Administration of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. phencyclidine, MK-801) has been shown to elicit behavioral abnormalities related to symptoms of schizophrenia, such as spontaneous locomotor activity and impaired sensorimotor gating, as represented by deficits of prepulse inhibition (PPI). We sought to determine whether transient blockade of NMDA receptors at the neonatal stage would produce dopamine supersensitivity around puberty, as manifested by these behavioral measures. For this purpose, we examined methamphetamine (MAP; 1.0 mg/kg, i.p.)-induced locomotor activity and PPI in pre- (postnatal day; PD 36-38) or post- (PD 64-66) puberty in rats administered MK-801 (0.2 mg/kg/day, s.c.) between PD 7 and PD 10. Neonatal MK-801 treatment augmented MAP-induced hyperlocomotion especially in the early adulthood, whereas spontaneous locomotor activity and rearing were not changed. MK-801 administration also disrupted PPI without affecting startle amplitudes around puberty. These findings suggest that transient exposure to MK-801 in the neonatal stage causes exaggerated dopamine transmission and cognitive deficits, particularly in the post-puberty stage. Copyright © 2010. Published by Elsevier B.V.

RATIONAL: Exposing animal models of mental illness to addictive drugs provides an approach to understanding the neural etiology of dual diagnosis disorders. Previous studies have shown that neonatal ventral hippocampal lesions (NVHL) in rats produce features of both schizophrenia and addiction vulnerability. OBJECTIVE: This study investigated ventral and dorsal striatal dopamine (DA) efflux in NVHL rats combined with behavioral sensitization to cocaine. METHODS: Adult NVHL vs. SHAM-operated rats underwent a 5-day injection series of cocaine (15 mg/kg/day) vs. saline. One week later, rats were cannulated in nucleus accumbens SHELL, CORE, or caudate-putamen. Another week later, in vivo microdialysis sampled DA during locomotor testing in which a single cocaine injection (15 mg/kg) was delivered. RESULTS: NVHLs and cocaine history significantly increased behavioral activation approximately 2-fold over SHAM-saline history rats. DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient. However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region. CONCLUSION: Differences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history. These findings suggest other neurotransmitter systems, and alterations in striatal network function post-synaptic to DA transmission are more important to understanding the interactive effects of addictive drugs and mental illness.

Parkinson’s disease is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia niara. Levodopa remains the most effective drug in the treatment of Parkinson’s disease. Unfortunately, with disease progression, levodopa reduces Parkinsonism at the cost of evoking abnormal involuntary movements known as levodopa-induced dyskinesia (LID). In this study, we found that levodopa/benserazide-loaded biodegradable microspheres reduce the expression of LID, which was easily evoked by administrating of the same dose of levodapa and benserazide in rats with Parkinson’s disease. Moreover, levodopa/benserazide-loaded biodegradable microspheres can improve the stepping of the lesioned forepaw in rats with Parkinson’s disease. These data showed that levodopa/benserazide-loaded biodegradable microspheres might be useful in the treatment of Parkinson’s disease and reducing the expression of LID in rats.

The central dopaminergic system plays a critical role in the reinforcing effects of nicotine, which are key determinants in the urge to smoke. Previous study has demonstrated that immediate administration of 10-mg aripiprazole significantly decreased various subjective responses to smoking. The present study investigated whether 2-week treatment with 10-mg aripiprazole could attenuate waking and postprandial urges to smoke in Chinese male and female heavy smokers. A randomized and placebo-controlled pilot clinical study was conducted to assess the effect of aripiprazole on various responses to smoking. The primary outcomes were subject’s ratings on questionnaires of smoking urge, withdrawal syndromes, and cigarette evaluation. All participants were administered either placebo or 10-mg aripiprazole for 2 weeks. Throughout the experiment, participants were required to self-report (1) smoking urge and nicotine withdrawal symptoms before their first cigarette after awakening and after lunch and (2) subjective responses to the first cigarette smoked of the day and after lunch. Aripiprazole was associated with significantly decreased waking and postprandial urges to smoke. Aripiprazole failed to produce a significant effect on overall nicotine withdrawal symptoms after awakening and after lunch. However, waking, but not postprandial, withdrawal craving and syndromes were significantly reduced by aripiprazole. Aripiprazole had no effect on the overall subjective responses to the first cigarette of the day and after lunch. The attenuating effects of aripiprazole on waking and postprandial urges to smoke demonstrate the promising effect of aripiprazole in the treatment of nicotine dependence.

