activation of acetylcholine receptors, influence the firing of dopamine neurons and therefore their responsiveness, ultimately affecting the release of dopamine in their forebrain targets. Brainstem cholinergic neurons are thus in a position to critically influence the activity of dopaminergic neurons in the midbrain, and thereby have a critical role in the expression of behavior. [Copyright &y& Elsevier]

Abstract: Following the injection of a retrograde tracer, gold-conjugated and inactivated wheatgerm agglutinin-horseradish peroxidase (WGA-apo-HRP-gold), into the dorsal tier of substantia nigra compacta (SNCD), histamine immunostaining was performed for the tuberomammillary nucleus (TMN) in order to investigate the projection from the TMN to the SNCD. At the rostral pole of the TMN, the retrograde labeling in the dorsomedial subdivision following medial SNCD injections was predominantly ipsilateral (78%), whereas only a few cells were located bilaterally following lateral SNCD injections. Following tracer injections along the medio-lateral location along the SNCD, the labeling at the ventrolateral TMN was bilateral with slightly ipsilateral (58–61%) dominance. At rostral and caudal TMN levels, clusters of labeled neurons were localized within two discrete columns of the ventrolateral TMN. At rostral TMN level, a lateral column of cells was located at the lateral tip of the ventrolateral TMN just medial to the internal capsule, while the medial column was close to the protruded region along the ventral, pial border. At the caudal TMN level, two columns were located on either side of the lateral mammillary nucleus. Taken together, the present study suggests that ventrolateral as well as dorsomedial TMN might provide arousal-related information to medial, intermediate, and lateral regions of the SNCD, which in turn influence extrapyramidal, behavioral functions performed by the substantia nigra compacta. [Copyright &y& Elsevier]

The detection of lower incidences of Parkinson's disease (PD) among smokers has sparked a renewed interest in the administration of (-) nicotine as a tool for the manipulation of the cholinergic system in experimental models of parkinsonism. This work evaluated five groups of Wistar rats (1: Healthy rats (n = 11), 2: Rats with lesions in the substantia nigra pars compacta (SNc) (n = 10), 3: Rats with SNc lesions, treated with (-) nicotine (n = 18), 4: Rats with false SNc lesions, obtained by treatment with physiological saline solution (PSS) (n = 10), 5: Rats with SNc lesions, treated with PSS (n = 10); measuring motor coordination and asymmetry, the extracellular concentrations of glutamate (Glu) and γ-aminobutyric acid (GABA) in the pedunculopontine nucleus (PPN), cell survival at the SNC, and the striatal expression of several neurotrophic factors. SNc-injured rats treated with (-) nicotine performed better and had smaller average numbers of errors at the largest diameter bridges when compared to untreated hemiparkinsonian rats. The treatment with (-) nicotine decreased the extracellular concentration of Glu and GABA at the PPN, attenuated motor asymmetry, promoted a higher striatal expression of brain-derived neurotrophic factor and diminished the loss of dopaminergic cells from the SNc. The results suggest a neuroprotective effect for (-) nicotine in the administration scheme employed in this study. [ABSTRACT FROM AUTHOR]

It is very important the manipulation of the cholinergic system in the experimental Parkinsonism through systemic (-) nicotine administration since the finding about the less incidence of Parkinson's disease between smoking people. The following experimental groups were evaluated: 1. non-treated rats (n = 11), 2. rats with lesion of the substantia nigra compacta (SNc) (n = 10), 3. rats treated with (-) nicotine and SNc lesioned (n = 18), 4. sham operated rats (n = 10), 5. rats with false pharmacological treatment and SNc lesioned (n = 10). The motor execution, motor asymmetry, extracellular concentration of glutamate (Glu), γ-aminobutiric acid (GABA) in pedunculopontine nucleus (PPN), the survival of dopaminergic cells and the striatal expression of neurotrophic factors were the variables studied. The rats treated with (-) nicotine showed an improvement in the motor execution and a minor number of errors during the execution in the Cross Bridges Test in comparison with the hemiparkinsonian rats without pharmacological treatment. In addition, the pharmacological treatment induced a decrease in the extracellular levels of Glu and GABA in PPN and also it attenuated the motor asymmetry of the rats. Simultaneously, the (-) nicotine administration promoted a higher brain derived neurotrophic factor striatal expression joint to a survival of the dopaminergic cells in the SNc. Ours results suggests a neuroprotector role for the (-) nicotine schedule applied in the present study. [ABSTRACT FROM AUTHOR]

