Rat Substantia Nigra Pars Reticulata Research Articles

High-Frequency Deep Brain Stimulation of the Substantia Nigra Pars Reticulata Facilitates Extinction and Prevents Reinstatement of Methamphetamine-Induced Conditioned Place Preference.

Persistent and stable drug memories lead to a high rate of relapse among addicts. A number of studies have found that intervention in addiction-related memories can effectively prevent relapse. Deep brain stimulation (DBS) exhibits distinct therapeutic effects and advantages in the treatment of neurological and psychiatric disorders. In addition, recent studies have also found that the substantia nigra pars reticulata (SNr) could serve as a promising target in the treatment of addiction. Therefore, the present study aimed to investigate the effect of DBS of the SNr on the reinstatement of drug-seeking behaviors. Electrodes were bilaterally implanted into the SNr of rats before training of methamphetamine-induced conditioned place preference (CPP). High-frequency (HF) or low-frequency (LF) DBS was then applied to the SNr during the drug-free extinction sessions. We found that HF DBS, during the extinction sessions, facilitated extinction of methamphetamine-induced CPP and prevented drug-primed reinstatement, while LF DBS impaired the extinction. Both HF and LF DBS did not affect locomotor activity or induce anxiety-like behaviors of rats. Finally, HF DBS had no effect on the formation of methamphetamine-induced CPP. In conclusion, our results suggest that HF DBS of the SNr could promote extinction and prevent reinstatement of methamphetamine-induced CPP, and the SNr may serve as a potential therapeutic target in the treatment of drug addiction.

Unbalanced Inhibitory/Excitatory Responses in the Substantia Nigra Pars Reticulata Underlie Cannabinoid-Related Slowness of Movements.

The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.SIGNIFICANCE STATEMENT The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an ad hoc behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.

Sensitive and Selective Measurement of Serotonin in Vivo Using Fast Cyclic Square-Wave Voltammetry.

Although N-shaped fast scan cyclic voltammetry (N-FSCV) is well-established as an electroanalytical method to measure extracellular serotonin concentrations in vivo, it is in need of improvement in both sensitivity and selectivity. Based on our previous studies using fast cyclic square-wave voltammetry (FCSWV) for in vivo dopamine measurements, we have modified this technique to optimize the detection of serotonin in vivo. A series of large amplitude square-shaped potentials was superimposed onto an N-shaped waveform to provide cycling through multiple redox reactions within the N-shaped waveform to enhance the sensitivity and selectivity to serotonin measurement when combined with a two-dimensional voltammogram. N-Shaped fast cyclic square-wave voltammetry (N-FCSWV) showed significantly higher sensitivity to serotonin compared to conventional N-FSCV. In addition, N-FCSWV showed better performance than conventional N-shaped FSCV in differentiating serotonin from its major interferents, dopamine and 5-hydroxyindoleascetic acid (5-HIAA). It was also confirmed that the large amplitude of the square waveform did not influence local neuronal activity, and it could monitor electrical stimulation evoked phasic release of serotonin in the rat substantia nigra pars reticulata (SNr) before and after systemic injection of escitalopram (ESCIT, 10 mg/kg i.p.), a serotonin selective reuptake inhibitor.

Eltoprazine prevents levodopa-induced dyskinesias by reducing causal interactions for theta oscillations in the dorsolateral striatum and substantia nigra pars reticulate

Oscillatory activities within basal ganglia (BG) circuitry in L-DOPA induced dyskinesia (LID), a condition that occurs in patients with Parkinson disease (PD), are not well understood. The aims of this study were firstly to investigate oscillations in main BG input and output structures—the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr), respectively— including the direction of oscillation information flow, and secondly to investigate the effects of 5-HT1A/B receptor agonism with eltoprazine on oscillatory activities and abnormal involuntary movements (AIMs) characteristic. To this end, we conducted local field potential (LFP) electrophysiology in the dStr and SNr of LID rats simultaneous with AIM scoring. The LFP data were submitted to power spectral density, coherence, and partial Granger causality analyses. AIM data were analyzed relative to simultaneous oscillatory activities, with and without eltoprazine. We obtained four major findings. 1) Theta band (5–8 Hz) oscillations were enhanced in the dStr and SNr of LID rats. 2) Theta power correlated with AIM scores in the 180-min period after the last LID-inducing L-DOPA injection, but not with daily summed AIM scores during LID development. 3) Oscillatory information flowed from the dStr to the SNr. 4) Chronic eltoprazine reduced BG theta activity in LID rats and normalized information flow directionality, relative to that in LID rats not given eltoprazine. These results indicate that dStr activity plays a determinative role in the causal interactions of theta oscillations and that serotonergic inhibition may suppress dyskinesia by reducing dStr-SNr theta activity and restoring theta network information flow.

