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Although the lateral habenula (LHb) is involved in the regulation of multiple brain functions and this region expresses abundant M-type potassium channel (M-channel) subunits Kv7.2 and Kv7.3, the role of M-channels in regulating working memory is unclear, particularly in Parkinson's disease (PD). Here we tested the effects of activation and blockade of LHb M-channels on working memory by the T-maze rewarded alternation test in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc). The SNc lesion induced working memory impairment, increased the firing rate of LHb neurons, decreased dopamine (DA) level in the ventral medial prefrontal cortex (vmPFC) and reduced the expression of Kv7.2 subunit in the LHb. Intra-LHb injection of M-channel activator retigabine induced enhancement of working memory in SNc sham-lesioned and SNc-lesioned rats; conversely, the injection of M-channel blocker XE-991 impaired working memory in the two groups of rats. However, doses producing significant effects in SNc-lesioned rats were higher than those in SNc sham-lesioned rats. Further, intra-LHb injection of retigabine decreased the firing rate of LHb neurons and increased release of DA and serotonin (5-HT) in the vmPFC, while XE-991 increased the firing rate and decreased DA and 5-HT release in the two groups of rats. Compared with SNc sham-lesioned rats, the duration of M-channel activation and blockade action on the firing rate of the neurons and release of DA and 5-HT was significantly shortened in SNc-lesioned rats, which was consistent with reduced expression of Kv7.2 subunit in the LHb after lesioning the SNc. Collectively, these findings suggest involvement of LHb Kv7.2 subunit-containing M-channels in working memory impairment in SNc-lesioned rats, and that enhanced or impaired working memory after activation or blockade of M-channels in the LHb is related to the changes in the firing activity of LHb neurons and DA and 5-HT release in the vmPFC.

The aim of the present study was to investigate the age‑related alterations in hypertensive brain damage in the hippocampi of spontaneously hypertensive rats (SHR) and the underlying mechanisms. Aging resulted in a significant increase in the number of activated astrocytes and apoptotic cells in the SHR group, which was accompanied by increased expression of oxidative stress markers (iNOS and gp47phox) and apoptotic regulatory proteins (Bax and caspase‑3). In addition, the expression of PPAR‑γ and Bcl‑2 were progressively reduced with increasing age in the SHR group. The 32 and 64‑week‑old SHRs exhibited significantly increased numbers of apoptotic cells, oxidative stress markers and pro‑apoptotic proteins compared with age‑matched WKY rats, which was accompanied by reduced expression of PPAR‑γ. Compared with the 16 and 32‑week‑old WKY group, the 64‑week‑old WKY rats exhibited increased oxidative stress and pro‑apoptotic markers, and increased levels apoptotic cells. In conclusion, the present study indicated that both aging and hypertension enhanced brain damage and oxidative stress injury in the hippocampi of SHRs, indicated by an increased presence of apoptotic cells and astrocytes. In addition, reduced expression of PPAR‑γ may contribute to the age‑related brain damage in SHRs.

The role of serotonin7 (5-HT7) receptors in the regulation of depression is poorly understood, particularly in Parkinson's disease-associated depression. Here we examined whether 5-HT7 receptors in the prelimbic (PrL) sub-region of the ventral medial prefrontal cortex (mPFC) involve in the regulation of depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-PrL injection of 5-HT7 receptor agonist AS19 (0.5, 1 and 2 μg/rat) increased sucrose consumption, and decreased immobility time in sham-operated and the lesioned rats, indicating the induction of antidepressant-like effects. Further, intra-PrL injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6 μg/rat) decreased sucrose consumption, and increased immobility time, indicating the induction of depressive-like responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 (2 μg/rat) increased dopamine, 5-hydroxytryptamine (5-HT) and noradrenaline (NA) levels in the mPFC, habenula and ventral hippocampus (vHip) in sham-operated and the lesioned rats; whereas SB269970 (6 μg/rat) decreased 5-HT levels in the habenula and vHip, and the levels of NA in the mPFC, habenula and vHip in the two groups of rats. The results suggest that 5-HT7 receptors in the PrL play an important role in the regulation of these behaviors, which attribute to changes in monoamine levels in the limbic and limbic-related brain regions after activation and blockade of 5-HT7 receptors.

At present, little is known about the role of serotoninThe open field and elevated plus maze (EPM) tests were performed to study the influence of MFB lesion and intra-PrL injection of 5-HTThe MFB lesion induced anxiety-like behaviors compared to sham-operated rats. Intra-PrL injection of AS19 showed anxiolytic effects by the open field and EPM tests in two groups of rats, and administration of SB269970 showed anxiogenic responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 increased dopamine, 5-HT and noradrenaline (NA) levels in the medial prefrontal cortex, ventral hippocampus and amygdala in two groups of rats, whereas SB269970 decreased 5-HT and NA levels in these brain regions.5-HT6-OHDA: 6-hydroxydopamine; DMSO: dimethyl sulfoxide; DA: dopamine; EPM: elevated plus maze; MFB: medial forebrain bundlem; PFC: medial prefrontal cortex; NA: noradrenaline; PD: Pakinson's disease; PrL: prelimbic; 5-HT: serotonin; vHip: ventral hippocampus.

The roles of lateral habenular nucleus (LHb) glutamate neurons and serotonin2C (5-HT2C) receptors in depression are poorly understood, particularly in Parkinson's disease-associated depression. Here we assessed the importance of LHb glutamate neurons and 5-HT2C receptors for depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. The lesion induced depressive-like responses compared to sham-operated rats. Intra-LHb injection of potent, selective 5-HT2C receptor agonist Ro60-0175 decreased sucrose consumption and increased immobility time in sham-operated rats, indicating the induction of depressive-like responses, and intra-LHb injection of Ro60-0175 further increased the expression of depressive-like behaviors in the lesioned rats. Activation of LHb 5-HT2C receptors by the local administration of Ro60-0175 increased the firing rate of EAAC1 (a neuronal glutamate transporter)-positive neurons and percentage of the neurons with burst-firing pattern in the two groups of rats. Compared to sham-operated rats, the duration of Ro60-0175 action on the firing rate of EAAC1-positive neurons was markedly prolonged in the lesioned rats. Intra-LHb injection of Ro60-0175 decreased dopamine, 5-HT and noradrenaline levels in the medial prefrontal cortex, habenula, hippocampus and amygdala in sham-operated and the lesioned rats. The lesion did not change the percentage of EAAC1/5-HT2C receptor co-expressing neurons in the LHb. These findings indicate that activation of 5-HT2C receptors in the LHb increases firing activity of LHb glutamate neurons and then decreases monoamine levels in several brain regions, which increase the expression of depressive-like behaviors. Further, our results also suggest that the lesion leads to hyperfunctionality of 5-HT2C receptors on glutamate neurons of the LHb.

