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Neurotransmission
Kinds of Neurotransmission Selected AbstractsDYSFUNCTION OF PURINERGIC REGULATION OF SYMPATHETIC NEUROTRANSMISSION IN SHR/NDMCR-CP (SHR-CP) RATCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 2004Naoko Tanaka SUMMARY 1.,The effect of 2-chloroadenosine (2CA), a P1 receptor agonist and ,,,-methylene ATP (,,mATP), a P2 receptor agonist, on the overflow of endogenous noradrenaline (NE) and the contractile response were examined in the electrically field-stimulated (EFS) (1 Hz) caudal artery obtained from Wistar-Kyoto (WKY) and SHR/NDmcr-cp (SHR-cp) rats. 2.,Both 2CA and ,,mATP reduced the EFS-evoked release of NE from the arteries of WKY. Also, 2CA significantly reduced the EFS-evoked contractile response in WKY, while it had no effect at all in SHR-cp. ,,mATP significantly reduced the EFS-evoked contractile response in both WKY and SHR-cp. Both 2CA and ,,mATP did not affect the contractile response induced by NE at 1 µmol/L. 3.,These results indicate that in the caudal arteries of SHR-cp, the P2 agonist but not the P1 agonist is functional in the prejunctional inhibitory regulation of adrenergic neurotransmission. This P1 dysfunction may play a role in the sympathetic hyperinnervation in metabolic syndrome. [source] Energy sources for glutamate neurotransmission in the retina: absence of the aspartate/glutamate carrier produces reliance on glycolysis in gliaJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Y. Xu Abstract The mitochondrial transporter, the aspartate/glutamate carrier (AGC), is a necessary component of the malate/aspartate cycle, which promotes the transfer into mitochondria of reducing equivalents generated in the cytosol during glycolysis. Without transfer of cytosolic reducing equivalents into mitochondria, neither glucose nor lactate can be completely oxidized. In the present study, immunohistochemistry was used to demonstrate the absence of AGC from retinal glia (Müller cells), but its presence in neurons and photoreceptor cells. To determine the influence of the absence of AGC on sources of ATP for glutamate neurotransmission, neurotransmission was estimated in both light- and dark-adapted retinas by measuring flux through the glutamate/glutamine cycle and the effect of light on ATP-generating reactions. Neurotransmission was 80% faster in the dark as expected, because photoreceptors become depolarized in the dark and this depolarization induces release of excitatory glutamate neurotransmitter. Oxidation of [U- 14C]glucose, [1- 14C]lactate, and [1- 14C]pyruvate in light- and dark-adapted excised retinas was estimated by collecting 14CO2. Neither glucose nor lactate oxidation that require participation of the malate/aspartate shuttle increased in the dark, but pyruvate oxidation that does not require the malate/aspartate shuttle increased to 36% in the dark. Aerobic glycolysis was estimated by measuring the rate of lactate appearance. Glycolysis was 37% faster in the dark. It appears that in the retina, ATP consumed during glutamatergic neurotransmission is replenished by ATP generated glycolytically within the retinal Müller cells and that oxidation of glucose within the Müller cells does not occur or occurs only slowly. [source] Estimation of endogenous adenosine activity at adenosine receptors in guinea-pig ileum using a new pharmacological methodACTA PHYSIOLOGICA, Issue 2 2010K. F. Nilsson Abstract Aim:, Adenosine modulates neurotransmission and in the intestine adenosine is continuously released both from nerves and from smooth muscle. The main effect is modulation of contractile activity by inhibition of neurotransmitter release and by direct smooth muscle relaxation. Estimation of adenosine concentration at the receptors is difficult due to metabolic inactivation. We hypothesized that endogenous adenosine concentrations can be calculated by using adenosine receptor antagonist and agonist and dose ratio (DR) equations. Methods:, Plexus-containing guinea-pig ileum longitudinal smooth muscle preparations were made to contract intermittently by electrical field stimulation in organ baths. Schild plot regressions were constructed with 2-chloroadenosine (agonist) and 8-(p -sulfophenyl)theophylline (8-PST; antagonist). In separate experiments the reversing or enhancing effect of 8-PST and the inhibiting effect of 2-chloroadenosine (CADO) were analysed in the absence or presence of an adenosine uptake inhibitor (dilazep), and nucleoside overflow was measured by HPLC. Results:, Using the obtained DR, baseline adenosine concentration was calculated to 28 nm expressed as CADO activity, which increased dose dependently after addition of 10,6 m dilazep to 150 nm (P < 0.05). HPLC measurements yielded a lower fractional increment (80%) in adenosine during dilazep, than found in the pharmacological determination (440%). Conclusion:, Endogenous adenosine is an important modulator of intestinal neuro-effector activity, operating in the linear part of the dose,response curve. Other adenosine-like agonists might contribute to neuromodulation and the derived formulas can be used to calculate endogenous agonist activity, which is markedly affected by nucleoside uptake inhibition. The method described should be suitable for other endogenous signalling molecules in many biological systems. [source] Activation of the basal forebrain by the orexin/hypocretin neuronesACTA PHYSIOLOGICA, Issue 3 2010E. Arrigoni Abstract The orexin neurones play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurones promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurones may promote arousal by exciting cortically projecting neurones of the BF. Orexin fibres synapse on BF cholinergic neurones and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurones, induces cortical release of