Effect of σ1 receptor antagonism on ethanol and natural reward seeking

σ1 Receptors have been implicated in cognitive function, anxiety, depression, and the regulation of stress responses. In addition, σ1 receptors have been shown to participate in the behavioral and motivational effects of psychostimulants. Recent studies have shown that σ1 receptor antagonism prevents ethanol-induced conditioned place preference in mice and excessive drinking in alcohol-dependent or alcohol-preferring rats. Therefore, this study was designed to determine whether this role for σ1 receptors extends to ethanol-seeking behavior using an animal model of relapse and tested whether the suppressant effect of a potent σ1 receptor antagonist, BD1047, generalizes to natural reward-seeking behavior. Two separate groups of rats were trained to orally self-administer 10% (w/v) ethanol or a highly palatable reinforcer, 3%/0.125% (w/v) glucose/saccharin (SuperSac), in the presence of a discriminative stimulus (S). Following extinction, during which the reinforcers and S were withheld, the presentation of the ethanol or SuperSac S produced comparable recovery of responding. BD1047 (1-20 mg/kg) exerted similar behavioral effects on both ethanol S-induced and SuperSac S-induced reinstatement, with the prevention of conditioned reinstatement only at the highest BD1047 dose. The present results show that σ1 receptor blockade under the present conditions exerts similar effects on conditioned reinstatement induced by ethanol-related and SuperSac-related stimuli, suggestive of overlapping neural mechanisms that control ethanol and natural reward seeking.     

AT-1001: a high affinity and selective α3β4 nicotinic acetylcholine receptor antagonist blocks nicotine self-administration in rats

Genomic and pharmacologic data have suggested the involvement of the α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) in drug seeking to nicotine and other drugs of abuse. In order to better examine this receptor subtype, we have identified and characterized the first high affinity and selective α3β4 nAChR antagonist, AT-1001, both in vitro and in vivo. This is the first reported compound with a Ki below 10 nM at α3β4 nAChR and >90-fold selectivity over the other major subtypes, the α4β2 and α7 nAChR. AT-1001 competes with epibatidine, allowing for [3H]epibatidine binding to be used for structure-activity studies, however, both receptor binding and ligand-induced Ca2? flux are not strictly competitive because increasing ligand concentration produces an apparent decrease in receptor number and maximal Ca2? fluorescence. AT-1001 also potently and reversibly blocks epibatidine-induced inward currents in HEK cells transfected with α3β4 nAChR. Importantly, AT-1001 potently and dose-dependently blocks nicotine self-administration in rats, without affecting food responding. When tested in a nucleus accumbens (NAcs) synaptosomal preparation, AT-1001 inhibits nicotine-induced [3H]dopamine release poorly and at significantly higher concentrations compared with mecamylamine and conotoxin MII. These results suggest that its inhibition of nicotine self-administration in rats is not directly due to a decrease in dopamine release from the NAc, and most likely involves an indirect pathway requiring α3β4 nAChR. In conclusion, our studies provide further evidence for the involvement of α3β4 nAChR in nicotine self-administration. These findings suggest the utility of this receptor as a target for smoking cessation medications, and highlight the potential of AT-1001 and congeners as clinically useful compounds.     

Enhancement of antipsychotic-like effects by combined treatment with the α1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats

Summary. Blockade of central α₁-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant α₁-adrenoceptor and dopamine D₂ receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the α₁-adrenoceptor antagonist prazosin (0.2 mg kg⁻¹ s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D₂ receptor antagonist raclopride (0.05–0.20 mg kg⁻¹ s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg⁻¹). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2 mg kg⁻¹ s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg⁻¹ s.c.). It is suggested that, in the presence of low dopamine D₂ receptor occupancy, additional α₁-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism. Received May 19, 2000; accepted July 3, 2000     

Acupuncture at Baihui and Dazhui reduces brain cell apoptosis in heroin readdicts简

Acupuncture at Baihui （GV20） and Dazhui （GV14） reduces neuronal loss and attenuates ultra- structural damage in cerebral ischemic rats. However, whether acupuncture can treat addiction and prevent readdiction through changes to brain cell ultrastructure remains unknown. In this study, cell apoptosis was observed in the hippocampus and frontal lobe of heroin readdicted rats by electron microscopy. Immunohistochemical staining displayed a reduction in Bcl-2 ex- pression and an increase in Bax expression in the hippocampus and frontal lobe. After rats were given acupuncture at Baihui and Dazhui, the pathological damage in the hippocampus and frontal lobe was significantly reduced, Bcl-2 expression was upregulated and Bax expression was downregulated. Acupuncture exerted a similar effect with methadone, a commonly used drug for clinical treatment of drug addiction. Experimental findings suggest that acupuncture at Dazhui and Baihui can prevent brain cell apoptosis in heroin readdicted rats.     