Serotonin2A (5-HT2A) receptors are highly expressed in the medial septum-diagonal band of Broca complex (MS-DB), especially in parvalbumin (PV)-positive neurons linked to hippocampal theta rhythm, which is involved in cognition. Cognitive impairments commonly occur in Parkinson's disease. Here we performed behavioral, electrophysiological, neurochemical and immunohistochemical studies in rats with complete unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB) to assess the importance of dopamine (DA) depletion and MS-DB 5-HT2A receptors for working memory. The MFB lesions resulted in working memory impairment and decreases in firing rate and density of MS-DB PV-positive neurons, peak frequency of hippocampal theta rhythm, and DA levels in septohippocampal system and medial prefrontal cortex (mPFC) compared to control rats. Intra-MS-DB injection of high affinity 5-HT2A receptor agonist TCB-2 enhanced working memory, increased firing rate of PV-positive neurons and peak frequency of hippocampal theta rhythm, elevated DA levels in the hippocampus and mPFC, and decreased 5-HT level in the hippocampus in control and lesioned rats. Compared to control rats, the duration of the excitatory effect produced by TCB-2 on the firing rate of PV-positive neurons was markedly shortened in lesioned rats, indicating dysfunction of 5-HT2A receptors. These findings suggest that unilateral lesions of the MFB in rats induced working memory deficit, and activation of MS-DB 5-HT2A receptors enhanced working memory, which may be due to changes in the activity of septohippocampal network and monoamine levels in the hippocampus and mPFC.

This study sought to assess whether unilateral lesions of the medial forebrain bundle (MFB) using 6-hydroxydopamine in rats are able to induce anxiety-like behaviors, the role of serotonin-1A (5-HT1A) receptors of the prelimbic (PrL) sub-region of ventral medial prefrontal cortex in the regulation of these behaviors, the density of 5-HT neurons in the dorsal raphe nucleus (DRN) and co-localization of 5-HT1A receptor and neuronal glutamate transporter EAAC1-immunoreactive (EAAC1-ir) cells in the PrL. Unilaterally lesioning the MFB induced anxiety-like behaviors as measured by the open-field and elevated plus maze tests when compared to sham-operated rats. Intra-PrL injection of 5-HT1A receptor agonist 8-OH-DPAT (50, 100, and 500 ng/rat) decreased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in sham-operated rats, indicating the induction of anxiogenic responses, and administration of 5-HT1A receptor antagonist WAY-100635 (60, 120, and 240 ng/rat) showed anxiolytic effects. However, 8-OH-DPAT, at the same doses, increased the percentage of time spent in the center of the open-field and percentages of open arm entries and open arm time in the lesioned rats, indicating the induction of anxiolytic effects, and WAY-100635 produced anxiogenic responses. Unilateral MFB lesion decreased the density of 5-HT neurons in the DRN, and percentage of EAAC1-ir cells expressing 5-HT1A receptors in the PrL. These results suggest that unilateral lesions of the MFB in rats may induce anxiety-like behaviors, and activation of 5-HT1A receptors in the PrL has anxiolytic effects in the rat model of Parkinson's disease.

Background Acute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved. Methods A systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN. Result The age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid. Conclusion The clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

The lateral habenula (LHb) is an important structure involved in various brain functions, because it controls the activity of dopaminergic and serotonergic systems in the midbrain. The impairment of working memory commonly occurs in Parkinson's disease; however, it is not clear whether the LHb involves in the regulation of working memory in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB). In this study, we found that the MFB lesions in rats decreased choice accuracy as measured by the T-maze rewarded alternation test compared to control rats, indicating the induction of working memory impairment, and decreased dopamine (DA) levels in the medial prefrontal cortex (mPFC), hippocampus and amygdala. Further, rats in the MFB and LHb lesion group showed increased choice accuracy compared to rats in the MFB lesion group, indicating the enhancement of working memory after lesioning the LHb. Neurochemical results found that lesions of the LHb increased DA levels in the mPFC, hippocampus and amygdala in the MFB and LHb lesion group, as well as serotonin (5-HT) level in the mPFC. These findings suggest that DA depletion plays a key role in working memory impairment, and lesions of the LHb improve working memory in the MFB-lesioned rats, which involves in increases in the levels of DA and 5-HT in the mPFC, hippocampus and amygdala. Additionally, the present results may have implications for improving our understanding of the neuropathology and/or treatment of PD.

At present, it is not clear whether α

This study examined the firing rate and pattern of electrophysiologically and chemically identified GABA interneurons in the dorsal raphe nucleus (DRN), and role of 5-HT1A receptor agonist 8-OH-DPAT and the medial prefrontal cortex (mPFC) in the firing activity in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The interneurons in rats with lesions of the SNc showed a more burst-firing, while having no change in the firing rate; the mPFC and combined mPFC and SNc lesions in rats decreased the firing rate of the interneurons and firing pattern shifted towards a more burst-firing compared to rats with sham lesions of the SNc, respectively. In rats with sham lesions of the SNc, administration of 8-OH-DPAT (1–243 μg/kg, i.v.) produced excitatory–inhibitory, excitatory and inhibitory effects in the firing rate of individual interneurons. However, when these effects were averaged over the group, 8-OH-DPAT had no significant effect on firing rate. In rats with lesions of the SNc, mPFC and the paired lesions, 8-OH-DPAT, at the same doses, inhibited all interneurons tested, respectively. Cumulative doses producing inhibition in rats with the paired lesions were higher than that of rats with lesions of the mPFC. In contrast to rats with sham lesions of the SNc, SNc lesion reduced expression of 5-HT1A receptor on parvalbumin positive neurons in the DRN, a subpopulation of GABA interneurons. Our results indicate that the SNc and mPFC regulate the firing activity of GABA interneurons in the DRN. Furthermore, response of likely GABA interneurons to systemic administration of 8-OH-DPAT is altered by lesion of the SNc and mPFC.