acetylcholine and promotes wakefulness. The orexin neurones also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurones that project to the cortex. Cholinergic neurones were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurones that project to the cortex seem to comprise at least two populations with some directly excited by orexin-A that may represent wake-active, GABAergic neurones, whereas others did not respond to orexin-A but were inhibited by dynorphin and may be sleep-active, GABAergic neurones. This evidence suggests that the BF is a key site through which orexins activate the cortex and promote behavioural arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance. [source] The role of inhibitory neurotransmission in locomotor circuits of the developing mammalian spinal cordACTA PHYSIOLOGICA, Issue 2 2009H. Nishimaru Abstract Neuronal circuits generating the basic coordinated limb movements during walking of terrestrial mammals are localized in the spinal cord. In these neuronal circuits, called central pattern generators (CPGs), inhibitory synaptic transmission plays a crucial part. Inhibitory synaptic transmission mediated by glycine and GABA is thought to be essential in coordinated activation of muscles during locomotion, in particular, controlling temporal and spatial activation patterns of muscles of each joint of each limb on the left and right side of the body. Inhibition is involved in other aspects of locomotion such as control of speed and stability of the rhythm. However, the precise roles of neurotransmitters and their receptors mediating inhibitory synaptic transmission in mammalian spinal CPGs remain unclear. Moreover, many of the inhibitory interneurones essential for output pattern of the CPG are yet to be identified. In this review, recent advances on these issues, mainly from studies in the developing rodent spinal cord utilizing electrophysiology, molecular and genetic approaches are discussed. [source] Influence of sympathetic and AT1 -receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive ratsACTA PHYSIOLOGICA, Issue 3 2009M. H. Abdulla Abstract Aim:, This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR). Methods:, Forty-eight SHR were subjected to 7 days of losartan (10 mg kg,1 day,1 p.o.), carvedilol (5 mg kg,1 day,1 p.o.) or losartan + carvedilol (10 mg kg,1 day,1 + 5 mg kg,1 day,1 p.o.). On day 8, the rats were anaesthetized and renal vasoconstrictor experiments performed. One group of rats underwent acute unilateral renal denervation. Results:, There were significant (P < 0.05) reductions in the renal vasoconstrictor responses to noradrenaline, phenylephrine, methoxamine and Ang II after losartan and carvedilol treatments compared with that in untreated rats (all P < 0.05). However, in renally denervated SHR treated with carvedilol, the vasoconstrictor responses to all the vasoactive agents were enhanced compared with those in SHR with intact renal nerves treated with carvedilol. Intact SHR given both losartan and carvedilol showed greater renal vasoconstrictor responses to the vasoactive agents than when given either losartan or carvedilol alone (all P < 0.05). Conclusion:, Carvedilol reduced the vasoconstrictor response to Ang II and all the adrenergic agonists in the presence of the renal nerves, but, following the removal of renal sympathetic activity, carvedilol enhanced the sensitivity of both renal ,1 -adrenoceptors and AT1 receptors to the vasoactive agents. Co-treatment with losartan and carvedilol reduced the renal vasoconstrictor responses to exogenously administered vasoactive agents but to a lesser extent than losartan or carvedilol alone. The results obtained demonstrate an interaction between Ang II receptors and adrenergic neurotransmission in the SHR. [source] Dopamine release in ventral striatum of pathological gamblers losing moneyACTA PSYCHIATRICA SCANDINAVICA, Issue 4 2010J. Linnet Linnet J, Peterson E, Doudet DJ, Gjedde A, Mųller A. Dopamine release in ventral striatum of pathological gamblers losing money. Objective:, To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue gambling despite losses, known as ,chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). Method:, We used Positron Emission Tomography (PET) with [11C]raclopride to measure dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). Results:, PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. Conclusion:, Our findings suggest a dopaminergic basis of monetary losses in pathological gambling, which might explain loss-chasing behavior. The findings may have implications for the understanding of dopamine dysfunctions and impaired decision-making in pathological gambling and substance-related addictions. [source] Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trialDEPRESSION AND ANXIETY, Issue 3 2008Moira Rynn M.D. Abstract Generalized anxiety disorder (GAD), a prevalent and chronic illness, is associated with dysregulation in both serotonergic and noradrenergic neurotransmission. Our study examined the efficacy, safety, and tolerability of duloxetine hydrochloride, a dual reuptake inhibitor of serotonin and norepinephrine, for short-term treatment of adults with GAD. In a 10-week, double-blind, progressive-titration, flexible-dose trial, 327 adult outpatients with a DSM-IV,defined GAD diagnosis were randomized to duloxetine 60,120,mg (DLX, N=168) or placebo (PLA, N=159) treatment. The primary efficacy measure was mean change from baseline to endpoint in Hamilton Anxiety Scale (HAMA) total score. Secondary outcome measures included response rate (HAMA total score reduction ,50% from baseline), Clinician Global Impression,Improvement (CGI-I) scores, and Sheehan Disability Scale (SDS) scores. Patients who received duloxetine treatment demonstrated significantly greater improvement in HAMA total