A different role of L-type antagonists for voltage-gated calcium channels (VGCC) has been previously identified in different types of experimental and clinical pain in man and animals. Present study examined the role of VGCC blocker – diltiazem administered icv (0.25, 0.5, 1.0 and/or 2.0mg in toto) on the development of pain related symptoms, clinical signs, plasma catecholamine level and the inhibition of reticulo-rumen motility caused by 5min lasting mechanical duodenum distension (DD) in the sheep. Experimental DD was conducted by insertion (during surgery) of rubber balloon into the duodenum and the distension by 40ml of warm water. Duodenal distension resulted in a significant increase of behavioural pain responses, tachycardia, hyperventilation, inhibition of reticulo-rumen contractions rate (from 85% to 45% during 15-20min), an increase of plasma catecholamine concentration (over sevenfold increase of epinephrine during 2h following DD, two-times norepinephrine and 84% increase of dopamine). Diltiazem infusion given 10min before DD decreased intensity of visceral nocifensive responses such as: behavioural changes, tachycardia, hyperventilation, reticulo-rumen motility and efficiently prevented appearance of catecholamine release. These data demonstrated that the development and persistence of acute duodenal pain depends on the activation of Ca(2+) ion flux leading to neurotransmitters release and modulation of membrane excitability. It seems that diltiazem given icv 10min prior to DD (as a source of acute visceral pain), inhibited specific receptors alpha(1) subunits of VGCCs in target tissues, prevent depolarization of cell membranes and release of neurotransmitters responsible for pain sensitivity in sheep. The observed antinociceptive action of VGCCs type-L blockers suggests that these channels play a crucial role in the modulation of acute visceral pain in sheep. Published by Elsevier India Pvt Ltd.

Previous reports have suggested that the herbal medicine Chunghyuldan (CHD, Qingxue-dan in Chinese and Daio-Orengedokuto in Japanese) has wide-ranging biological effects, including anti-hyperlipidaemic, anti-ischaemic, anti-inflammatory and antioxidant activities. Reactive oxygen species (ROS)-mediated mitochondrial dysfunction is thought to be one of the major pathological mechanisms responsible for Parkinson’s disease (PD) and may underlie the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) that is a hallmark of this disease. In this study, we examined the neuroprotective effects of CHD in PD models produced by treatment with neurotoxins that act via ROS-mediated mitochondrial dysfunction. In an in vitro PD model using 6-hydroxydopamine, CHD applied at concentrations of 10 and 100 mug/ml exhibited significant protective effects in PC12 cells by inhibiting intracellular ROS generation. CHD applied at 10 and 100 mug/ml also prevented 6-hydroxydopamine-induced mitochondrial depolarization and elevation of caspase-3 activity. At the same doses, CHD showed regulatory effects on the haem oxygenase-1 and gp91 phagocytic oxidase which have critical roles in generating ROS. In addition, CHD protected dopaminergic neurons in a primary mesencephalic culture against MPP+ neurotoxicity. In an in vivo PD model produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (20 mg/kg, 4 times, i.p.), co-administration of CHD (50 mg/kg, 5 days, p.o.) ameliorated PD-like behavioural symptoms (bradykinesia) and reduced dopaminergic neuronal damage in the SNpc and striatum as measured by immunocytochemistry. These results demonstrate the neuroprotective effects of CHD in PD models that are mediated through inhibition of ROS generation and associated mitochondrial dysfunction.

Abstract Dystonia is a neurological disorder characterized by involuntary movements. We examined striatal dopamine function in hyperactive transgenic mice generated as a model of dystonia. Evoked extracellular dopamine concentration was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices from non-transgenic mice, transgenic mice with a positive motor phenotype, and phenotype-negative transgenic littermates. Peak single-pulse evoked dopamine concentration was significantly lower in phenotype-positive mice than in non-transgenic or phenotype-negative mice, but indistinguishable between non-transgenic and phenotype-negative mice. Phenotype-positive mice also had higher functional D2 dopamine autoreceptor sensitivity than non-transgenic mice, which would be consistent with lower extracellular dopamine in vivo. Multiple-pulse (phasic) stimulation (5 pulses, 10-100 Hz) revealed an enhanced frequency dependence of evoked dopamine release in phenotype-positive versus non-transgenic or phenotype-negative mice, which was exacerbated when extracellular Ca(2+) concentration was lowered. Enhanced sensitivity to phasic stimulation in phenotype-positive mice was reminiscent of the pattern seen with antagonism of nicotinic acetylcholine receptors. Consistent with a role for altered cholinergic regulation, the difference phasic responsiveness among groups was lost when nicotinic receptors were blocked by mecamylamine. Together, these data implicate compromised dopamine release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model.