The lateral habenula (LHb) plays an important role in the regulation of depression. At present, it is not clear whether GABA

The prevalence of diabetes in China has surged from 0.67% before 1980 to 11.6% currently. It is even higher than the prevalence in the United States. Certainly, China's economic open-ups, improving living standard, and modernization have propagated the surge. From a traditional public-health point of view, increased food intake and decreased exercise were the main contributors. A new knowledge of colon microbiota could be applied to provide a second harvest of food energy; for example, large molecules of carbohydrates, which are undigested by the stomach and small intestine, produce by-products that the body can absorb in the colon. Colon microbiota can ferment these carbohydrates to the short-chain fatty acid butyrate. This is an energy source that may even cause nonalcoholic fatty liver. How these colon microbiota contribute to the surge of diabetes and whether this new knowledge can be used to control diabetes and metabolic syndrome are questions for future scientific studies. Clinically, however, colon microbiota have had immediate applications; fecal microbiota have been transplanted from healthy persons to treat recurrent Clostridium difficile infection at Mayo Clinic. In addition, a stool biobank of healthy persons was established at Mayo Clinic for future clinical applications.

In the present study, effect of SR 57227A, a selective 5-hydroxytryptamine-3 (5-HT3) receptor agonist, on the firing activity of pyramidal neurons in the medial prefrontal cortex (mPFC) was studied in normal rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Systemic administration of SR 57227A (40–640 μg/kg, i.v.) decreased the mean firing rate of pyramidal neurons in normal and the lesioned rats. This inhibition was significant only at doses higher than 320 μg/kg and 640 μg/kg in normal and the lesioned rats, respectively, and was reversed by i.v. administration of 5-HT3 receptor antagonist tropisetron or GABAA receptor antagonist bicuculline. Furthermore, local application of SR 57227A (0.01 μg) in the mPFC inhibited the firing rate of pyramidal neurons in normal rats while having no effect on firing rate in the lesioned rats. The i.v. administration of bicuculline excited the pyramidal neurons in normal rats, and then local application of SR 57227A did not alter the mean firing rate of these neurons. However, these two drugs did not affect the activity of the pyramidal neurons in the lesioned rats. We conclude that activation of 5-HT3 receptors inhibited pyramidal neurons in the mPFC of normal rats via GABAergic interneurons, and degeneration of the nigrostriatal pathway decreased response of the pyramidal neurons to SR 57227A, suggesting the dysfunction of 5-HT3 receptors and/or down-regulation of the expression on GABAergic interneurons in the lesioned rats.

In the present study, we examined changes in the firing rate and firing pattern of putative slow-spiking (SS) and fast-spiking (FS) interneurons in medial prefrontal cortex (mPFC) and the effect of 5-hydroxytryptamine-3 (5-HT(3)) receptor agonist SR 57227A on the neuronal firing in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) by using extracellular recording. The lesion of the SNc in rats decreased the firing rate of FS interneurons and the firing pattern of both SS and FS interneurons changed towards a more burst-firing. Systemic administration of SR 57227A (40-640 microg/kg, i.v.) increased the firing rate of SS interneurons, and decreased FS interneurons in sham-operated and the lesioned rats, respectively. The doses producing excitation or inhibition in the lesioned rats were higher than sham-operated rats. The local application of SR 57227A (0.01 microg) in mPFC excited SS interneurons, and inhibited FS interneurons in sham-operated rats, while having no effects on firing rate in the lesioned rats. Systemic administration of GABA(A) receptor antagonist bicuculline (2 mg/kg, i.v.) excited FS interneurons in sham-operated rats, whereas bicuculline did not change the activity of FS interneurons in the lesioned rats. Our findings indicate that the putative SS and FS interneurons activity is modulated through activation of 5-HT(3) receptor by direct or indirect action, and the lesion of the SNc leads to changes in firing activity of the SS and FS interneurons and decreased response of these interneurons to SR 57227A, suggesting dysfunction and/or down-regulation of 5-HT(3) receptor on interneurons in the 6-hydroxydopamine-lesioned rats.

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.

The aim of the present study was to investigate changes in the firing rate and pattern of interneurons in the medial prefrontal cortex (mPFC), and effects of 5-HT(2A/2C) receptor agonist DOI and antagonist ritanserin, and the selective 5-HT(2C) receptor antagonist SB 242084 on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by extracellular recording in vivo. The lesion of the SNc decreased the firing rate of the interneurons compared to sham-lesioned rats, and firing pattern of these interneurons changed toward a more burst-firing. Administration of DOI (20-320 microg/kg, i.v.) dose-dependently increased the firing rate of all interneurons examined in sham-lesioned and the 6-OHDA-lesioned rats. The excitation was significant at doses higher than 40 microg/kg and 320 microg/kg in sham-lesioned and the 6-OHDA-lesioned rats, respectively. This dose, which produced marked effect in the 6-OHDA-lesioned rats, was much higher than that of sham-lesioned rats. The local application of DOI (5 microg) in mPFC increased the firing rate of the interneurons in sham-lesioned rats, while having no effect on the firing rate in the 6-OHDA-lesioned rats. The excitatory effect of DOI in sham-lesioned and the 6-OHDA-lesioned rats was completely or partially reversed by ritanserin or SB 242084. The results of our study show that lesion of the SNc leads to a decrease in the firing rate of interneurons in mPFC and fire with a more burst pattern, and decreased response of the interneurons to DOI in rat.

Increasing evidence indicates that the excessive glutamate release onto substantia nigra pars compacta (SNpc) dopaminergic neurons may play an important role in the progression of nigral degeneration. We examined the effects of chronic, systemic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, in firing activity of SNpc dopaminergic neurons in 6-hydroxydopamine (6-OHDA) partially lesioned rats. In 6-OHDA-lesioned rats treated with vehicle, injection of 6-OHDA (4 μg) into the medial forebrain bundle produced a partial lesion, 39% loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNpc. In partially lesioned rats, the electrophysiological characteristics of SNpc dopaminergic neurons showed that the firing rate of these neurons increased compared with sham-operated rats and the firing pattern also changed towards a burstier one. Chronic, systemic treatment of MPEP (3 mg/kg/day, 14 days) attenuated loss of TH-ir neurons and normalized the hyperactive firing activity in the SNpc induced by partial unilateral dopamine depletion lesions. In addition, no significant differences were found in the responsiveness of SNpc dopaminergic neurons to intravenous cumulative apomorphine in sham-operated, vehicle-treated and MPEP-treated rats, while ED50 values for apomorphine in MPEP-treated rats were decreased as compared with vehicle-treated rats. These data demonstrate that the surviving dopaminergic neurons in the SNpc are hyperactive in an experimental model of moderate Parkinson's disease (PD). In this model, chronic, systemic MPEP treatment has the neuroprotective effect and reverses the abnormal firing activity of dopaminergic neurons, suggesting that MPEP has an important implication for the treatment of PD.