Loss of striatal cannabinoid CB1 receptor function in attention-deficit / hyperactivity disorder mice with point-mutation of the dopamine transporter

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.     

Purine receptor antagonist modulates serology and affective behaviors in lupus-prone mice: evidence of autoimmune-induced pain?

Neurologic and psychiatric (NP) manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous disease onset in the MRL/MpJ-Fas^lpr/J (MRL-lpr) mouse model of NP–SLE is accompanied by increased autoantibodies, pro-inflammatory cytokines and behavioral dysfunction which precede neuroinflammation and structural brain lesions. The role of purinergic receptors in the regulation of immunity and behavior remains largely unexplored in the field of neuropsychiatry. To examine the possibility that purinoception is involved in the development of affective behaviors, the P2X purinoceptor antagonist, suramin, was administered to lupus-prone mice from 5 to 14 weeks of age. In addition to food and water measures, novel object and sucrose preference tests were performed to assess neophobic anxiety- and anhedonic-like behaviors. Enzyme-linked immunosorbant assays for anti-nuclear antibodies (ANA) and pro-inflammatory cytokines were employed in immunopathological analyses. Changes in dendritic morphology in the hippocampal CA1 region were examined by a Golgi impregnation method. Suramin significantly lowered serum ANA and prevented behavioral deficits, but did not prevent neuronal atrophy in MRL-lpr animals. In a new batch of asymptomatic mice, systemic administration of corticosterone was found to induce aberrations in CA1 dendrites, comparable to the “stress” of chronic disease. The precise mechanism(s) through which purine receptor inhibition exerted beneficial effects is not known. The present data supports the hypothesis that activation of the peripheral immune system induces nociceptive-related behavioral symptomatology which is attenuated by the analgesic effects of suramin. Hypercortisolemia may also initiate neuronal damage, and metabolic perturbations may underlie neuro-immuno-endocrine imbalances in MRL-lpr mice.     

Selective inhibition of metabotropic glutamate type 1 alpha receptor (mGluR1α) reduces cell proliferation and migration following status epilepticus in early development

The present study examined whether a single or multiple episode(s) of status epilepticus induced with kainic acid (KA) during the first 3 weeks of postnatal (P) development would aberrantly stimulate proliferation zones that alters migration to potentially injured areas and whether they would be blocked by selective Group I mGluR antagonists. mGluR1α (LY367385) and mGluR5 (MPEP) antagonists were administered 2 h following KA-induced status epilepticus and animals were examined after 7 days. Proliferating cells of the subventricular zone (SVZ), third ventricle, hippocampus, amygdala cortical complex were analyzed with the proliferative marker, Ki67; and two complementary retrograde dye tracers. Proliferation increased in extrahippocampal limbic structures when KA was administered on P13 or P20 which correlated with number of injured cells at the older age. LY367385 post-treatment caused striking decreases in proliferation in all limbic structures in the presence and absence of injury, whereas a reduction with MPEP was observed only within the amygdala cortical complex (Amg/ERcx) in the presence of multiple seizures (3 × KA). After 3 × KA and LY367385 post-treatments, diminished co-staining of dye tracers with Ki67 was observed within the Amg/ERcx despite high levels of progenitors marked by the retrograde tracers in this region. This indicates that not only was local proliferation within the SVZ and distant structures inhibited, but also that migration itself was reduced indirectly since there were less cells to migrate from the SVZ. Co-labeling with biomarkers provided evidence for neuronal differentiation suggesting potential aberrant integration may occur in distant locations, and that targeting of mGluR1α receptors may be a potential therapeutic strategy for future development.     

Ablation of spinal cord estrogen receptor α-expressing interneurons reduces chemically induced modalities of pain and itch

Estrogens are presumed to underlie, at least in part, the greater pain sensitivity and chronic pain prevalence that women experience compared to men. Although previous studies revealed populations of estrogen receptor-expressing neurons in primary afferents and in superficial dorsal horn neurons, there is little to no information as to the contribution of these neurons to the generation of acute and chronic pain. Here we molecularly characterized neurons in the mouse superficial spinal cord dorsal horn that express estrogen receptor α (ERα) and explored the behavioral consequences of their ablation. We found that spinal ERα-positive neurons are largely excitatory interneurons and many coexpress substance P, a marker for a discrete subset of nociceptive, excitatory interneurons. After viral, caspase-mediated ablation of spinal ERα-expressing cells, we observed a significant decrease in the first phase of the formalin test, but in male mice only. ERα-expressing neuron-ablation also reduced pruritogen-induced scratching in both male and female mice. There were no ablation-related changes in mechanical or heat withdrawal thresholds or in capsaicin-induced nocifensive behavior. In chronic pain models, we found no change in Complete Freund's adjuvant-induced thermal or mechanical hypersensitivity, or in partial sciatic nerve injury-induced mechanical allodynia. We conclude that ERα labels a subpopulation of excitatory interneurons that are specifically involved in chemically evoked persistent pain and pruritogen-induced itch.     

