One-pot synthesis and enzyme-responsiveness of amphiphilic doxorubicin prodrug nanomicelles for cancer therapeutics.

In this study, we report a one-pot synthesis and enzyme-responsiveness of polyethylene glycol (PEG) and glutamic acid (Glu)-based amphiphilic doxorubicin (DOX) prodrug nanomicelles for cancer therapeutics. The nanomicelles were accomplished by esterification and amidation reactions. The nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) data confirmed the structure of nanomicelles. The DOX-loaded nanomicelles showed a DLS-measured average size of 107 nm and excellent stability in phosphate-buffered saline (PBS) for 7 days. The drug loading and cumulative release rates were measured by ultraviolet-visible (UV-vis) spectrophotometry at 481 nm. The cumulative release rate could reach 100% in an enzyme-rich environment. Further, the therapeutic efficiency of nanomicelles to cancer cells was determined by cell viability and cellular uptake and distribution using HeLa cells. The cell viability study showed that the DOX-loaded nanomicelles could effectively inhibit the HeLa cell proliferation. The cellular uptake study confirmed that the nanomicelles could be effectively ingested by HeLa cells and distributed into cell nuclei. Based on the collective experimental data, this study demonstrated that the synthesized nanomicellar prodrug of DOX is a potential candidate for cancer therapeutics.

DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. OBJECTIVE: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. METHODS: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aß plaques and neuroinflammation in the brain. IL-1ß, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. RESULTS: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aß deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1ß and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. CONCLUSION: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

[Effects of LncRNA H19 on Proliferation of Human Colorectal Cancer SW620 Cells].

OBJECTIVE: To determine the expression level of long non-coding RNA (lncRNA) imprinted maternallyexpressed transcript (H19) in colorectal cancer tissues and its effect on proliferation of colorectal cancer SW620 cells. METHODS: Real-time quantitative PCR (qRT-PCR) was applied to detect the expression of H19 in 20 paired tumor tissues and adjacent normal tissues,and in normal NCM460 cells and colorectal cancer SW480,HCT116 and SW620 cells. The specific small interfering RNA for H19 (si-H19 group) or negative control sequence (si-NC group) were transfected into SW620 cells. Proliferation of the transfected cells was detected using flow cytometry,CCK8 assay and clone formation experiment. The expressions of CyclinD1 and cyclin dependent kinase 4 (CDK4) were detected by qRT-PCR and Western blot. RESULTS: The expression levels of H19 in colorectal cancer tissues and cells were higher compared with those in adjacent normal tissues and normal NCM460 cells. Lower H19 level,cell activities and cell clone numbers were found in si-H19 transfected cells compared with those in si-NC transfected cells ( P<0.05). si-H19transfected cells had decreased expression of CyclinD1 and CDK4 ( P<0.05). CONCLUSION: H19expression in colorectal cancer is high. Knock-down H19 expression can inhibit proliferation of colorectal cancer cells,which provides a potential strategy for targeted therapy of colorectal cancer.

[The improvement of periodontal teaching mode based on PDCA theory].

PURPOSE: To evaluate the effect of PDCA teaching mode on clinical ability in the process of periodontal clinical internship. METHODS: Forty-eight undergraduate interns coming from School of Stomatology, China Medical University were divided into 2 groups, one group received traditional teaching mode, the other group received a teaching mode based on PDCA cycle. At the end of internship, every student was assessed by theoretical examinations, case reports and clinical skill practice. χ2-test was used to determine the significant difference in clinical ability between the two groups. Statistical analysis was carried out using SPSS 13.0 software package. RESULTS: In clinical skill examination, 17 students in PDCA teaching mode group got "excellent" grade , 8 students got "good" grade, none student got "passed" grade; in traditional teaching mode group, 7 students got "excellent" grade, 16 students got "good" grade, 1 student got "passed" grade. The difference between the two groups was statistically significant (P<0.05). In the theoretical examinations and case reports, 16 students in PDCA teaching mode group got "excellent" grade, 8 students got "good" grade, none student got "passed" grade; in traditional teaching mode group, 12 students got "excellent" grade, 9 students got "good" grade, and 3 students got "passed" grade. The difference between the two groups wasn't statistically significant (P>0.05). CONCLUSIONS: PDCA teaching will train each student in a personalized mode, which is beneficial to finding defects existed in clinical practice and reinforcing the ability of communication and clinical practice.

Serotonin7 receptors in the lateral habenular nucleus regulate depressive-like behaviors in the hemiparkinsonian rats.

Preclinical studies indicate that serotonin7 (5-HT7) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT7 receptor agonist AS19 (1, 2 and 4µg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6µg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4µg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6µg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors.

Periodontal status of Pakistani orthodontic patients.