Several studies have shown that the 5-hydroxytryptamine (serotonin, 5-HT) system is severely affected after degeneration of nigrostriatal dopaminergic neurons. In the present study, we examined the changes in the firing rate and firing pattern of the dorsal and median raphe nuclei (DRN and MRN) 5-HT neurons, and the effect of the selective 5-HT(1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist (N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of DRN and MRN 5-HT neurons compared with normal rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. The lower dose of 8-OH-DPAT, 4 microg/kg (cumulative doses, i.v.), completely inhibited the firing activity of all DRN and MRN 5-HT neurons examined in normal and sham rats. In contrast to normal and sham rats, only the higher doses of 8-OH-DPAT, 128 and 64 microg/kg, completely inhibited the firing rate of DRN and MRN 5-HT neurons in 6-OHDA-lesioned rats, respectively. Furthermore, the local application of 8-OH-DPAT, 1.5 microg, in the DRN completely inhibited the firing rate of 5-HT neurons in normal and sham rats, while having no effect on firing rate in the lesioned rats. Altogether, these results indicate that lesion of the nigrostriatal pathway leads to hyperactivity of DRN and MRN 5-HT neurons, suggesting the implication of the DRN and MRN in the pathophysiology of Parkinson's disease, and the decreased response of these 5-HT neurons to 5-HT(1A) receptor stimulation, reflecting 5-HT(1A) receptor dysfunction in 6-OHDA-lesioned rats.

Several studies have shown that the neuronal activity of the pedunculopontine nucleus is increased in Parkinson's disease. In the present study, the changes were examined in the firing rate and firing pattern of presumed cholinergic and non-cholinergic neurons in the pedunculopontine nucleus of 6-hydroxydopamine-lesioned rats by using extracellular recording. In the lesioned rats, the mean firing rate of both presumed cholinergic and non-cholinergic neurons in the pedunculopontine nucleus increased significantly compared to normal rats. With regard to firing pattern, the majority of presumed cholinergic and non-cholinergic neurons fired regularly in normal rats. After substantia nigra pars compacta-lesion, the percentage of presumed non-cholinergic neurons exhibiting irregular pattern increased significantly compared to normal rats, while having no significant change in the firing pattern of presumed cholinergic neurons. Collectively, these results indicate that the presumed cholinergic and non-cholinergic neurons in the pedunculopontine nucleus are overactive in 6-hydroxydopamine-lesioned rats, particularly, presumed non-cholinergic neuron firing is more irregular, which suggests that the firing activity of presumed cholinergic and non-cholinergic neurons is affected by the different afferents from the basal ganglia and related structures.

The aim of the present study was to investigate changes in the firing activity of thalamic parafascicular nucleus (PF) neurons at different time periods after 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) and the role of the pedunculopontine nucleus (PPN) in these changes. In normal rats, the firing rate of PF neurons was 3.66+/-0.37 spikes/s. In rats with 6-OHDA lesions of the SNc, the firing rate of PF neurons slightly decreased to 3.19+/-0.35 spikes/s during the third week compared to normal rats, unexpectedly, as moving on to fifth week, the firing rate increased significantly to 4.82+/-0.31 spikes/s. In rats with ibotenic acid lesions of the PPN, the firing rate decreased significantly to 1.98+/-0.19 spikes/s compared to normal rats. When the SNc and PPN were double lesioned, the firing rate of PF neurons decreased significantly to 2.36+/-0.23 spikes/s during the third week and 2.16+/-0.16 spikes/s during the fifth week post-lesions. The separate lesions of the PPN, SNc, and double lesion of both in the rats did not change the firing pattern of PF neurons compared to normal rats. These findings demonstrate that PF neurons are hyperactive in the 6-OHDA-lesioned rats suggesting the implication of this nucleus in the pathophysiology of parkinsonism. Furthermore, the fact that the PPN lesions induced a decrease in the firing rate of PF neurons in normal and SNc-lesioned rats suggests that the PF is under major control of the PPN.

Depression is a common symptom in Parkinson's disease (PD), but its pathophysiology remains unclear. Several lines of studies have revealed that the prelimbic (PrL) sub-region of the ventral medial prefrontal cortex and 5-HT1A receptors are involved in the regulation of depression. In this study, we examined whether complete unilateral lesions of the medial forebrain bundle (MFB) using 6-hydroxydopamine in rats are able to induce depressive-like behaviors, the role of PrL 5-HT1A receptors in the regulation of these behaviors, and co-localization of 5-HT1A receptor and neuronal glutamate transporter EAAC1-immunoreactive (EAAC1-ir) neurons in the PrL. The MFB lesions induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. The intra-PrL injection of 5HT1A receptor agonist 8-OH-DPAT (50, 100, and 500ng/rat) increased sucrose consumption, and decreased immobility time in both sham-operated and the lesioned rats, indicating the induction of antidepressant effects. Furthermore, the intra-PrL injection of 5HT1A receptor antagonist WAY-100635 (60, 120, and 240ng/rat) showed a decrease in sucrose consumption, and an increase in immobility time, indicating the induction of depressive-like responses. However, the effective doses in the lesioned rats were higher than those in sham-operated rats, which attribute to down-regulation of 5-HT1A receptor expression on EAAC1-ir neurons in the PrL of the lesioned rats. These findings suggest that unilateral lesions of the MFB in rats may induce depressive-like behaviors, and 5-HT1A receptors of the PrL play an important role in the regulation of these behaviors.

DL111-IT, a non-hormonal contragestional agent, revealed synergistic effects in combination with mifepristone (RU486) in some species. The present study was undertaken to clarify the role of DL111-IT when used alone or plus RU486 on uterine polyamines biosynthesis, histologic alteration of decidual cells, and antifertility activity in rats. The levels of polyamines in pregnant rat uterus were determined by formed benzoyl chloride derivatives of polyamines for RP-HPLC. The results showed that all the treated groups including DL111-IT 2.8 mg. kg(-1). d(-1), RU486 3.0 mg. kg(-1). d(-1), and DL111-IT 0.56 mg. kg(-1). d(-1) plus RU486 0.6 mg. kg(-1). d(-1) caused 100% early pregnancy arrest. Uterine putrescine, spermidine, and spermine levels in comparison with vehicle control were declined significantly from d7 of gestation (1 day after treatment) to d9 or d14 (3 days or 8 days after treatment) by Duncan's multiple range test, and accompanied by histologic alterations, edema, degeneration and dissolution of decidual cells with nuclei indefinite in appearance on d8 of gestation (2 days after treatment). The combined administration at lower doses caused the most injury. The data verified that the decrease in uterine polyamine levels and subsequent decidual cells injuries were the critical role of early pregnancy arrest induced by DL111-IT or RU486. The two compounds used in combination with lower dosages revealed greatly synergistic effects.