Morphine reduces mouse microglial engulfment induced by lipopolysaccharide and interferon-γ via δ opioid receptor and p38 mitogen-activated protein kinase

Objective To investigate the effects of morphine on microglial phagocytosis during neuroinflammation.

Methods C8-B4 mouse microglial cells were exposed to various concentrations of morphine after the stimulation with lipopolysaccharide and interferon-γ and then fluorescent immunostaining was performed to assess the percentage of microglia that engulfed fluorescent microspheres in total microglia. Naloxone, β funaltrexamine, or naltrindole was used with 1 μM morphine to assess the involvement of specific opioid receptor. P38 and phosphorylated p38 were determined by Western blotting. A p38 mitogen-activated protein kinase (MAPK) activator (anisomycin 0.1 μM) or inhibitor (SB 203580, 20 μM) was used to determine the involvement of p38 MAPK pathway.

Results Morphine decreased lipopolysaccharide and interferon-γ-induced microglial engulfment except the highest concentration (10 μM) and both naloxone and naltrindole (a selective δ opioid receptor antagonist) attenuated morphine effect (p < 0.001). The phosphorylated p38 was up-regulated in lipopolysaccharide and interferon-γ group compared with control group (p < 0.001). This up-regulation was decreased by 1 μM morphine (p < 0.001). However, naltrindole abolished this morphine effect (p = 0.015). SB203580 blocked the increased microglial engulfment induced by lipopolysaccharide and interferon-γ (p < 0.001); whereas, anisomycin enhanced the morphine-induced decrease of engulfment (p < 0.001).

Conclusion Morphine reduced mouse microglial engulfment induced by lipopolysaccharide and interferon-γ. This morphine effect seems to be mediated by δ opioid receptor and via p38 MAPK inhibition.     

Effects of cannabinoid CB₁ receptor antagonist rimonabant on acquisition and reinstatement of psychostimulant reward memory in mice

Drug addiction processes are considered to be mainly controlled by the mesocorticolimbic dopamine system. Cannabinoids, a class of psychoactive drugs of abuse, elicit their rewarding and pharmacological effects through the endocannabinoid system. Previous research has indicated that dopaminergic neurons in the mesocorticolimbic system are also under the control of the endocannabinoid system. Recently, evidence has suggested that the endocannabinoid system may also participate in the modulation of the common reward system. The present study examined whether rimonabant, a cannabinoid CB? receptor antagonist, disrupts the acquisition and reinstatement of psychostimulant reward memory measured by conditioned place preference (CPP). Mice were trained to acquire methamphetamine or cocaine-induced CPP. A priming injection of methamphetamine (0.5 mg/kg, i.p.) or cocaine (5 mg/kg, i.p.) was respectively given to reinstate methamphetamine or cocaine-induced CPP after extinction. Vehicle or rimonabant (1 or 3 mg/kg, i.p.) was administered at different time-points: 30 min before each CPP training session (acquisition) or 30 min before the priming injection (reinstatement). Rimonabant at doses of 1 and 3 mg/kg significantly inhibited the acquisition of methamphetamine- and cocaine-induced CPP. At the high dose (3 mg/kg), rimonabant disrupted the reinstatement of extinguished methamphetamine- or cocaine-induced CPP. These findings indicate that cannabinoid CB? receptors play a major role in psychostimulant reward memory, and rimonabant may be a potential pharmacotherapy for psychostimulant addiction.     