The objective of this study was to evaluate and compare the periodontal status of orthodontic patients and non-orthodontic patients, aged 15-28 years, of both genders. The cross-sectional study included 100 orthodontic and 100 non-orthodontic patients evaluated using a Community Periodontal Index for Treatment Need (CPITN) probe on the index teeth. A questionnaire was distributed to the participants to assess and evaluate the use of oral hygiene aids. The data were analyzed using SPSS version 17, and various comparisons were performed using the chi-square test. The study revealed that there was a statistically significant association in CPITN scores between the orthodontic and non-orthodontic patients (p < 0.01). The study showed that patients undergoing orthodontic treatment have increased plaque accumulation and probing depth resulting in periodontal tissue destruction. Proper oral hygiene practices and interdental aids should be employed to control plaque.

Activation of 5-HT1A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease.

Although the medial subdivision of the central nucleus of the amygdala (CeM) and serotonin-1A (5-HT1A) receptors are involved in the regulation of anxiety, their roles in Parkinson's disease (PD)-associated anxiety are still unknown. Here we assessed the importance of CeM 5-HT1A receptors for anxiety in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). The lesion induced anxiety-like behaviors, increased the firing rate and burst-firing pattern of CeM γ-aminobutyric acid (GABA) neurons, as well as decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip). Intra-CeM injection of the selective 5-HT1A receptor agonist 8-OH-DPAT produced anxiolytic effects in the lesioned rats, and decreased the firing rate of CeM GABAergic neurons in two groups of rats. Compared to sham-operated rats, the duration of the inhibitory effect on the firing rate of GABAergic neurons was shortened in the lesioned rats. The injection increased DA levels in the mPFC and amygdala in two groups of rats and the vHip in the lesioned rats, and increased 5-HT level in the lesioned rats, whereas it decreased NA levels in the mPFC in two groups of rats and the vHip in the lesioned rats. Moreover, the mean density of 5-HT1A receptor and GABA double-labeled neurons in the CeM was reduced after the lesioning. These results suggest that activation of CeM 5-HT1A receptor produces anxiolytic effects in the 6-OHDA-lesioned rats, which involves decreased firing rate of the GABAergic neurons, and changed monoamine levels in the limbic and limbic-related brain regions.

Activation of serotonin(2C) receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat.

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.

Activation of serotonin2A receptors in the medial septum-diagonal band of Broca complex enhanced working memory in the hemiparkinsonian rats.

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.

Anxiolytic effects of prelimbic 5-HT(1A) receptor activation in the hemiparkinsonian rat.

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.

Periodontal status of Pakistani orthodontic patients

The objective of this study was to evaluate and compare the periodontal status of orthodontic patients and non-orthodontic patients, aged 15–28 years, of both genders. The cross-sectional study included 100 orthodontic and 100 non-orthodontic patients evaluated using a Community Periodontal Index for Treatment Need (CPITN) probe on the index teeth. A questionnaire was distributed to the participants to assess and evaluate the use of oral hygiene aids. The data were analyzed using SPSS version 17, and various comparisons were performed using the chi-square test. The study revealed that there was a statistically significant association in CPITN scores between the orthodontic and non-orthodontic patients (p < 0.01). The study showed that patients undergoing orthodontic treatment have increased plaque accumulation and probing depth resulting in periodontal tissue destruction. Proper oral hygiene practices and interdental aids should be employed to control plaque.

Additional noradrenergic depletion aggravates forelimb akinesia and abnormal subthalamic nucleus activity in a rat model of Parkinson's disease.

AIMS: This study aims to identify the contribution of additional noradrenergic depletion to forelimb akinesia and abnormal subthalamic nucleus (STN) firing activity in Parkinson's disease (PD). MAIN METHODS: Forelimb akinesia behaviors were tested in awake rats with noradrenergic N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions, unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra pars compacta (SNc) and with combined 6-OHDA and DSP-4 lesions. STN extracellular single-unit and local field potential (LFP) activities were examined in the animals that were anesthetized with urethane. KEY FINDINGS: The adjusting steps and the contralateral touches of rats in the forelimb akinesia behavior tests were markedly inhibited by a further noradrenergic lesion with DSP-4 in 6-OHDA+DSP-4-lesioned group when compared with those of 6-OHDA-lesioned animals (P<0.05 for all comparisons). Meanwhile, the neuronal firing pattern of STN also changed significantly towards more bursty in 6-OHDA + DSP-4-lesioned group (P <0 .05). Compared with 6-OHDA-lesioned animals, an additional noradrenergic lesion increased the 0.3-2.5 Hz oscillatory activity and the spike power of STN neurons (P < 0.01 for both comparisons), and strengthened the synchronized oscillation between subthalamic neuronal firing and LFP activity in 6-OHDA + DSP-4-lesioned group (P < 0.01). SIGNIFICANCE: The results provide evidence to support the correlation between noradrenergic depletion and the further exaggerated dysfunction of STN electrical activity in PD and suggest that an aberrant noradrenergic system might play a specific role in the motor deficits of PD.