l-3,4-Dihydroxyphenylalanine (L-DOPA) is the most widely used drug for the treatment of Parkinson's disease. Unfortunately, chronic administration of this dopamine precursor causes L-DOPA-induced dyskinesia (LID), which is a debilitating complication whose pathogenesis remains unclear. In this study, we compared gene expression profiles of sensorimotor striatum tissue derived from LID and non-LID 6-hydroxydopamine-lesioned rats treated with L-DOPA. Total RNA was amplified, transcribed and hybridized to Agilent Whole Rat Genome Oligo Microarray chips. Quantitative real-time reverse transcription PCR was conducted to validate the microarray data. We detected 382 upregulated genes and 115 downregulated genes in LID rats when compared with that of non-LID subjects with Significance Analysis for Microarrays software. The differentially expressed genes were mainly associated with postsynaptic cell membranes, synapses, and neurotransmitter receptors. Gene Set Analysis (GSA) software was used to identify differentially expressed gene ontology (GO) categories and pathways. The GSA found that "long-term depression" and "retrograde endocannabinoid signaling" pathways were downregulated, whereas a set of lipid metabolism-related GO categories and pathways were upregulated in LID rats compared with non-LID controls. Our study provides further experimental evidence to support the direct correlation between abnormal striatal synaptic plasticity and the induction of LID, and it suggests that the dysfunction of the retrograde endocannabinoid signaling system, a lipid-based neuromodulatory system, and the relevant alteration of the related lipid metabolism processes might play an important role in the pathogenesis of LID.

The parvalbumin (PV)-positive neurons in the medial septum-diagonal band of Broca complex (MS-DB) play an important role in the generation of hippocampal theta rhythm involved in cognitive functions. These neurons in this region express a high density of 5-HT1A receptors which regulate the neuronal activity and consequently affect the theta rhythm. In this study, we examined changes in the theta-related firing activity of PV-positive neurons in the MS-DB, their response to 5-HT1A receptor stimulation and the corresponding hippocampal theta rhythm, and the density of PV-positive neurons and their co-localization with 5-HT1A receptors in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc decreased the rhythmically bursting activity of PV-positive neurons and the peak frequency of hippocampal theta rhythm. Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.5-128 µg/kg, i.v.) inhibited the firing rate of PV-positive neurons and disrupted rhythmically bursting activity of the neurons and the theta rhythm in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition and disruption in the lesioned rats were higher than that of sham-operated rats. Furthermore, local application of 8-OH-DPAT (0.005 μg) in the MS-DB also inhibited the firing rate of PV-positive neurons and disrupted their rhythmically bursting activity in sham-operated rats, while having no effect on PV-positive neurons in the lesioned rats. The lesion of the SNc decreased the density of PV-positive neurons in the MS-DB, and percentage of PV-positive neurons expressing 5-HT1A receptors. These results indicate that the lesion of the SNc leads to suppression of PV-positive neurons in the MS-DB and hippocampal theta rhythm. Furthermore, the lesion decreases the response of these neurons to 5-HT1A receptor stimulation, which attributes to dysfunction and/or down-regulation of 5-HT1A receptor expression on these neurons. These changes may be involved in cognitive impairments of Parkinson's disease.

Here we report that juxtacellular labeled GABA interneurons in the basolateral amygdaloid nucleus anterior part (BLA) of rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) showed a more burst-firing pattern, while having no change in the firing rate. In sham-operated and the lesioned rats, systemic administration of 5-HT(2A/2C) receptor agonist DOI produced excitation, inhibition and unchanged in the firing rate of the interneurons, and the mean response of DOI was excitatory. However, cumulative dose producing excitation in the lesioned rats was higher than that of sham-operated rats. The local administration of DOI in the BLA also produced three types of responses in two groups of rats. Furthermore, the local administration of DOI excited the interneurons in sham-operated rats, whereas the mean firing rate of the interneurons in the lesioned rats was not affected at the same dose. The excitatory effect of the majority of the interneurons after systemic and local administration of DOI was not reversed by the selective 5-HT(2C) receptor antagonist SB242084, and the inhibitory effect of DOI in all the interneurons examined was reversed by GABA(A) receptor antagonist picrotoxinin. The SNc lesion in rats did not change the density of GAD67/5-HT(2A) receptor co-expressing neurons in the BLA. These results indicate that the SNc lesion changes the firing activity of BLA GABA interneurons. Moreover, DOI regulated the firing activity of the interneurons mainly through activation of 5-HT(2A) receptor, and the lesion led to a decreased response of the interneurons to DOI, which attributes to dysfunction of 5-HT(2A) receptor on these interneurons.

5-Hydroxytryptamine(1A) (5-HT(1A)) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT(1A) receptor agonist 8-OH-DPAT and change in expression of 5-HT(1A) receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 μg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 μg/kg) was significantly higher than that of sham-operated rats (27 μg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 μg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT(1A) receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT(1A) receptor stimulation, which attributes to down-regulation of 5-HT(1A) receptor expression in these interneurons.

To investigate the expression of matrix metalloproteinase-2 (MMP-2) and insulin-like growth factor-1 (IGF-1) in gastric carcinoma and their clinicopathological significance.Expressions of MMP-2 and IGF-1 were examined by using immunohistochemical SP staining and cross-compared with clinicopathological features of gastric carcinoma.High expression of MMP-2 and IGF-1 were observed in 70.4% (307/436) and 49.5% (216/436) of gastric carcinoma tissues respectively, significantly higher than those in non-tumor gastric mucosa (3.3% and 5.4%, respectively; all P0.05). The high expression rate of MMP-2 and IGF-1 were significantly associated with the patient age, tumor size, tumor location, Lauren classification, TNM staging, depth of tumor infiltration, presence of vessel invasion, lymph node and distant metastasis (all P0.05). In addition, the expression of MMP-2 was positively linked with the expression level of IGF-1 (P0.05). Univariate analysis showed that high expression of MMP-2, was significantly associated with poor prognosis of tumor of TNM stage I and II (all P0.05), high expression of IGF-1 was significantly correlated with poor prognosis of patients with TNM stage I, II and III tumor (all P0.05). Cox multivariate analysis indicated that the high expressions of MMP-2 and IGF-1 could be independent prognostic indices for gastric carcinoma.High expression of MMP-2 and IGF-1 proteins are significantly correlated with the invasion and metastasis of gastric carcinoma, it is helpful to simultaneously detect the expressions of MMP-2 and IGF-1 proteins in predicting prognosis of patients with gastric carcinoma.