Anticonvulsant effects after grafting of rat, porcine, and human mesencephalic neural progenitor cells into the rat subthalamic nucleus

Cell transplantation based therapy is a promising strategy for treating intractable epilepsies. Inhibition of the subthalamic nucleus (STN) or substantia nigra pars reticulata (SNr) is a powerful experimental approach for remote control of different partial seizure types, when targeting the seizure focus is not amenable. Here, we tested the hypothesis that grafting of embryonic/fetal neural precursor cells (NPCs) from various species (rat, human, pig) into STN or SNr of adult rats induces anticonvulsant effects. To rationally refine this approach, we included NPCs derived from the medial ganglionic eminence (MGE) and ventral mesencephalon (VM), both of which are able to develop a GABAergic phenotype. All VM- and MGE-derived cells showed intense migration behavior after grafting into adult rats, developed characteristics of inhibitory interneurons, and survived at least up to 4 months after transplantation. By using the intravenous pentylenetetrazole (PTZ) seizure threshold test in adult rats, transient anticonvulsant effects were observed after bilateral grafting of NPCs derived from human and porcine VM into STN, but not after SNr injection (site-specificity). In contrast, MGE-derived NPCs did not cause anticonvulsant effects after grafting into STN or SNr (cell-specificity). Neither induction of status epilepticus by lithium-pilocarpine to induce neuronal damage prior to the PTZ test nor pretreatment of MGE cells with retinoic acid and potassium chloride to increase differentiation into GABAergic neurons could enhance anticonvulsant effectiveness of MGE cells. This is the first proof-of-principle study showing anticonvulsant effects by bilateral xenotransplantation of NPCs into the STN. Our study highlights the value of VM-derived NPCs for interneuron-based cell grafting targeting the STN.

Progressive brain metabolic changes under deep brain stimulation of subthalamic nucleus in parkinsonian rats.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an efficient neurosurgical treatment for advanced Parkinson's disease. Non-invasive metabolic neuroimaging during the course of DBS in animal models may contribute to our understanding of its action mechanisms. Here, DBS was adapted to in vivo proton magnetic resonance spectroscopy at 11.7 T in the rat to follow metabolic changes in main basal ganglia structures, the striatum, and the substantia nigra pars reticulata (SNr). Measurements were repeated OFF and ON acute and subchronic (7 days) STN-DBS in control and parkinsonian (6-hydroxydopamine lesion) conditions. Acute DBS reversed the increases in glutamate, glutamine, and GABA levels induced by the dopamine lesion in the striatum but not in the SNr. Subchronic DBS normalized GABA in both the striatum and SNr, and glutamate in the striatum. Taurine levels were markedly decreased under subchronic DBS in the striatum and SNr in both lesioned and unlesioned rats. Microdialysis in the striatum further showed that extracellular taurine was increased. These data reveal that STN-DBS has duration-dependent metabolic effects in the basal ganglia, consistent with development of adaptive mechanisms. In addition to counteracting defects induced by the dopamine lesion, prolonged DBS has proper effects independent of the pathological condition. Non-invasive metabolic neuroimaging might be useful to understand the physiological mechanisms of deep brain stimulation (DBS). Here, we demonstrate the feasibility of repeated high-field proton magnetic resonance spectroscopy of basal ganglia structures under subthalamic nucleus DBS in control and parkinsonian rats. Results show that DBS has both rapid and delayed effects either dependent or independent of disease state.

Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

Disruption of dopaminergic transmission remodels tripartite synapse morphology and astrocytic calcium activity within substantia nigra pars reticulata.

The substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia circuitry particularly sensitive to pathological dopamine depletion. Indeed, hyperactivity of SNr neurons is known to be responsible for some motor disorders characteristic of Parkinson's disease. The neuronal processing of basal ganglia dysfunction is well understood but, paradoxically, the role of astrocytes in the regulation of SNr activity has rarely been considered. We thus investigated the influence of the disruption of dopaminergic transmission on plastic changes at tripartite glutamatergic synapses in the rat SNr and on astrocyte calcium activity. In 6-hydroxydopamine-lesioned rats, we observed structural plastic changes of tripartite glutamatergic synapses and perisynaptic astrocytic processes. These findings suggest that subthalamonigral synapses undergo morphological changes that accompany the pathophysiological processes of Parkinson's disease. The pharmacological blockade of dopaminergic transmission (with sulpiride and SCH-23390) increased astrocyte calcium excitability, synchrony and gap junction coupling within the SNr, suggesting a functional adaptation of astrocytes to dopamine transmission disruption in this output nucleus. This hyperactivity is partly reversed by subthalamic nucleus high-frequency stimulation which has emerged as an efficient symptomatic treatment for Parkinson's disease. Therefore, our results demonstrate structural and functional reshaping of neuronal and glial elements highlighting a functional plasticity of neuroglial interactions when dopamine transmission is disrupted.

Elevated potassium provides an ionic mechanism for deep brain stimulation in the hemiparkinsonian rat

The mechanism of high-frequency stimulation used in deep brain stimulation (DBS) for Parkinson's disease (PD) has not been completely elucidated. Previously, high-frequency stimulation of the rat entopeduncular nucleus, a basal ganglia output nucleus, elicited an increase in [K(+)](e) to 18 mm, in vitro. In this study, we assessed whether elevated K(+) can elicit DBS-like therapeutic effects in hemiparkinsonian rats by employing the limb-use asymmetry test and the self-adjusting stepping test. We then identified how these effects were meditated with in-vivo and in-vitro electrophysiology. Forelimb akinesia improved in hemiparkinsonian rats undergoing both tests after 20 mm KCl injection into the substantia nigra pars reticulata (SNr) or the subthalamic nucleus. In the SNr, neuronal spiking activity decreased from 38.2 ± 1.2 to 14.6 ± 1.6 Hz and attenuated SNr beta-frequency (12-30 Hz) oscillations after K(+) treatment. These oscillations are commonly associated with akinesia/bradykinesia in patients with PD and animal models of PD. Pressure ejection of 20 mm KCl onto SNr neurons in vitro caused a depolarisation block and sustained quiescence of SNr activity. In conclusion, our data showed that elevated K(+) injection into the hemiparkinsonian rat SNr improved forelimb akinesia, which coincided with a decrease in SNr neuronal spiking activity and desynchronised activity in SNr beta frequency, and subsequently an overall increase in ventral medial thalamic neuronal activity. Moreover, these findings also suggest that elevated K(+) may provide an ionic mechanism that can contribute to the therapeutic effects of DBS for the motor treatment of advanced PD.

In vivo electrochemical evidence for simultaneous 5-HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation.

Exploring the mechanisms of serotonin [5-hydroxytryptamine (5-HT)] in the brain requires an in vivo method that combines fast temporal resolution with chemical selectivity. Fast-scan cyclic voltammetry is a technique with sufficient temporal and chemical resolution for probing dynamic 5-HT neurotransmission events; however, traditionally it has not been possible to probe in vivo 5-HT mechanisms. Recently, we optimized fast-scan cyclic voltammetry for measuring 5-HT release and uptake in vivo in the substantia nigra pars reticulata (SNR) with electrical stimulation of the dorsal raphe nucleus (DRN) in the rat brain. Here, we address technical challenges associated with rat DRN surgery by electrically stimulating 5-HT projections in the medial forebrain bundle (MFB), a more accessible anatomical location. MFB stimulation elicits 5-HT in the SNR; furthermore, we find simultaneous release of an additional species. We use electrochemical and pharmacological methods and describe physiological, anatomical and independent chemical analyses to identify this species as histamine. We also show pharmacologically that increasing the lifetime of extracellular histamine significantly decreases 5-HT release, most likely because of increased activation of histamine H-3 receptors that inhibit 5-HT release. Despite this, under physiological conditions, we find by kinetic comparisons of DRN and MFB stimulations that the simultaneous release of histamine does not interfere with the quantitative 5-HT concentration profile. We therefore present a novel and robust electrical stimulation of the MFB that is technically less challenging than DRN stimulation to study 5-HT and histamine release in the SNR.