The theta-related firing activity of parvalbumin-positive neurons in the medial septum-diagonal band of Broca complex and their response to 5-HT1A receptor stimulation in a rat model of Parkinson's disease.

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.

The response of juxtacellular labeled GABA interneurons in the basolateral amygdaloid nucleus anterior part to 5-HT2A/2C receptor activation is decreased in rats with 6-hydroxydopamine lesions.

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.

Microinjection of morphine into thalamic nucleus submedius depresses bee venom-induced inflammatory pain in the rat.

Previous studies have provided evidence of the existence of a pain modulatory feedback pathway consisting of thalamic nucleus submedius (Sm)-ventrolateral orbital cortex-periaqueductal grey pathway, which is activated during acute pain and leads to depression of transmission of nociceptive information in the spinal dorsal horn. The aim of this study was to test the hypothesis that morphine microinjection into the Sm decreased spontaneous pain and bilateral thermal hyperalgesia, as well as ipsilateral mechanical allodynia, induced by subcutaneous injections of bee venom into the rat hind paw. Morphine (1.0, 2.5 or 5.0 microg in 0.5 microL) injected into the Sm, contralateral to the bee venom-injected paw, depressed spontaneous nociceptive behaviour in a dose-dependent manner. Furthermore, morphine significantly decreased bilateral thermal hyperalgesia and ipsilateral mechanical allodynia 2 h after bee venom injection. These morphine-induced effects were antagonized by 1.0 microg naloxone (an opioid antagonist) microinjected into the Sm 5 min before morphine administration. The results provided further support for the important role of the Sm and Sm-opioid receptors in inhibiting nociceptive behaviour and indicated for the first time that Sm opioid receptors were also effective in inhibiting the hypersensitivity provoked by bee venom-induced inflammation.

The selective 5-HT(1A) receptor antagonist WAY-100635 increases neuronal activity of the basolateral nucleus of the amygdala in 6-hydroxydopamine-lesioned rats.

In the present study, extracellular recording was used to examine the neuronal activity of the basolateral nucleus (BL) of the amygdala and the effects of systemic administration of the selective 5-HT(1A) receptor antagonist WAY-100635 on the neuronal activity in the normal rats and rats with 6-hydroxydopamine (6-OHDA)-produced lesions in the substantia nigra pars compacta (SNc). The results showed that the firing rates of BL projection neurons and interneurons were (0.39±0.04) Hz and (0.83±0.16) Hz in the normal rats, and (0.32±0.04) Hz and (0.53±0.12) Hz in 6-OHDA-lesioned rats. There was no significant difference in the firing rates of BL projection neurons and interneurons between the normal and 6-OHDA-lesioned rats. In the normal rats, all BL projection neurons fired in burst; 94% of BL interneurons fired in burst and 6% fired irregularly. In 6-OHDA-lesioned rats, 85% of BL projection neurons displayed a burst firing pattern and 15% fired irregularly; 86% of BL interneurons had a burst firing pattern and 14% fired irregularly. The distribution of firing patterns of projection neurons and interneurons in the BL in 6-OHDA-lesioned rats did not differ from that in the normal rats. Systemic administration of WAY-100635 at 0.1 mg/kg body weight did not change the mean firing rates of projection neurons and interneurons in the BL in both normal and 6-OHDA-lesioned rats. However, a higher dose of WAY-100635 at 0.5 mg/kg body weight significantly decreased the mean firing rate of BL projection neurons from (0.43±0.07) to (0.15±0.02) Hz in the normal rats (P<0.01), but significantly increased the activity of BL projection neurons in 6-OHDA-lesioned rats from (0.37±0.08) to (0.69±0.18) Hz (P<0.004). The mean firing rates of BL interneurons in the normal and 6-OHDA-lesioned rats did not change after administration of a higher dose of WAY-100635 at 0.5 mg/kg body weight. These results demonstrate that the activity of BL neurons after substantia nigra dopaminergic lesion in the SNc is regulated by activation of intrinsic and extrinsic inputs, and that 5-HT(1A) receptors significantly contribute to the regulation of the activity of BL projection neurons in both normal and 6-OHDA-lesioned rats. Furthermore, WAY-100635 induced an increase in the mean firing rate of projection neurons in the BL in 6-OHDA-lesioned rats, suggesting that 5-HT(1A) receptor is likely to play a role in generating affective symptoms in Parkinson's disease.

The selective 5-HT1A receptor antagonist WAY-100635 inhibits neuronal activity of the ventromedial prefrontal cortex in a rodent model of Parkinson's disease.

OBJECTIVE: 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. METHODS: Single unit responses were recorded extracellularly with glass microelectrodes from ventral mPFC neurons in normal rats and 6-OHDA unilaterally lesioned rats in vivo. RESULTS: 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. CONCLUSION: 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.