scores (P=.02); a higher response rate (P=.03), and greater improvement (P=.04) than patients who received placebo. Duloxetine-treated patients were also significantly more improved than placebo-treated patients on SDS global functional (P<.01) and work, social, and family/home impairment scores (P<.05). The rate of discontinuation due to adverse events (AEs) was higher for the duloxetine group compared with the placebo group (P=.002). The AEs most frequently associated with duloxetine were nausea, dizziness, and somnolence. Duloxetine was an efficacious, safe, and well-tolerated treatment that resulted in clinically significant improvements in symptom severity and functioning for patients with GAD. Depression and Anxiety 0:1,8, 2007. © 2007 Wiley-Liss, Inc. [source] Activity of nAChRs containing ,9 subunits modulates synapse stabilization via bidirectional signaling programsDEVELOPMENTAL NEUROBIOLOGY, Issue 14 2009Vidya Murthy Abstract Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) ,9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR ,9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in ,9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the ,9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult ,9 null mice. Finally, by using mice expressing the nondesensitizing ,9 L9,T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source] Supraspinal input is dispensable to generate glycine-mediated locomotive behaviors in the zebrafish embryoDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2006Gerald B. Downes Abstract The anatomy of the developing zebrafish spinal cord is relatively simple but, despite this simplicity, it generates a sequence of three patterns of locomotive behaviors. The first behavior exhibited is spontaneous movement, then touch-evoked coiling, and finally swimming. Previous studies in zebrafish have suggested that spontaneous movements occur independent of supraspinal input and do not require chemical neurotransmission, while touch-evoked coiling and swimming depend on glycinergic neurotransmission as well as supraspinal input. In contrast, studies in other vertebrate preparations have shown that spontaneous movement requires glycine and other neurotransmitters and that later behaviors do not require supraspinal input. Here, we use lesion analysis combined with high-speed kinematic analysis to re-examine the role of glycine and supraspinal input in each of the three behaviors. We find that, similar to other vertebrate preparations, supraspinal input is not essential for spontaneous movement, touch-evoked coiling, or swimming behavior. Moreover, we find that blockade of glycinergic neurotransmission decreases the rate of spontaneous movement and impairs touch-evoked coiling and swimming, suggesting that glycinergic neurotransmission plays critical yet distinct roles for individual patterns of locomotive behaviors. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Expanding field of purinergic signalingDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Geoffrey Burnstock Abstract This article attempts to paint a broad picture of the extraordinary explosive recent developments in the purinergic signaling field. After a brief historical review and update of purinoceptor subtypes, the focus is on the physiological roles of purines and pyrimidines. These are considered both in terms of short-term signaling in neurotransmission, secretion, and vasodilatation and in long-term (trophic) signaling in development, regeneration, proliferation, and cell death. Examples of trophic signaling include cartilage development in limb buds, glial cell proliferation, development of skeletal muscle, changes in receptor expression in smooth-muscle phenotypes, maturation of testicular spermatids, and bone remodeling. Plasticity of purinoceptor expression in pathological conditions is described, including the increase in the purinergic component of parasympathetic nervous control of the human bladder in interstitial cystitis and outflow obstruction and in sympathetic cotransmitter control of blood vessels in hypertensive rats, the appearance of P2X7 receptors in the glomeruli of the kidney from diabetic and transgenic hypertensive animal models, and up-regulation of P2X1 and P2Y2 receptor mRNA in hearts of rats with congestive heart failure. The role of P2X3 receptors in nociception is considered, and a new hypothesis about purinergic mechanosensory transduction in the gut is explored. A personal view of some of the areas ripe for future development concludes this article, including a discussion of different strategies that could lead to the development of purinergic therapeutic agents. Drug Dev. Res. 52:1,10, 2001. © 2001 Wiley-Liss, Inc. [source] Neuroprotection in emerging psychotic disordersEARLY INTERVENTION IN PSYCHIATRY, Issue 2 2007Gregor Berger Abstract Aim:, The emerging phase of psychotic disorders is pleomorphic and fluctuates in presentation. Hence, from a clinical perspective, treatment modalities are often unclear. This paper investigates the rational and potential use of neuroprotective agents in emerging psychotic disorders. Methods:, Medline databases were searched from 1966 to 2006 followed by the cross-checking of references using following keywords: neuroprotection, apoptosis, natural cell death, neurodevelopment, plasticity, neurogenesis, combined with brain and schizophrenia. Results:, Agents such as atypical antipsychotics, antidepressants, omega-3 fatty acids, modulators of glutamateric neurotransmission (e.g. ampakines, glycine, memantine), erythropoietin, N -acetylcysteine, COX-2 inhibitors or antioxidants have neuroprotective (anti-apoptotic) properties and may therefore be able to protect brain maturational processes disturbed in emerging psychotic disorders. Clinical trials suggest that atypical