Impact of expected value on neural activity in rat substantia nigra pars reticulata

The substantia nigra pars reticulata (SNr) is thought to serve as the output of the basal ganglia, whereby associative information from striatum influences behavior via disinhibition of downstream motor areas to motivate behavior. Unfortunately, few studies have examined activity in SNr in rats making decisions based on the value of predicted reward similar to those conducted in primates. To fill this void, we recorded from single neurons in SNr while rats performed a choice task in which different odor cues indicated what reward was available on the left or on the right. The value of reward associated with a leftward or rightward movement was manipulated by varying the size of and delay to reward in separate blocks of trials. Rats were faster or slower depending on whether the expected reward value was high or low, respectively. The number of neurons that increased firing during performance of the task outnumbered those that decreased firing. Both increases and decreases were modulated by expected value and response direction. Neurons that fired more or less strongly for larger reward tended to fire, respectively, more or less strongly for immediate reward, reflecting their common motivational output. Finally, value selectivity was present prior to presentation of cues indicating the nature of the upcoming behavioral response for both increasing- and decreasing-type neurons, reflecting the internal bias or preparatory set of the rat. These results emphasize the importance of increasing-type neurons on behavioral output when animals are making decisions based on predicted reward value.

The impact of maternal separation on the number of tyrosine hydroxylase-expressing midbrain neurons during different stages of ontogenesis

Early life stressors have life-long functional and anatomical consequences. Though many neurotransmitters are involved in the functional impact of early life stress, dopamine seems to be important because of its roles in motor control, adaptation to stressful conditions, mood, cognition, attention and reward. Thus, in the present study, we investigated the way that early life stress, in the form of maternal separation (MS), affects the populations of tyrosine hydroxylase-immunoreactive (TH-IR) dopaminergic neurons in rat midbrain structures during ontogenesis. We included in the study the sub-regions of the substantia nigra (SN) and the ventral tegmental area (VTA). In both the control and MS rats, we found that the estimated total number of TH-expressing neurons fluctuated during ontogenesis. Moreover, MS influenced the number of TH-IR cells, especially in the SN pars reticulata (SNr) and VTA. Shortly after the termination of MS, on postnatal day (PND) 15, a decrease in the estimated total number of TH-IR neurons was observed in the SNr and VTA (in both males and females). On PND 35, MS caused a transient increase in the number of TH-IR cells only in the SNr of female rats. On PND 70, MS affected the number of TH-IR neurons in the VTA of females; specifically, an increase in the number of these cells was observed. Additionally, MS did not alter TH-IR cell sizes or the total levels of TH (measured by Western blot analysis) in the SN and VTA for all stages of ontogenesis in both males and females. The results from the study herein indicate that early life stress has enduring effects on the populations of midbrain TH-expressing dopaminergic neurons (especially in female rats), which are critically important for dopamine-regulated brain function throughout ontogenesis.

In vivo electrochemical evidence for simultaneous 5-HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation: In vivo electrochemical characterization of 5-HT

In vivo electrochemical evidence for simultaneous 5-HT and histamine release in the rat substantia nigra pars reticulata following medial forebrain bundle stimulation: In vivo electrochemical characterization of 5-HT

Functional heterogeneity of NMDA receptors in rat substantia nigra pars compacta and reticulata neurones

The nigra substantia nigra pars compacta (SNc) and substantia pars reticulata (SNr) form two major basal ganglia components with different functional roles. SNc dopaminergic (DA) neurones are vulnerable to cell death in Parkinson's disease, and NMDA receptor activation is a potential contributing mechanism. We have investigated the sensitivity of whole-cell and synaptic NMDA responses to intracellular ATP and GTP application in the SNc and SNr from rats on postnatal day (P) 7 and P28. Both NMDA current density (pA/pF) and desensitization to prolonged or repeated NMDA application were greater in the SNr than in the SNc. When ATP levels were not supplemented, responses to prolonged NMDA administration desensitized in P7 SNc DA neurones but not at P28. At P28, SNr neurones desensitized more than SNc neurones, with or without added ATP. Responses to brief NMDA applications and synaptic NMDA currents were not sensitive to inclusion of ATP in the pipette solution. To investigate these differences between the SNc and SNr, NR2 subunit-selective antagonists were tested. NMDA currents were inhibited by ifenprodil (10 microM) and UBP141 (4 microM), but not by Zn(2+) (100 nm), in both the SNr and SNc, suggesting that SNc and SNr neurones express similar receptor subunits; NR2B and NR2D, but not NR2A. The different NMDA response properties in the SNc and SNr may be caused by differences in receptor modulation and/or trafficking. The vulnerability of SNc DA neurones to cell death is not correlated with NMDA current density or receptor subtypes, but could in part be related to inadequate NMDA receptor desensitization.