Although increasing evidence indicates that psychiatric symptoms are crucial characteristic of the early stage of Parkinson's disease (PD) and precede motor impairments, the neuronal firing activity of the basolateral nucleus of the amygdala (BLA) in the psychiatric symptom of PD and the involved mechanism are still unclear. In the present study, we examined the changes in emotional and cognitive tests not focused on motor fluency and firing activity of projection neurons in the BLA rats with 6-hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum, and the effects of apomorphine and the medial prefrontal cortex (mPFC) on these changes. Injection of 6-OHDA (10.5 μg) into the dorsal striatum produced 18-22% and 26-30% loss of tyrosine hydroxylase immunoreactive neurons in the ventral tegmental area and substantia nigra pars compacta of rats, respectively. The striatal lesions induced anxiety-like responses in the rats but did not result in depressive-like behavior or cognitive impairments. In the lesioned rats, the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and the firing pattern of BLA projection neurons was not changed. No significant differences were observed either in behaviors or firing activity of BLA projection neurons by further ibotenic acid lesions of the mPFC in the lesioned rats. Systemic administration of cumulative apomorphine (10-160 μg/kg) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA-lesioned and combined 6-OHDA- and mPFC-lesioned rats, but the latter needed more apomorphine stimulation. These data suggest that the anxiety in early stage of PD is possibly related to the decrease in firing activity of BLA projection neurons, which may be regulated by the activation of dopamine receptor in the mPFC.

Degeneration of noradrenergic neurons in the locus coeruleus (LC) and dysfunction of the prefrontal cortex were regarded as playing a specific role in the occurrence of non-motor symptoms in Parkinson's disease. The present study examined the spontaneous firing rate and firing pattern of medial prefrontal cortex (mPFC) pyramidal neurons, and effects of alpha(2)-adrenoceptor agonist UK-14,304 and antagonist yohimbine on the neuronal activity in rats with 6-hydroxydopamine lesions of the LC, medial forebrain bundle (MFB) and with combined MFB and LC lesions. The firing rate of mPFC pyramidal neurons in rats with lesions of the LC and with combine LC and MFB lesions is significantly higher than that of normal and MFB-lesioned rats and the firing pattern of these neurons in rats with lesions of the LC and with combine LC and MFB lesions also changed significantly towards more regular compared with normal and MFB-lesioned rats. The local administration of UK-14,304 in the mPFC inhibited the firing activity of the pyramidal neurons in normal rats and rats with lesions of the LC, MFB and with combined LC and MFB lesions, while yohimbine increased the firing activity of the pyramidal neurons. These results indicate that the lesions of the LC lead to hyperactivity of mPFC pyramidal neurons in normal and MFB-lesioned rats, and the postsynaptic alpha(2)-adrenoceptors may partially mediate the inhibitory effects of LC-noradrenergic system on the firing activity of pyramidal neurons in the mPFC, suggesting that LC-noradrenergic system plays an important role in the functional disorders of mPFC in Parkinson's disease.

The role of noradrenergic depletion of the locus coeruleus (LC) in the pathophysiology of Parkinson's disease (PD) is still unclear. In the present study, apomorphine-induced circling behavior and extracellular firing activity of substantia nigra pars reticulata (SNr) neurons were examined in rats with unilateral 6-hydroxydopamine lesions of the LC, substantia nigra pars compacta (SNc) and with combined SNc and LC lesions. A moderate contralateral circling was observed in rats with LC lesions after apomorphine. Moreover, the circling behavior was obviously increased by further lesions of LC in SNc-lesioned rats. Extracellular recordings indicated that the firing rate of SNr neurons increased significantly and the firing pattern of these neurons also changed towards more irregular and bursty after SNc lesioning as compared to sham-lesioned rats, while the firing rate and pattern were unaffected in rats with simple lesions of the LC. However, the firing rate of SNr neurons in rats with combined LC and SNc lesions increased significantly when compared to that of rats with simple lesions of the SNc, although the firing pattern was not altered. Furthermore, SNc lesions in rats increased the firing rate of SNr neurons with irregular firing pattern, and additional LC lesions in SNc-lesioned rats increased the firing rate of SNr neurons with regular and irregular firing pattern. These results indicate that lesions of the LC intensify apomorphine-induced circling behavior and lead to a further hyperactivity of SNr neurons in a rat model of PD, suggesting that LC-noradrenergic system is involved in the motor dysfunction of PD.

To investigate the changes in the firing activity of noradrenergic neurons in the locus coeruleus (LC) in a rat model of Parkinson disease (PD).2 and 4 weeks after unilateral lesion of the nigrostriatal pathway in the rat by local injection of 6-hydroxydopamine (6-OHDA) into the right substantia nigra pars compacta (SNc), the firing activity of noradrenergic neurons in LC was recorded by extracellular single unit recording.The firing rate of LC noradrenergic neurons increased significantly 2 and 4 weeks after 6-OHDA lesions compared to normal rats, respectively (P0.05). The percentage of irregularly firing neurons was obviously higher than that of normal rats during the fourth week after SNc lesion (P0.05).LC noradrenergic neurons are overactive and more irregular in 6-OHDA-lesioned rats. These changes suggest an implication of the LC in the pathophysiological mechanism of PD.

In the present study, we examined changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC), and the effects of 5-HT(2A/2C) receptor agonist DOI and antagonist ritanserin on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of pyramidal neurons compared to sham-operated rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. Systemic administration of DOI (20-320 microg/kg, i.v.) increased the mean firing rate of pyramidal neurons in sham-operated and the lesioned rats. The excitation was significant only at doses higher than 160 microg/kg and 320 microg/kg in sham-operated and the lesioned rats, respectively. In addition, the local application of DOI, 5 microg, in mPFC inhibited the firing rate of pyramidal neurons in sham-operated rats, while having no effect on firing rate in the lesioned rats. After treatment with GABAA receptor antagonist picrotoxinin, the local application of DOI, at the same dose, increased the mean firing rate of the neurons in sham-operated rats; however, DOI did not alter the firing activity of the neurons in the lesioned rats. These results indicate that the lesion of the nigrostriatal pathway leads to hyperactivity of pyramidal neurons in mPFC, and the decreased response of pyramidal neurons to DOI, suggesting dysfunction of 5-HT2A and 5-HT2C receptors on pyramidal neurons and GABAergic interneurons in the 6-OHDA-lesioned rats.