antipsychotics, antidepressants, omega-3 fatty acids and low-dose lithium as sole treatments were able to improve symptoms and functioning, and delay or in some cases even prevent the onset of frank psychosis. Initially these substances have been chosen because they have been used either as sole or augmentation treatments in established psychotic disorders. However, chronicity and already effective treatments may overshadow their potential clinical use in emerging (prodromal) psychosis. Conclusion:, Neuroprotection as a new treatment paradigm for at-risk mental states seems to be promising and pilot data are suggestive that more benign interventions may already be sufficient to delay or even prevent the onset of frank psychosis. A coordinated research effort will be necessary to address the question which agents should be used under which circumstances. [source] Mercury-induced reproductive impairment in fish,,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2009Kate L. Crump Abstract Mercury is a potent neurotoxin, and increasing levels have led to concern for human and wildlife health in many regions of the world. During the past three decades, studies in fish have examined the effects of sublethal mercury exposure on a range of endpoints within the reproductive axis. Mercury studies have varied from highly concentrated aqueous exposures to ecologically relevant dietary exposures using levels comparable to those currently found in the environment. This review summarizes data from both laboratory and field studies supporting the hypothesis that mercury in the aquatic environment impacts the reproductive health of fish. The evidence presented suggests that the inhibitory effects of mercury on reproduction occur at multiple sites within the reproductive axis, including the hypothalamus, pituitary, and gonads. Accumulation of mercury in the fish brain has resulted in reduced neurosecretory material, hypothalamic neuron degeneration, and alterations in parameters of monoaminergic neurotransmission. At the level of the pituitary, mercury exposure has reduced and/or inactivated gonadotropin-secreting cells. Finally, studies have examined the effects of mercury on the reproductive organs and demonstrated a range of effects, including reductions in gonad size, circulating reproductive steroids, gamete production, and spawning success. Despite some variation between studies, there appears to be sufficient evidence from laboratory studies to link exposure to mercury with reproductive impairment in many fish species. Currently, the mechanisms underlying these effects are unknown; however, several physiological and cellular mechanisms are proposed within this review. [source] Antiepileptic drugs combined with high-frequency electrical stimulation in the ventral hippocampus modify pilocarpine-induced status epilepticus in ratsEPILEPSIA, Issue 3 2010Manola Cuellar-Herrera Summary Purpose:, To evaluate the effects of high-frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium-pilocarpine (LP). Methods:, Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 ,s width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results:, HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion:, Subeffective doses of antiepileptic drugs that increase the ,-aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS-induced anticonvulsant effects. [source] Substantial Thalamostriatal Dopaminergic Defect in Unverricht-Lundborg DiseaseEPILEPSIA, Issue 9 2007Miikka Korja Summary:,Purpose: Unverricht-Lundborg disease (ULD) is currently classified as progressive myoclonus epilepsy. Myoclonus, the characteristic symptom in ULD, suggests that dopamine neurotransmission may be involved in the pathophysiology of ULD. Our purpose was to examine brain dopaminergic function in ULD patients. Methods: Four genetically and clinically diagnosed ULD patients and eight healthy controls were scanned with [11C]raclopride-PET. PET images were coregistered to individual 1.5T MR images and region-of-interest analysis was performed for the striatum and thalamus. Standardized uptake values and individual voxel-wise binding potential maps of the patients and controls were also analyzed. Results: ULD patients had markedly higher (31,54%) dopamine D2-like receptor availabilities than healthy controls in both the striatum and the thalamus. The proportionally highest binding potentials were detected in the thalamus. There were no significant differences in the cerebellar uptake of [11C]raclopride in ULD patients versus healthy controls. Voxel-based results were in accordance with the region-of-interest analysis. Conclusions: These results suggest that dopaminergic modulation at the level of the striatum and thalamus could be a crucial factor contributing to the symptoms of ULD. In the light of our data, we propose that ULD with dopamine dysfunction and dyskinetic symptoms shares certain pathophysiological mechanisms with classical movement disorders. Future studies are therefore warranted to study the effect of dopaminergic pharmacotherapy in ULD. [source] Lamotrigine Therapy of Epilepsy in Tuberous SclerosisEPILEPSIA, Issue 7 2001David Neal Franz Summary: ,Purpose: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial-onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox,Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC. Methods: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG. Results: Twenty-four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty-eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent. Conclusions: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy. [source] PRECLINICAL STUDY: FULL ARTICLE: Effects of fatty acid amide hydrolase inhibition on neuronal responses to nicotine, cocaine and morphine in the nucleus accumbens shell and ventral tegmental area: involvement