PKC links Gq‐coupled receptors to DAT‐mediated dopamine release

The dopamine transporter (DAT) mediates dopamine uptake in many brain areas and has been suggested to underlie dopamine release in the substantia nigra pars reticulata. This release modulates basal ganglia output and motor performance. It is triggered by glutamatergic subthalamic afferents. We show here that activation of (G(q)-coupled) group I metabotropic glutamate receptors are sufficient to induce dopamine release in rat substantia nigra pars reticulata slices. Release was measured by amperometry and inhibited by a DAT antagonist. In a DAT-expressing cell line, dopamine release could be induced by activation of G(q)-coupled muscarinic receptors. Release was measured by HPLC and inhibited by a DAT antagonist. In both paradigms, activation of protein kinase C (PKC) was necessary and sufficient for dopamine release, suggesting that G(q)-coupled receptors can induce DAT-mediated dopamine release through PKC, and providing a physiological role for the known regulation of DAT-mediated release by PKC. Activation of muscarinic receptors and PKC also induced release from a cell line expressing the norepinephrine transporter, suggesting that transport-mediated release might be relevant in further brain areas.

Changes in firing rate and pattern of GABAergic neurons in subregions of the substantia nigra pars reticulata in rat models of Parkinson's disease

The substantia nigra pars reticulata (SNr) plays a key role in the pathophysiology of Parkinson's disease (PD). It has been well documented that the SNr is not a homogeneous structure, and the lateral and medial subregions of the SNr receive different projections from the sensorimotor and limbic striatum, respectively. However, specific changes in firing activity of SNr subregions in PD remain unclear. In the present study, the spontaneous firing activity of GABAergic neurons in the lateral and medial SNr of rats with unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) or medial forebrain bundle (MFB) has been examined. Extracellular recordings indicated that the firing rate of lateral SNr neurons increased significantly and firing pattern of these neurons changed towards more irregular and bursty after SNc or MFB lesions compared to normal rats. In contrast, the firing rate and pattern of medial SNr neurons in rats with SNc lesions were unaltered when compared with that of normal rats. However, MFB lesions in rats decreased the firing rate of medial SNr neurons and firing pattern of these neurons changed towards more bursty. In addition, SNc lesions in rats increased the firing rate of the neurons with regular and irregular firing patterns within lateral but not in medial SNr, while the firing rate of the neurons within lateral and medial SNr with each firing pattern was not altered after MFB lesions. These results suggest that GABAergic neurons of SNr subregions have differential change of firing activity in the pathophysiology of PD.

5-HT1B receptor regulation of serotonin (5-HT) release by endogenous 5-HT in the substantia nigra

Axonal release of serotonin (5-hydroxytryptamine, 5-HT) in the CNS is typically regulated by presynaptic 5-HT autoreceptors. Release of 5-HT in substantia nigra pars reticulata (SNr), a principal output from the basal ganglia, has seemed an interesting exception to this rule. The SNr receives one of the highest densities of 5-HT innervation in mammalian brain and yet negative feedback regulation of axonal 5-HT release by endogenous 5-HT has not been identified here. We explored whether we could identify autoregulation of 5-HT release by 5-HT1B receptors in rat SNr slices using fast-scan cyclic voltammetry at carbon-fiber microelectrodes to detect 5-HT release evoked by discrete stimuli (50 Hz, 20 pulses) paired over short intervals (1–10 s) within which any autoreceptor control should occur. Evoked 5-HT release exhibited short-term depression after an initial stimulus that recovered by 10 s. Antagonists for 5-HT1B receptors, isamoltane (1 μM) or SB 224-289 (1 μM), did not modify release during a stimulus train, but rather, they modestly relieved depression of subsequent release evoked after a short delay (≤2 s). Release was not modified by antagonists for GABA (picrotoxin, 100 μM, saclofen, 50 μM) or histamine-H3 (thioperamide, 10 μM) receptors. These data indicate that 5-HT release can activate a 5-HT1B-receptor autoinhibition of subsequent release, which is mediated directly via 5-HT axons and not via GABAergic or histaminergic inputs. These data reveal that 5-HT release in SNr is not devoid of autoreceptor regulation by endogenous 5-HT, but rather is under modest control which only weakly limits 5-HT signaling.

Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat

The responsiveness of the rat anterior substantia nigra pars reticulata (SNR) GABAergic neurons to GABAAergic drugs changes with age and gender, altering its role in seizure control. To determine whether maturational and gender-specific differences in the properties of spontaneous GABAARs-mediated inhibitory postsynaptic currents (sIPSCs) underlie these events, we studied sIPSCs at baseline and after application of the α1 GABAARs subunit selective agonist zolpidem, at postnatal days (PN) 5–9, PN12–15, and PN28–32. Results were correlated with the α1 and α3 GABAARs subunit immunoreactivity (-ir) at PN5, PN15, and PN30, using immunochemistry. The mean frequency, amplitude and charge transfer increased whereas the 10–90% rise time and decay time accelerated with age in both genders. The faster sIPSC kinetics in older rats were paralleled by increased α1-ir and decreased α3-ir. At PN5–9, males had more robust sIPSCs (frequency, amplitude, charge carried per event and charge transfer) than females. At PN28–32, males exhibited higher amplitudes and faster kinetics than females. The zolpidem-induced increase of decay times, amplitude and charge transfer and α1-ir expression were the lowest in PN5–9 males but increased with age, in both genders. Our findings demonstrate that alterations in GABAARs subunit expression partially underlie age- and gender-specific sIPSC changes in SNR neurons. However, the observation of gender differences in sIPSC kinetics that cannot be attributed to changes in perisomatic α1 expression suggests the existence of additional gender-specific factors that control the sIPSC kinetics in rat SNR.

Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease

Striatal interneurons play key roles in basal ganglia function and related disorders by modulating the activity of striatal projection neurons. Here we have injected rabies virus (RV) into either the rat substantia nigra pars reticulata or the globus pallidus and took advantage of the trans-synaptic spread of RV to unequivocally identify the interneurons connected to striatonigral- or striatopallidal-projecting neurons, respectively. Large numbers of RV-infected parvalbumin (PV+/RV+) and cholinergic (ChAT+/RV+) interneurons were detected in control conditions, and they showed marked changes following intranigral 6-hydroxydopamine injection. The number of ChAT+/RV+ interneurons innervating striatopallidal neurons increased concomitant with a reduction in the number of PV+/RV+ interneurons, while the two interneuron populations connected to striatonigral neurons were clearly reduced. These data provide the first evidence of synaptic reorganization between striatal interneurons and projection neurons, notably a switch of cholinergic innervation onto striatopallidal neurons, which could contribute to imbalanced striatal outflow in parkinsonian state.

Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy: Ibuprofen restores its motor activity

Patients with hepatic encephalopathy show altered motor function, psychomotor slowing, and hypokinesia, which are reproduced in rats with portacaval shunts (PCS). Increased extracellular glutamate in substantia nigra pars reticulata (SNr) is responsible for hypokinesia in PCS rats. The mechanisms by which liver failure leads to increased extracellular glutamate in SNr remain unclear. Inflammation seems to act synergistically with hyperammonemia to induce neurological alterations in hepatic encephalopathy. It is therefore possible that inflammation-associated alterations may contribute to motor alterations in hepatic encephalopathy. The aim of this work was to assess whether treatment with an antiinflammatory, ibuprofen, is able to normalize extracellular glutamate in SNr and/or to improve hypokinesia in PCS rats. The amounts of the glutamate transporters GLT-1 and EAAC-1 are reduced by 26% and 32%, respectively, in SNr of PCS rats. This reduction is associated with a tenfold increase in extracellular glutamate in SNr and a reduction in motor activity. Chronic treatment with 30 mg/kg ibuprofen completely normalizes the amount of GLT-1 and EAAC-1 and significantly reduces (by 53%) extracellular glutamate in SNr of PCS rats. Moreover, ibuprofen, at 15 or 30 (but not at 5) mg/kg/day, completely eliminates hypokinesia, restoring normal motor activity. This supports the idea that inflammation is a main contributor to the induction of hypokinesia in hepatic encephalopathy. Moreover, these data point to the possible therapeutic utility of decreasing inflammation, by safe procedures, in the treatment of the motor deficits in patients with hepatic encephalopathy.