The specificity and molecular basis of α1-adrenoceptor and CXCR chemokine receptor dimerization

It is now well established that rhodopsin-like, family-A G protein-coupled receptors (GPCRs) can exist within homo- and heterodimeric/oligomeric complexes. However, limited information is currently available on the molecular basis of these interactions or their selectivity. Using the alpha1-adrenoceptor family as a model, this has been examined using assays including coimmunoprecipitation, saturation bioluminescence resonance energy transfer (BRET), time-resolved fluorescence resonance energy transfer (FRET), and bimolecular fluorescence complementation. We demonstrate key roles for transmembrane helices I and IV in homodimeric/oligomeric interactions of the alpha1b-adrenoceptor and suggest that other interactions indicate that this GPCR can exist as a higher-order oligomeric complex. Literature reports on heterodimerization between chemokine receptor family members and the effects or otherwise of agonist ligands are complex. It was recently indicated that although the CXCR2 receptor is able to homodimerize, this is not the case for the closely related CXCR1 receptor and that these two GPCRs do not heterodimerize. We have reinvestigated these issues using combinations of coimmunoprecipitation, saturation BRET, and a novel endoplasmic reticulum-trapping strategy. Unlike the previous report, we demonstrate that CXCR1 is able to both homodimerize and heterodimerize with the CXCR2 receptor and that the relative affinity of these interactions suggests that with coexpression of these two GPCRs a random mixture of homo- and heterodimers will be present.     

The A1 receptor agonist R-Pia reduces the imbalance between cerebral glucose metabolism and blood flow during status epilepticus: Could this mechanism be involved with neuroprotection?

It is well known that the uncoupling between local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF), i.e. decrease in LCBF rates with high LCGU, is frequently associated with seizure-induced neuronal damage. This study was performed to assess if the neuroprotective effect of the adenosinergic A₁ receptor agonist R-N-phenylisopropyladenosine (R-Pia) injected prior to pilocarpine is able to reduce the uncoupling between LCGU and LCBF during status epilepticus (SE). Four groups of rats were studied: Saline, Pilo, R-Pia + Saline and R-Pia + Pilo. For LCGU and LCBF studies, rats were subjected to autoradiography using [¹⁴C]-2-deoxyglucose and [¹⁴C]-iodoantypirine, respectively. Radioligands were injected 4 h after SE onset. Neuronal loss was evaluated by Fluorojade-B (FJB) at two time points after SE onset (24 h and 7 days). The results showed a significant increase in LCGU in almost all brain regions studied in the Pilo and R-Pia + Pilo groups compared to controls. However, in R-Pia pretreated rats, the uncoupling between LCGU and LCBF was moderated in a limited number of structures as substantia nigra pars reticulata and hippocampal formation rather in favor of hyperperfusion. Significant increases in LCBF were observed in the entorhinal cortex, thalamic nuclei, mammillary body, red nucleus, zona incerta, pontine nucleus and visual cortex. The neuroprotective effect of R-Pia assessed by FJB showed a lower density of degenerating cells in the hippocampal formation, piriform cortex and basolateral amygdala. In conclusion our data shows that the neuroprotective effect of R-Pia was accompanied by a compensatory metabolic input in brain areas involved with seizures generation.     

Arg972 insulin receptor substrate-1 polymorphism and risk and severity of Alzheimer’s disease

We explored the association between the Arg972 insulin receptor substrate-1 (IRS1) polymorphism and the risk and severity of Alzheimer’s disease (AD). We genotyped the Arg972 IRS1 (rs1801278) polymorphism in 1123 pairs of age, sex, body mass index, residence area and education level-matched Han Chinese AD patients and controls. AD severity was assessed with Mini-Mental State Examination (MMSE) scores. The AA (homozygous Arg972 IRS1) and GA (heterozygous Arg972 IRS1) genotypes were associated with an increased risk of AD after adjustment for comorbidities including type 2 diabetes mellitus, coronary heart disease, and hypertension (p < 0.001; adjusted odds ratio [OR] 3.93 and 2.90, respectively). The A allele was associated with an increased risk of AD after adjustment for comorbidities (p < 0.001; adjusted OR 2.26; 95% confidence interval 1.92–2.80). The percentage of Arg972 IRS1 AA homozygotes was higher in the MMSE score ⩽14 category than in the MMSE score 15–26 category overall and in each age group (p < 0.001), while the wild type IRS1 GG homozygotes were predominantly found in the MMSE score 15–26 category overall and in each age group. The GG homozygote group had higher MMSE score than the GA heterozygote group, which in turn had higher MMSE score than the AA homozygote group overall and in each age group (p < 0.05). In conclusion, the Arg972 IRS1 polymorphism is an independent risk factor for AD and the A allele has a gene dosage effect on AD severity in Han Chinese. This study adds fresh insights into the pathogenesis of AD.     

CB1 agonist ACEA protects neurons and reduces the cognitive impairment of AβPP/PS1 mice

The present study shows that chronic administration of the cannabinoid receptor type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-β (Aβ) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Aβ42 oligomers in primary cultures of cortical neurons, and reverses Aβ-induced dephosphorylation of glycogen synthase kinase-3β (GSK3β) in vitro and in vivo. Reduced activity of GSK3β in ACEA-treated mice is further supported by the reduced amount of phospho-tau (Thr181) in neuritic processes around Aβ plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3β inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-γ. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease.     