The changes in the firing rate and firing pattern of pyramidal neurons in medial prefrontal cortex (mPFC) and the effects of selective 5-hydroxytryptamine-(1A) (5-HT(1A)) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the firing activity of the neurons were studied in sham-lesioned rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc increased the firing rate of pyramidal neurons significantly compared to sham-lesioned rats, and the firing pattern of these neurons also changed significantly towards a more burst-firing. The systemic administration of 8-OH-DPAT at doses in the range of 0.5-128 microg/kg showed an excitatory-inhibitory effect on the firing rate of pyramidal neurons in mPFC of sham-lesioned rats. At lower doses, 0.5-32 microg/kg, it evoked excitation of the neurons, and at a high dose, i.e. 128 microg/kg, inhibited the activity of the neurons. In contrast to sham-lesioned rats, 8-OH-DPAT, at the same doses, showed no excitatory effect in the lesioned rats although the inhibitory phase of the effect of 8-OH-DPAT on the firing rate of pyramidal neurons in mPFC was still present. Furthermore, the local application of 8-OH-DPAT, 5 microg, in mPFC inhibited the firing rate of pyramidal neurons in sham-lesioned rats, while having no effect on firing rate in the lesioned rats. The excitatory or inhibitory effects of 8-OH-DPAT were reversed by WAY-100635, indicating that these effects are mediated by 5-HT(1A) receptor. Altogether, these results indicate that the lesion of the SNc leads to hyperactivity of pyramidal neurons in mPFC and the abnormality of response of these neurons to 5-HT(1A) receptor stimulation, suggesting that mPFC may be involved in the pathophysiology of the psychiatric disturbance of Parkinson's disease.

The subthalamic nucleus is innervated by 5-HT afferents from the dorsal raphe nucleus and expresses high density of 5-HT(2C) receptors. However, the role of these receptors in neuronal firing of subthalamic neurons in vivo is unknown. In the present study, we examined the changes in the firing rate and firing pattern of subthalamic neurons, and the effect of the nonselective 5-HT(2C) receptor agonist m-CPP and selective antagonist SB242084 on the neuronal firing of subthalamic neurons in normal rats, sham rats, and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Results showed an increase in the percentage of subthalamic neurons exhibiting burst-firing pattern with no change in firing rate during the third week after the lesion compared to normal rats. The systemic administration of m-CPP (20-320 microg/kg, i.v.) dose-dependently increased the firing rate of subthalamic neurons, and the local application of m-CPP, 4 microg, in the subthalamic nucleus also increased the firing rate of subthalamic neurons in the lesioned rats. Similarly, at the same doses, the systemic and local administration of m-CPP induced the excitatory effects on subthalamic neurons in normal and sham rats. The excitatory effect of m-CPP was reversed by the subsequent administration of SB242084 (200 microg/kg, i.v.). These results suggest that the response of subthalamic neurons to 5-HT(2C) receptor stimulation is not altered after 6-hydroxydopamine lesions of the substantia nigra pars compacta.

The ventral part of the medial prefrontal cortex (mPFC) plays an important role in initiation and control of voluntary movement, mood and cognition. However, after the degeneration of the nigrostriatal pathway, the neuronal activity of the ventral mPFC and the role of serotonin(1A) (5-hydroxytryptamine, 5-HT(1A)) receptors in the firing of the neurons are still unknown. The present study is to investigate the change of neuronal activity in the ventral mPFC and the effect of systemic administration of the selective 5-HT(1A) receptor antagonist WAY-100635 on the activity of the neurons in normal and 6-hydroxydopamine (6-OHDA)-lesioned rats.Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesioned rats in vivo.6-OHDA lesion of the substantia nigra pars compacta (SNc) significantly increased the firing rate with no change in the firing pattern of neurons of the ventral mPFC in rats. Systemic administration of WAY-100635 (0.1 mg/kg, i.v.) did not change the mean firing rate and firing pattern of ventral mPFC neurons in normal rats. In contrast, WAY-100635 significantly decreased the mean firing rate of the neurons in rats with 6-OHDA lesion of the SNc.These data suggest that the degeneration of the nigrostriatal pathway results in an increase of neuronal activity of ventral mPFC and dysfunction of 5-HT(1A) receptor.

To study galactagogue effect of Maidang Rutong granule on the lactation rats.The experiments were designed to observe the efficiency of Maidang Rutong granule on lactescence, serum prolactin, and morphology of mammary gland with rat galactozemia model established by injecting l-dopa.Maidang Rutong granule showed significant enhancement for lactescence and the offspring's body weight. It could antagonize the decrease of serum prolactin and the atrophy of mammary gland induced by l-dopa.Maidang Rutong granule exhibited significant galactagogue effect on the l-dopa-induced galactozemia in rats.

Thiazolidinediones (TZDs) such as rosiglitazone are antidiabetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma agents improve diabetes by increasing insulin sensitivity and enhancing the differentiation of preadipocytes into adipocytes. The present study aimed to identify if 1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-3-indoleacetitic acid (GY3), a newly synthesized indole compound, could enhance adipocytes differentiation and insulin sensitivity. The results showed that both GY3 and rosiglitazone significantly increased the lipid accumulating of 3T3-L1 adipocytes induced by isobutylmethylxanthine, dexamethasone and insulin mixture, but GY3 (not rosiglitazone) failed to increase the lipid accumulation when induced by insulin alone. In addition, GY3- or rosiglitaozne-induced protein expression of GLUT4 and adiponectin was determined by Western blot analysis. GY3 activated PPARalpha weakly but did not affect PPARgamma, while rosiglitazone activated PPARgamma significantly, suggesting different mechanisms between GY3 and rosiglitazone on adipocyte differentiation. Furthermore, both GY3 and rosiglitazone enhanced the adiponectin and insulin pathway proteins expression and adiponectin secretion in mature adipocytes, but only GY3 not rosiglitazone elevated gene expression of leptin and resistin. Both GY3 and rosiglitazone enhanced glucose consumption in HepG2 cells especially in the presence of insulin. In the in vivo study, GY3 decreased serum glucose and insulin in db/db mice, indicating the insulin sensitizing effect might contribute to its antidiabetic mechanism. Altogether, these results suggest that GY3 could improve insulin resistance and lower glucose level, GY3 and its derivatives might be developed as a substitution therapy for diseases with insulin resistance.