Abstract: Based on electrophysiological, neurochemical and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) and dopamine (DA) function to promote waking (W) and to inhibit slow wave sleep (SWS) and/or rapid-eye-movement sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during SWS and virtually cease activity during REMS. On the other hand, DA cells in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) do not change their mean firing rate across the sleep–wake cycle. It has been proposed that DA cells in the midbrain show a change in temporal pattern rather than firing rate during the sleep–wake cycle. Available evidence tends to indicate that during W and REMS an increase of burst firing activity of DA neurons occurs together with an enhanced release of DA in the VTA, the nucleus accumbens and several forebrain structures. Recently, DA neurons were characterised in the ventral periaqueductal grey matter (VPAG) that express Fos protein during W. Lesioning of these cells resulted in an increase of SWS and REMS, which led to the proposal that VPAG DA neurons may play a role in the promotion of W. Systemic injection of full agonists at postsynaptic 5-HT1A (8-OH-DPAT, flesinoxan), 5-HT1B (CGS 12066B, CP-94,253), 5-HT2A/2C (DOI, DOM) and 5-HT3 (m-chlorophenylbiguanide) receptors increases W and reduces SWS and REMS. On the other hand, microdialysis perfusion or direct infusion of 8-OH-DPAT or flesinoxan into the DRN, where somatodendritic 5-HT1A receptors are located, significantly increases REMS. Systemic administration of the selective DA D1 receptor agonist SKF 38393 induces behavioural arousal together with an increase of W and a reduction of sleep. On the other hand, injection of a DA D2 receptor agonist (apomorphine, bromocriptine, quinpirole) gives rise to biphasic effects, such that low doses reduce W and augment SWS and REMS whereas large doses induce the opposite effects. Not much is known about dopamine–serotonin interaction in the regulation of sleep and W. It has been shown that VTA and SNc DA neurons and DRN 5-HT neurons influence each other. Thus, depending on the receptor subtype involved, 5-HT either facilitates or inhibits the functioning of DA cells. On the other hand, activation of DA D2-like receptors in the DRN increases the activity of 5-HT neurons. Thus, it can be speculated that local microinjection of DA and 5-HT ligands into the DRN and the VTA/SNc, respectively, would affect the actions of the corresponding neurons on sleep and W. [Copyright &y& Elsevier]

Abstract: Iptakalim hydrochloride, a novel cardiovascular ATP-sensitive K+ (KATP) channel opener, has shown remarkable antihypertensive and neuroprotective effects in a variety of studies using in vivo and in vitro preparations. We recently found that iptakalim blocked human α4-containing nicotinic acetylcholine receptors (nAChRs) heterologously expressed in the human SH-EP1 cell line. In the present study, we examined the effects of iptakalim on several neurotransmitter-induced current responses in single DA neurons freshly dissociated from rat substantia nigra pars compacta (SNc), using perforated patch-clamp recordings combined with a U-tube rapid drug application. In identified DA neurons under voltage-clamp configuration, glutamate-, NMDA-, and GABA-induced currents were insensitive to co-application with iptakalim (100μM), while whole-cell currents induced by ACh (1mM+1μM atropine) or an α4β2 nicotinic acetylcholine receptors relatively selective agonist, RJR-2403 (300μM), were eliminated by iptakalim. Iptakalim inhibited RJR-2403-induced current in a concentration-dependent manner, and reduced maximal RJR-2403-induced currents at the highest agonist concentration, suggesting a non-competitive block. In current-clamp mode, iptakalim failed to affect resting membrane potential and spontaneous action potential firing, but abolished RJR-2403-induced neuronal firing acceleration. Together, these results indicate that in dissociated SNc DA neurons, α4-containing nAChRs, rather than ionotropic glutamate receptors, GABAA receptors or perhaps K-ATP channels are the sensitive targets to mediate iptakalim''s pharmacological roles. [Copyright &y& Elsevier]

Prolonged stress induces neural maladaptations in the mesolimbic dopamine (DA) system and produces emotional and behavioral disorders. However, the effects of stress on activity of DA neurons are diverse and complex that hinge on the type, duration, intensity, and controllability of stressors. Here, controlling the duration, intensity, and type of the stressors to be identical, we observed the effects of stressor controllability on the activity of substantia nigra pars compacta (SNc) DA neurons in mice. We found that both lack and loss of control (LOC) over shock enhance the basal activity and intrinsic excitability of SNc DA neurons via modulation of I h current, but not via corticosterone serum level. Moreover, LOC over shock produces more significant enhancement in the basal activity of SNc DA neurons than that produced by shock per se, and therefore attenuates the response to natural reward. This attenuation can be reversed by control over shock. These results indicate that although chronic stress per se tends to enhance the basal activity of SNc DA neurons, LOC over the stressor is able to induce a larger enhancement in the basal activity of SNc DA neurons and produce more severe behavioral deficits. However, control over stress ameliorates the deleterious effects of stress, highlighting the role of stress controllability., (Copyright © 2021 Yao et al.)

The mechanism by which estrogen protects dopaminergic neurons has not yet been clarified. It is not known if changes in RhoA/Rho kinase activity are involved in the enhanced vulnerability of dopaminergic neurons observed after estrogen depletion. The present study shows that the MPTP-induced loss of dopaminergic neurons is increased by estrogen depletion and inhibited by estrogen replacement, the Rho kinase inhibitor Y27632 and deletion of the angiotensin type-1 receptor. In ovariectomized mice, treatment with MPTP induced a marked increase in Rho kinase activity, and RhoA and RhocK II mRNA and protein expression, which were significantly higher than in ovariectomized mice treated with MPTP and estrogen replacement or type-1 receptor deletion. Estrogen depletion increased Rho kinase activity, via enhancement of the angiotensin type-1 receptor pathway, and Rho kinase activation increased type-1 receptor expression suggesting a vicious cycle in which Rho kinase and type-1 receptor activate each other and promote the degenerative process. The results suggest that type-1 receptor antagonists and Rho kinase inhibitors may provide a new neuroprotective strategy, which may circumvent the potential risks of estrogen replacement therapy and be particularly useful in elderly women or women affected by long-term lack of estrogen., (Copyright © 2013 Elsevier Inc. All rights reserved.)