Recent advances in the understanding of the etiology, epidemiology, diagnosis, and treatment of fibromyalgia must be applied in clinical practice to achieve optimal patient outcomes. Current evidence indicates that fibromyalgia is a hyperalgesic state, resulting from a generalized problem with augmented pain processing that likely results from the way the spinal cord and the brain process pain and other sensory information. The descending pain pathway involving serotonin, norepinephrine, and dopamine, as opposed to the descending opioid pain pathway, appears to be selectively attenuated. Newer treatment options targeted at the pain mechanisms include the alpha(2)-delta pregabalin, which binds to the alpha(2)-delta subunit of voltage-gated calcium channels in neurons, and the serotonin-norepinephrine dual reuptake inhibitors duloxetine and milnacipran. The US Food and Drug Administration (FDA) has approved pregabalin, duloxetine, and milnacipran for the management of fibromyalgia. In addition to pharmacologic therapy, patient education, cognitive behavioral therapy, aerobic exercise, and strength and flexibility training are important components of care. An individualized treatment plan should be developed with consideration of each patient’s unique combination of fibromyalgia symptoms, functional level, and the presence of the comorbid psychiatric and medical conditions that are common in patients with fibromyalgia. This educational activity provides clinicians with the tools necessary to differentiate fibromyalgia syndrome from other chronic pain conditions through a review of recent clinical data and an application of an advanced understanding of pain pathways. Strategies to manage patients with comorbid conditions are explored, with an emphasis on the importance of a multidisciplinary approach to patient care. Online Access: http://www.cmeaccess.com/cme/ajm_fibro_program/

This study investigated the involvement of advanced glycation end products (AGEs) that may be nonenzymatically linked to alpha-synuclein accumulation in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL/6 mouse model of parkinsonism. MPTP (20 mg/kg) was intraperitoneally administrated once daily for 30 days to the MPTP group while a saline only solution was administered to the control group. Results show that the immunoreactivities of the tyrosine hydroxylase and dopamine transporter significantly decreased in the striatum and the substantia nigra (SN) in the MPTP model compared to the subjects in the control group. alpha-synuclein was co-localized with N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL), which are well-known AGEs, in tyrosine hydroxylase-positive dopaminergic neurons in the MPTP brains. alpha-synuclein was also shown to be deposited in the CD11b-positive activated microglia. Some AGEs-modified proteins (CML-, CEL-, pentosidine-, or pyrraline-modified proteins) and an oligomeric form of alpha-synuclein appear to have almost the same molecular weight, specifically between 50 and 75 kDa; in addition, these formations were more strongly deposited in the SN region of the MPTP brains than in the control brains. Moreover, the oligomeric form of alpha-synuclein was modified with CML in the SNs of both the control and MPTP brains. This study, for the first time, shows that chronic dopaminergic neurodegeneration by MPTP can lead to the depositing of an oligomeric form of alpha-synuclein, CML-linked alpha-synuclein, and CEL-, pentosidine-, or pyrraline-linked proteins between 50 and 75 kDa. It is thus suggested that CML, especially a CML-linked alpha-synuclein oligomer between 50 and 75 kDa, may be, at least in part, involved in the aggregation of the alpha-synuclein induced by MPTP intoxication. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Parkinson’s disease (PD), a progressive neurodegenerative movement disorder, is known to be caused by diverse pathological conditions resulting from dysfunction of the ubiquitin-proteasome system (UPS), mitochondria, and oxidative stress leading to preferential nigral dopamine (DA) neuron degeneration in the substantia nigra. In the present study, we evaluated the novel D3 receptor-preferring agonist D-264 in a mouse model of PD to evaluate its neuroprotective properties against both the nigrostriatal dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and the proteasome inhibitor lactacystin-induced dopaminergic degeneration. C57BL/6 male mice either were given MPTP by intraperitoneal injection twice per day for 2 successive days at a dose 20 mg/kg or were microinjected with lactacystin bilaterally (1.25 mug/side) into the medial forebrain bundle (MFB). Pretreatment with D-264 (1 mg/kg and 5 mg/kg, intraperitoneally, once per day), started 7 days before administration of MPTP or lactacystin. We found that D-264 significantly improved behavioral performance, attenuated both MPTP- and lactacystin-induced DA neuron loss, and blocked proteasomal inhibition and microglial activation in the substantia nigra (SN). Furthermore, D-264 treatment was shown to increase the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived factor (GDNF) in MPTP- and lactacystin-treated mice, possibly indicating, at least in part, the mechanism of neuroprotection by D-264. Furthermore, pretreatment with the D3 receptor antagonist U99194 significantly altered the effect of neuroprotection conferred by D-264. Collectively, our study demonstrates that D-264 can prevent neurodegeneration induced by the selective neurotoxin MPTP and the UPS inhibitor lactacystin. The results indicate that D-264 could potentially serve as a symptomatic and neuroprotective treatment agent for PD. (c) 2010 Wiley-Liss, Inc.