The subthalamic nucleus receives serotonergic projections from the dorsal raphe nucleus. However, the role of serotonergic innervation in the activity of subthalamic neurons in vivo is unknown. The aim of the present work is to study the changes in the firing of subthalamic neurons in rats with 5,7-dihydroxytryptamine lesions of the dorsal raphe nucleus and rats with combined 5,7-dihydroxytryptamine lesions in the dorsal raphe nucleus and 6-hydroxydopamine lesions in the substantia nigra pars compacta by using single-unit extracellular recordings. In rats with 5,7-dihydroxytryptamine lesions of the dorsal raphe nucleus, the firing rate of subthalamic neurons increased significantly compared with normal rats and the firing pattern changed significantly towards a more bursting firing in the majority of the neurons observed. In rats with combined dorsal raphe nucleus and substantia nigra pars compacta lesions, the firing rate and firing pattern of subthalamic neurons did not show a significant difference compared to rats with lesions of the substantia nigra pars compacta. However, dorsal raphe nucleus and substantia nigra pars compacta lesions combined increased significantly the percentage of subthalamic neurons with burst-firing pattern compared to normal rats, while having no effect on their firing rate. These results show that the serotonergic efferent projections of the dorsal raphe nucleus significantly influence on the activity of subthalamic neurons and that the loss of dopaminergic projection by substantia nigra pars compacta lesion decreases the effect of the lesions of the dorsal raphe nucleus on subthalamic nucleus neuronal activity, suggesting that the role of the dorsal raphe nucleus may be exerted by the dorsal raphe nucleus-substantia nigra pars compacta-subthalamic nucleus pathway.

To explore the neuro-protective effect and mechanism of qingkailing injection (QKL) against cerebral injury caused by E. coli-meningitis (CM).The CM model rabbits were treated by ampicillin with QKL as adjuvant. The leukocyte count and protein content in cerebral spinal fluid (CSF), the contents of water, sodium, potassium and calcium in cerebral tissues were measured before, 16 h and 26 h after Bacillus coli injection respectively. The expression of matrix metalloproteinase-9 (MMP-9) was determined at the same time.Adjunctive treatment with QKL can not only inhibit the increase of leukocyte cells, protein content in CSF, and water, sodium, calcium content in cerebral tissues, but also the decrease of potassium content revealed during simple antibiotic treatment. It also can decrease the expression of MMP-9 in cerebral tissues of rabbits with CM.As an adjunctive treatment, QKL can prevent transient inflammatory reaction and aggravation of brain injury in CM induced by simple antibiotic treatment, its mechanisms might relate with calcium antagonism and attenuation of MMP-9 expression in brain tissues.

In vivo extracellular recordings were made in the subthalamic nucleus (STN) of intact control rats and rats with 5,7-dihydroxytryptamine (5,7-DHT) -produced lesion of dorsal raphe nucleus (DRN). The results showed that the firing rate of STN neurons in control rats and DRN-lesioned rats were (6.93+/-6.55) Hz and (11.27+/-9.31) Hz, respectively, and the firing rate of DRN-lesioned rats significantly increased when compared to the control rats (P0.01). In control rats, 13% of STN neurons discharged regularly, 46% irregularly and 41% in bursts. In DRN-lesioned rats, 9% of STN neurons discharged regularly, 14% irregularly and 77% in bursts, the percentage of STN neurons firing in bursts was obviously higher than that of the control rats (P0.01). In addition, the mean interspike interval coefficient of variation of STN neurons in control rats and DRN-lesioned rats were (0.05+/-0.04) and (0.11+/-0.09), respectively. The mean interspike interval coefficient of variation of DRN-lesioned rats was significantly higher than that of the control rats (P0.001). These results show that the firing rate and the bursting pattern rate of neurons in STN of DRN-lesioned rats increase significantly, suggesting that DRN inhibits the neuronal activity of the subthalamic neurons in the intact rat.

In the present study, changes of the neuronal activity of 5-hydroxytrypamine (5-HT) neurons of dorsal raphe nucleus(DRN) in a rat model of Parkinson's disease (PD) were investigated with glass microelectrode recording. The results showed that the discharge rates of 5-HT neurons in control and PD rats were (1.61+/-0.56) Hz and (2.61+/-1.97) Hz, respectively. The discharge rate of PD rats was significantly increased when compared to that of the control rats. In control rats, 79% of 5-HT neurons discharged regularly and 21% in bursts. In PD rats, however, 36% of 5-HT neurons discharged regularly, 16% irregularly and 47% in bursts. The percentage of 5-HT neurons discharging in bursts was obviously higher than that of the control rats (P0.05). The data suggest that the discharge rate and bursting pattern of 5-HT neurons in DRN are increased in a rat model of Parkinson's disease.

The effects of a non-selective inhibitor of cyclo-oxygenase (COX) indomethacin, and exogenous prostaglandin E(2) (PGE(2)) on A(delta) units and C units in the saphenous nerve of diabetic hyperalgesic rats were studied. The results showed that the conduction velocity of A(delta) units and C units and their mechanical threshold in diabetic hyperalgesic rats were obviously decreased, and a small number of A(delta) units (4/24) and C units (2/18) produced increased spontaneous activities. Intraperitoneal injection of indomethacin in diabetic hyperalgesic rats significantly relieved mechanical hyperalgesia, and resulted in a decrease in spontaneous afferent activities of the A(delta) units and C units. Subcutaneous injection of exogenous PGE(2) into the diabetic hyperalgesic and control rats produced a significant decrease in mechanical threshold of the A(delta) units and C units, and elicited discharge from 3 A(delta) units (3/24) and 1 C unit (1/18) in diabetic hyperalgesic rats and from 2 A(delta) units (2/13) in control rats. The present data suggest that the synthesis and release of PGs are increased in diabetic neuropathy, PGs can sensitize and /or activate A(delta) units and C units and elicit hyperalgesia and allodynia in diabetic rats.

The effectiveness of DL111-IT and RU486 given alone and in combination for terminating early pregnancy was tested in the rat, mouse, and hamster. In the mouse and rat, the combination of RU486 and DL111-IT is much more effective in terminating pregnancy than either of the two compounds used alone (single or multiple treatment). A low-effective dose of DL111-IT in combination with a non-effective or a sub-effective dose of RU486, exerted additive or synergistic effects resulting in resorption of embryos and termination of pregnancy. The serum progesterone concentrations were significantly suppressed by these combinations when pregnancy was terminated. In the hamster, single treatment with DL111-IT plus RU486 exhibited a strong effect on interrupting early pregnancy. The ED50 of RU486 in combination of a non-effective dose of DL111-IT was decreased to 163-fold lower dose than RU486 given alone. It is concluded that in mouse, rat, and hamster, the synergistic action between DL111-IT and RU486 not only greatly enhances efficacy in terminating pregnancy but also reduces substantially the dose required to produce this effect.