Neonatal paternal deprivation or early deprivation reduces adult parental behavior and central estrogen receptor α expression in mandarin voles (Microtus mandarinus)

Previous studies on parental behavior have primarily focused on maternal behavior, with little research directed at observing paternal behavior. The effects of neonatal paternal deprivation and early deprivation on adult parental behavior and estrogen receptor α (ERα) especially remain unclear. This study examined whether paternal deprivation or early deprivation has long-term effects on the parental behavior and central ERα expression of adult mandarin vole offspring. The parental behaviors of adult mandarin voles that suffered paternal deprivation or early deprivation were observed with their own pups at 0, 13 and 21 days of age. Central ERα expression was also examined in adult virgin voles with different neonatal treatments using immunocytochemistry. The results indicated that (1) levels of parental care and sociability in adult offspring were reduced due to paternal deprivation and early deprivation; (2) ERα expression in the stria terminalis (BNST), medial preoptic area (MPOA), ventromedial hypothalamic nucleus (VMH) and arcuate hypothalamic nucleus (Arc) were also reduced by paternal deprivation and early deprivation; (3) ERα expression in the BNST, MPOA, and VMH of control females was higher than that of control males, but ERα expression in the Arc was lower. Our findings show that paternal care plays an important role in the development of parental behavior in offspring. Also, because paternal deprivation and early deprivation impaired sexual differences, the alteration of parental behavior may be associated with decreased ERα expression.     

The neuronal sortilin-related receptor gene SORL1 and late-onset Alzheimer’s disease

Recent studies indicate that two clusters of single nucleotide polymorphisms in the neuronal sortilin-related receptor gene (SORL1) are causally associated with late-onset Alzheimer’s disease (AD). At the cellular level, SORL1 is thought to be involved in intracellular trafficking of amyloid precursor protein. When this gene is suppressed, toxic amyloid β production is increased, and high levels of amyloid β are associated with a higher AD risk. Extending the cellular findings, gene expression studies show that SORL1 is differentially expressed in AD patients compared with controls. Furthermore, several genetic studies have identified allelic and haplotypic SORL1 variants associated with late-onset AD, and these variants confer small to modest risk of AD. Taken together, the evidence for SORL1 as a causative gene is compelling. However, putative variants have not yet been identified. Further research is necessary to determine its utility as a diagnostic marker of AD or as a target for new therapeutic approaches.     

AQW051, a novel and selective nicotinic acetylcholine receptor α7 partial agonist,reduces l-Dopa-induced dyskinesias and extends the duration of l-Dopa effects in parkinsonian monkeys

Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure–effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa.     

Dynorphin A (1–8) inhibits oxidative stress and apoptosis in MCAO rats,affording neuroprotection through NMDA receptor and κ-opioid receptor channels

The contents of Dynorphin A(1–8) decreased gradually in ischemic cortices in rats and an intracerebroventricular administration of synthetic Dynorphin A(1–8) reduced the volume of cerebral infarction in our previous research. However, the specific protective mechanism is unclear and Dynorphin A(1–8) is unlikely to cross the blood-brain barrier (BBB) by noninvasive oral or intravenous administration as a macromolecule neuropeptide. In this study, intranasal administration was used to middle cerebral artery occlusion(MCAO) rats to assessed the therapeutic effects of Dynorphin A(1–8) by evaluating behavior, volume of cerebral infarct, cerebral edema ratio, histological observation. Then apoptosis neuron rate was detected by TUNEL staining. Immunohistochemical staining was carried out to explore the alteration of Bcl-2, Bax and Caspase-3. Finally, κ-opioid receptor antagonist and N-methyl-d-aspartate(NMDA) receptor antagonist were used to explore its possible mechanism. We found that MCAO rats under intranasal administration of Dynorphin A(1–8) showed better behavioral improvement, higher extent of Bcl-2, activity of SOD along with much lower level of infarction volume, brain water content, number of cell apoptosis, extent of Bax and Caspase-3, and concentration of MDA compared with those in MCAO model group and intravenous Dynorphin A(1–8) group. Administration of nor-BNI or MK-801 reversed these neuroprotective effects of intranasal Dynorphin A(1–8). In summary, Dynorphin A(1–8), with advantages of intranasal administration, could be effectively delivered to central nervous system(CNS). Dynorphin A(1–8) inhibited oxidative stress and apoptosis against cerebral ischemia/reperfusion injury, affording neuroprotection through NMDA receptor and κ-opioid receptor channels.