of PPAR-, nuclear receptorsADDICTION BIOLOGY, Issue 3 2010Antonio Luchicchi ABSTRACT The endocannabinoid system regulates neurotransmission in brain regions relevant to neurobiological and behavioral actions of addicting drugs. We recently demonstrated that inhibition by URB597 of fatty acid amide hydrolase (FAAH), the main enzyme that degrades the endogenous cannabinoid N-acylethanolamine (NAE) anandamide and the endogenous non-cannabinoid NAEs oleoylethanolamide and palmitoylethanolamide, blocks nicotine-induced excitation of ventral tegmental area (VTA) dopamine (DA) neurons and DA release in the shell of the nucleus accumbens (ShNAc), as well as nicotine-induced drug self-administration, conditioned place preference and relapse in rats. Here, we studied whether effects of FAAH inhibition on nicotine-induced changes in activity of VTA DA neurons were specific for nicotine or extended to two drugs of abuse acting through different mechanisms, cocaine and morphine. We also evaluated whether FAAH inhibition affects nicotine-, cocaine- or morphine-induced actions in the ShNAc. Experiments involved single-unit electrophysiological recordings from DA neurons in the VTA and medium spiny neurons in the ShNAc in anesthetized rats. We found that URB597 blocked effects of nicotine and cocaine in the ShNAc through activation of both surface cannabinoid CB1-receptors and alpha-type peroxisome proliferator-activated nuclear receptor. URB597 did not alter the effects of either cocaine or morphine on VTA DA neurons. These results show that the blockade of nicotine-induced excitation of VTA DA neurons, which we previously described, is selective for nicotine and indicate novel mechanisms recruited to regulate the effects of addicting drugs within the ShNAc of the brain reward system. [source] GENETIC STUDY: Interaction of SLC6A4 and DRD2 polymorphisms is associated with a history of delirium tremensADDICTION BIOLOGY, Issue 1 2010Victor M. Karpyak ABSTRACT Several genetic polymorphisms have been reported to be associated with alcohol withdrawal seizures (AWS) and delirium tremens (DT). To replicate and further explore these findings, we investigated the effects of 12 previously reported candidate genetic variations in two groups of alcohol-dependent European Americans with a history of withdrawal, which differed according to the presence (n = 112) or absence (n = 92) of AWS and/or DT. Associations of AWS and/or DT with the genomic and clinical characteristics and gene,gene interaction effects were investigated using logistic regression models. None of the polymorphisms were significantly associated with AWS/DT after correction for multiple testing. However, we found a significant interaction effect of the SLC6A4 promoter polymorphism (5-HTTLPR) and DRD2 exon 8 single nucleotide polymorphism rs6276 on AWS and/or DT history (P = 0.009), which became more significant after adjustment for lifetime maximum number of drinks consumed per 24 hours (P < 0.001). Subsequent analysis revealed an even stronger association of the SLC6A4,DRD2 interaction with DT (P < 0.0001), which remained significant after Bonferroni correction. Results reveal decreased likelihood of DT in alcoholics that carry the DRD2 rs6276 G allele and SLC6A4 LL genotype. This study provides the first evidence to implicate the interaction between serotonin and dopamine neurotransmission in the etiology of DT. Replication is necessary to verify this potentially important finding. [source] REVIEW: Identifying the neural circuitry of alcohol craving and relapse vulnerabilityADDICTION BIOLOGY, Issue 1 2009Andreas Heinz ABSTRACT With no further intervention, relapse rates in detoxified alcoholics are high and usually exceed 80% of all detoxified patients. It has been suggested that stress and exposure to priming doses of alcohol and to alcohol-associated stimuli (cues) contribute to the relapse risk after detoxification. This article focuses on neuronal correlates of cue responses in detoxified alcoholics. Current brain imaging studies indicate that dysfunction of dopaminergic, glutamatergic and opioidergic neurotransmission in the brain reward system (ventral striatum including the nucleus accumbens) can be associated with alcohol craving and functional brain activation in neuronal systems that process attentional relevant stimuli, reward expectancy and experience. Increased functional brain activation elicited by such alcohol-associated cues predicted an increased relapse risk, whereas high brain activity elicited by affectively positive stimuli may represent a protective factor and was correlated with a decreased prospective relapse risk. These findings are discussed with respect to psychotherapeutic and pharmacological treatment options. [source] GENETIC STUDY: Tryptophan hydroxylase 2 gene and alcohol use among college studentsADDICTION BIOLOGY, Issue 3-4 2008Paul Gacek ABSTRACT Genes that regulate serotonin activity are regarded as promising predictors of heavy alcohol use. Tryptophan hydroxylase (TPH2) plays an important role in serotonergic neurotransmission by serving as the rate-limiting enzyme for serotonin biosynthesis in the midbrain and serotonergic neurons. Despite the link between TPH2 and serotonergic function, TPH2's role in the pathogenesis of alcohol-use disorders remains unclear. The goal of this study was to examine whether a variation in the TPH2 gene is associated with risky alcohol consumption. Specifically, this study examined whether the TPH2 G-703T polymorphism predicted alcohol consumption among college students. In two successive years, 351 undergraduates were asked to record their alcohol use each day for 30 days using an Internet-based electronic diary. Participants' DNA was collected and polymerase chain reaction genotyping was performed. Results show that alcohol consumption was not associated with the TPH2 G-703T polymorphism alone, or the interaction of TPH2 with two other candidate polymorphisms (TPH1 C218A and the SLC6A4 tri-allelic 5-HTTLPR), or negative life events. In conclusion, this study supports recent null findings relating TPH2 to drinking outcomes. It also extends these findings by showing null interactions with the TPH1 C218A polymorphism, the SLC6A4 tri-allelic 5-HTTLPR polymorphism and environmental stressors in predicting sub-clinical alcohol use among Caucasian American young adults. [source] Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalusEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2007M. Tullberg Normal pressure hydrocephalus (NPH) is characterized by disturbed cerebrospinal fluid (CSF) dynamics and white matter lesions (WML). Although the morphology of these lesions is described, little is known about the biochemistry. Our aim was to explore the relationship between ventricular CSF markers, periventricular WML and postoperative clinical outcome in patients with NPH. We analysed lumbar and ventricular concentrations of 10 CSF markers, 12 clinical symptoms and signs, magnetic resonance imaging (MRI) periventricular white matter hyperintensities (PVH) and ventricular size before and 3 months after shunt surgery in 35 patients with NPH. Higher ventricular CSF neurofilament protein (NFL), an axonal marker, correlated with more extensive PVH. A larger postoperative reduction in NFL correlated with larger reduction in PVH and a more pronounced overall improvement. Albumin ratio, HMPG, NPY, VIP and GD3 increased postoperatively whereas NFL, tau and HVA decreased. Variations in ventricular size were not associated with CSF concentrations of any marker. We conclude that NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as PVH. Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis. [source] Adenosine drives recycled vesicles to a slow-release pool at the mouse neuromuscular junctionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2010Paula P. Perissinotti Abstract The effects of adenosine on neurotransmission have been widely studied by monitoring transmitter release. However, the effects of adenosine on vesicle recycling are still unknown. We used fluorescence microscopy of FM2-10-labeled synaptic vesicles in combination with intracellular recordings to examine whether adenosine regulates vesicle recycling during high-frequency stimulation at mouse neuromuscular junctions. The A1 adenosine receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine) increased the quantal content released during the first endplate potential, suggesting that vesicle exocytosis can be restricted by endogenous adenosine, which accordingly decreases the size of the recycling vesicle pool. Staining protocols designed to label specific vesicle pools that differ in their kinetics of release showed that all vesicles retrieved in the presence of 8-cyclopentyl-1,3-dipropylxanthine were recycled towards the fast-release pool, favoring its loading with FM2-10 and suggesting that endogenous adenosine promotes vesicle recycling towards the slow-release pool. In accordance with this effect, exogenous applied adenosine prevented the replenishment of the fast-release vesicle pool and, thus, hindered its loading with the dye. We had found that, during high-frequency stimulation, Ca2+ influx through L-type channels directs newly formed vesicles to a fast-release pool (Perissinotti et al., 2008). We demonstrated that adenosine did not prevent the effect of the L-type blocker on transmitter release. Therefore, activation of the A1 receptor promotes vesicle recycling towards the slow-release pool without a direct effect on the L-type channel. Further studies are necessary to elucidate the molecular mechanisms involved in the regulation of vesicle recycling by adenosine. [source] Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanismsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009V. I. Chefer Abstract Mu opioid receptor (MOR) regulation of somatodendritic dopamine neurotransmission in the ventral tegmental area (VTA) was investigated using conventional microdialysis in freely moving rats and mice. Reverse dialysis of the MOR agonist DAMGO (50 and 100 ,m) into the VTA of rats produced a concentration-dependent increase in dialysate dopamine concentrations. Basal dopamine overflow in the VTA was unaltered in mice lacking the MOR gene. However, basal ,-aminobutyric acid (GABA) overflow in these animals was significantly increased, whereas glutamate overflow was decreased. Intra-VTA perfusion of DAMGO into wild-type (WT) mice increased dopamine overflow. GABA concentrations were decreased, whereas glutamate concentrations in the VTA were unaltered. Consistent with the loss of MOR, no effect of DAMGO was observed in MOR knockout (KO) mice. These data provide the first direct demonstration of tonically active MOR systems in the VTA that regulate basal glutamatergic and GABAergic neurotransmission in this region. We hypothesize that increased GABAergic neurotransmission following constitutive deletion of MOR is due to the elimination of a tonic inhibitory influence of MOR on GABAergic neurons in the VTA, whereas decreased glutamatergic neurotransmission in MOR KO mice is a consequence of intensified GABA tone on glutamatergic neurons and/or terminals. As a consequence, somatodendritic dopamine release is unaltered. Furthermore, MOR KO mice do not exhibit the positive correlation between basal dopamine levels and the glutamate/GABA ratio observed in WT mice. Together, our findings indicate a critical role of VTA MOR in maintaining an intricate balance between excitatory and inhibitory inputs to dopaminergic neurons. [source] Astrocyte-derived kynurenic acid modulates basal and evoked cortical acetylcholine releaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2009A. Zmarowski Abstract We tested the hypothesis that fluctuations in the levels of kynurenic acid (KYNA), an endogenous antagonist of the ,7 nicotinic acetylcholine (ACh) receptor, modulate extracellular ACh levels in the medial prefrontal cortex in rats. Decreases in cortical KYNA levels were achieved by local perfusion of S -ESBA, a selective inhibitor of the astrocytic enzyme kynurenine aminotransferase II (KAT II), which catalyses the formation of KYNA from its precursor l -kynurenine. At 5 mm, S -ESBA caused a 30% reduction in extracellular KYNA levels, which was accompanied by a two-threefold increase in basal cortical ACh levels. Co-perfusion of KYNA in the endogenous range (100 nm), which by itself tended to reduce basal ACh levels, blocked the ability of S -ESBA to raise extracellular ACh levels. KYNA perfusion (100 nm) also prevented the evoked ACh release caused by d -amphetamine (2.0 mg/kg). This effect was duplicated by the systemic administration of kynurenine (50 mg/kg), which resulted in a significant increase in cortical KYNA formation. Jointly, these data indicate that astrocytes, by producing and releasing KYNA, have the ability to modulate cortical cholinergic neurotransmission under both basal and stimulated conditions. As cortical KYNA levels are elevated in individuals with schizophrenia, and in light of the established role of cortical ACh in executive functions, our findings suggest that drugs capable of attenuating the production of KYNA may be of benefit in the treatment of cognitive deficits in schizophrenia. [source] Mechanisms of substrate transport-induced clustering of a glial glutamate transporter GLT-1 in astroglial,neuronal culturesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2008Takayuki Nakagawa Abstract Glutamate uptake by the Na+ -dependent glutamate transporter GLT-1, which is predominantly expressed in astrocytes, is crucial for regulating glutamate concentration at the synaptic cleft and achieving proper excitatory neurotransmission. A body of evidence suggests that GLT-1 constitutively traffics between the plasma membrane and endosomes via an endocytosis/recycling pathway, and forms a cluster. Here, we report substrate transport via GLT-1-induced formation of GLT-1 cluster accompanied by intracellular trafficking in rat astroglial,neuronal cultures. We constructed a recombinant adenovirus expressing enhanced green fluorescence protein (EGFP)-tagged GLT-1. Adenoviral infection resulted in the expression of functional GLT-1,EGFP preferentially in astrocytes, partly as clusters. Treatment with glutamate, but not N -methyl-D-aspartate, dramatically increased the number of GLT-1 clusters within 1 h. The estimated EC50 value of glutamate was 240 ,m. In addition, glutamate decreased the cell surface expression and increased the intracellular expression of GLT-1. The GLT-1 clusters were found in early and recycling endosomes and partly in lysosomes, and were inhibited by blockade of endocytotic pathways. Ionotropic and metabotropic glutamate receptor antagonists had no effect on glutamate-induced GLT-1 clustering. The non-transportable glutamate uptake inhibitors (2S,3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate and dihydrokainate, as well as Na+ -free conditions, prevented the glutamate-induced GLT-1 clustering, whereas the competitive substrates, aspartate and L- trans -pyrrolidine-2,4-dicarboxylate, induced GLT-1 clustering. Furthermore, the Na+/K+ -ATPase inhibitor, ouabain, and the Na+ ionophores, gramicidin and monensin, produced GLT-1 clustering. Modulators of intracellular Ca2+signaling or membrane depolarization had no effect on GLT-1 clustering. Taken together, these results suggest that Na+ influx associated with GLT-1 substrate transport triggers the formation of GLT-1 clusters accompanied by intracellular trafficking via endocytotic pathways in astrocytes. [source] Concepts of neural nitric oxide-mediated transmissionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2008John Garthwaite Abstract As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modifications in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of amplification of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success. [source] Neonatal maternal separation and enhancement of the inspiratory (phrenic) response to hypoxia in adult rats: disruption of GABAergic neurotransmission in the nucleus tractus solitariusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2008Richard Kinkead Abstract Neonatal maternal separation (NMS) alters respiratory control development. Adult male rats previously subjected to NMS show a hypoxic ventilatory response 25% greater than controls. During hypoxia, ,-aminobutyric acid (GABA) release within the nucleus tractus solitarius (NTS) modulates the magnitude of the ventilatory response. Because development of GABAergic receptors is sensitive to NMS, we tested the hypothesis that in adults, a change in responsiveness to GABA within the NTS contributes to NMS-related enhancement of the inspiratory (phrenic) response to hypoxia. Pups subjected to NMS were placed in an incubator for 3 h/day for 10 consecutive days [postnatal days 3 to 12]. Controls were undisturbed. Adult (8,10 weeks old) rats were anaesthetized (urethane; 1.6 g/kg), paralysed and artificially ventilated to record phrenic activity. Rats either received a 50-nL microinjection of GABA (5 µm) or phosphate-buffered saline (sham) within the caudal NTS, or no injection prior to being exposed to hypoxia (FiO2 = 0.12; 5 min). NMS enhanced both the frequency and amplitude components of the phrenic response to hypoxia vs controls. GABA microinjection attenuated the phrenic responses in NMS rats only. This result is supported by ligand binding autoradiography results showing that the number of GABAA receptors within the NTS was 69% greater in NMS vs controls. Despite this increase, the phrenic response to hypoxia of NMS rats is larger than controls, suggesting that the higher responsiveness to GABA microinjection within the NTS is part of a mechanism that aims to compensate for: (i) a deficient GABAergic modulation; (ii) enhancement of excitatory inputs converging onto this structure; or (iii) both. [source] Developmental changes in the BDNF-induced modulation of inhibitory synaptic transmission in the Kölliker,Fuse nucleus of ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Miriam Kron Abstract The Kölliker,Fuse nucleus (KF), part of the pontine respiratory group, is involved in the control of respiratory phase duration, and receives both excitatory and inhibitory afferent input from various other brain regions. There is evidence for developmental changes in the modulation of excitatory inputs to the KF by the neurotrophin brain-derived neurotrophic factor (BDNF). In the present study we investigated if BDNF exerts developmental effects on inhibitory synaptic transmission in the KF. Recordings of inhibitory postsynaptic currents (IPSCs) in KF neurons in a pontine slice preparation revealed general developmental changes. Recording of spontaneous and evoked IPSCs (sIPSCs, eIPSCS) revealed that neonatally the ,-aminobutyric acid (GABA)ergic fraction of IPSCs was predominant, while in later developmental stages glycinergic neurotransmission significantly increased. Bath-application of BDNF significantly reduced sIPSC frequency in all developmental stages, while BDNF-mediated modulation on eIPSCs showed developmental differences. The eIPSCs mean amplitude was uniformly and significantly reduced following BDNF application only in neurons from rats younger than postnatal day 10. At later postnatal stages the response pattern became heterogeneous, and both augmentations and reductions of eIPSC amplitudes occurred. All BDNF effects on eIPSCs and sIPSCs were reversed with the tyrosine kinase receptor-B inhibitor K252a. We conclude that developmental changes in inhibitory neurotransmission, including the BDNF-mediated modulation of eIPSCs, relate to the postnatal maturation of the KF. The changes in BDNF-mediated modulation of IPSCs in the KF may have strong implications for developmental changes in synaptic plasticity and the adaptation of the breathing pattern to afferent inputs. [source] MDMA self-administration in rats: acquisition, progressive ratio responding and serotonin transporter bindingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2007Susan Schenk Abstract 3,4-Methylenedioxymethamphetamine (MDMA) self-administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug-naļve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self-administration was measured during daily 6-h sessions. Dose,effect data were obtained for MDMA (0.25,1.0 mg/kg/infusion) self-administration under a progressive ratio (PR) schedule of reinforcement. The effect of experimenter- or self-administered MDMA on [3H] paroxetine binding in several brain regions was measured. Acquisition of MDMA self-administration was highly variable and not different for 0.25 or 1.0 mg/kg/infusion progressed with approximately 60% of the rats acquiring reliable self-administration during the 15-day test period. The percentage of rats that acquired MDMA self-administration was lower than the percentage of rats that acquired cocaine (0.5 mg/kg/infusion) self-administration, and cocaine self-administration was acquired with a shorter latency. Responding maintained by MDMA was dose dependent, and breakpoints under a PR schedule increased with dose. Radioligand binding and autoradiography demonstrated lower densities of serotonin transporter sites (SERT) in MDMA self-administering rats as compared with controls across brain regions. The reduction in SERT densities was comparable in magnitude to rats treated with experimenter-administered doses of MDMA. These data support the idea that MDMA is a drug with high abuse liability, and long-term self-administration may lead to long-lasting deficits in serotonin neurotransmission. [source] Differential expression of PKC beta II in the rat organ of CortiEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2007S. Ladrech Abstract To investigate a possible involvement of protein kinase C (PKC) in cochlear efferent neurotransmission, we studied the expression of the calcium-dependent PKC beta II isoform in the rat organ of Corti at different postnatal ages using immunofluorescence and immunoelectron microscopy. We found evidence of PKC beta II as early as postnatal day (PND) 5 in efferent axons running in the inner spiral bundle and in Hensen cells. At PND 8, we also found PKC beta II in efferents targeting outer hair cells (OHCs), and a slight detection at the synaptic pole in the first row of the basal and middle cochlear turns. At PND 12, PKC beta II expression declined in the efferent fibres contacting OHCs, whereas expression was concentrated at the postsynaptic membrane, from the basal and middle turns. The adult-like pattern of PKC beta II distribution was observed at PND 20. Throughout the cochlea, we found PKC beta II expression in the Hensen cells, non-sensory cells involved in potassium re-cycling, and lateral efferent terminals of the inner spiral bundle. In addition, we observed expression in OHCs at the postsynaptic membrane facing the endings of the medial efferent system, with the exception of some OHCs located in the most apical region of the cochlea. These data therefore suggest an involvement of PKC beta II in both cochlear efferent neurotransmission and ion homeostasis. Among other functions, PKC beta II could play a role in the efferent control of OHC activity. [source] | |||||||||||||||||||||||||||||||