Same old: 2007

Wednesday 28 November 2007

Embodying Cultured Networks with a Robotic Drawing Arm.

Embodying Cultured Networks with a Robotic Drawing Arm.

Conf Proc IEEE Eng Med Biol Soc. 2007;1:2996-2999

Authors: Bakkum DJ, Chao ZC, Gamblen P, Ben-Ary G, Shkolnik AG, Demarse TB, Potter SM

The advanced and robust computational power of the brain is shown by the complex behaviors it produces. By embodying living cultured neuronal networks with a robotic or simulated animal (animat) and situating them within an environment, we study how the basic principles of neuronal network communication can culminate into adaptive goal-directed behavior. We engineered a closed-loop biological-robotic drawing machine and explored sensory-motor mappings and training. Preliminary results suggest that real-time performance-based feedback allowed an animat to draw in desired directions. This approach may help instruct the future design of artificial neural systems and of the algorithms to interface sensory and motor prostheses with the brain.

PMID: 18002625 [PubMed - as supplied by publisher]

How do TTX and AP5 affect the post-recovery neuronal network activity synchronization?

How do TTX and AP5 affect the post-recovery neuronal network activity synchronization?

Conf Proc IEEE Eng Med Biol Soc. 2007;1:3012-3015

Authors: Esposti F, Signorini MG, Lamanna J, Gullo F, Wanke E

A lot of methods were created in last decade for the spatio-temporal analysis of multi-electrode array (MEA) neuronal data sets. The greater part of these methods does not consider the network as a whole but performs an analysis channel by channel. In this paper we illustrate how a very simple approach that considers the total network activity, is able to show interesting neuronal network features. In particular we perform two different analyses: a connectivity examination studying networks at different days in vitro and an analysis of the long period effects of the administration of two common neuro-active drugs, i.e. TTX and AP5. Our analysis is performed considering burst topology, i.e. cataloguing network bursts as Global (if they involve more than the 25% of the MEA channels) or Local (if less that 25%). This division allows, in the first analysis, to understand the network connectivity (increasing from div 1 to 6) and decreasing till reaching a plateau (from div 6 to 10). The second analysis highlights a substantial difference between the long period effects of TTX and AP5. While TTX induces a massive Global activity explosion, sign of a prolonged inhibitory synapse depression, AP5 shows only a modest Local activity increase, mark of the low effect of NMDA receptors on a mature neuronal network without inputs.

PMID: 18002629 [PubMed - as supplied by publisher]

Different cannabinoids exhibit different electrophysiological properties.

Different cannabinoids exhibit different electrophysiological properties.

NIDA Res Monogr. 1987;79:67-81

Authors: Turkanis SA, Karler R

PMID: 3125481 [PubMed - indexed for MEDLINE]

Marijuana use and the risk of new onset seizures.

Marijuana use and the risk of new onset seizures.

Trans Am Clin Climatol Assoc. 1992;103:176-81

Authors: Brust JC, Ng SK, Hauser AW, Susser M

PMID: 1413377 [PubMed - indexed for MEDLINE]

Blogged with Flock

[Results of a standardized survey on the medical use of cannabis products in the German-speaking area]

[Results of a standardized survey on the medical use of cannabis products in the German-speaking area]

Forsch Komplementarmed. 1999 Oct;6 Suppl 3:28-36

Authors: Schnelle M, Grotenhermen F, Reif M, Gorter RW

The plant Cannabis sativa has a long history of medical use in the treatment of pain and spasms, the promotion of sleep, and the suppression of nausea and vomiting. However, in the early 70s cannabis was classified in the Narcotic Acts in countries all over the world as having no therapeutic benefit; therefore, it cannot be prescribed by physicians or dispensed by pharmacists. In the light of this contradictory situation an increasing number of patients practices a self-prescription with cannabis products for relieving a variety of symptoms. An anonymous standardized survey of the medical use of cannabis and cannabis products of patients in Germany, Austria and Switzerland was conducted by the Association for Cannabis as Medicine (Cologne, Germany). During about one year 170 subjects participated in this survey; questionnaires of 128 patients could be included into the evaluation. 68% of these participants were males, 32% females, with a total mean age of 37.5 (+/- 9.6) years. The most frequently mentioned indications for medicinal cannabis use were depression (12.0%), multiple sclerosis (10.8%), HIV-infection (9.0%), migraine (6.6%), asthma (6.0%), back pain (5.4%), hepatitis C (4. 8%), sleeping disorders (4.8%), epilepsy (3.6%), spasticity (3.6%), headache (3.6%), alcoholism (3.0%), glaucoma (3.0%), nausea (3.0%), disk prolapse (2.4%), and spinal cord injury (2.4%). The majority of patients used natural cannabis products such as marihuana, hashish and an alcoholic tincture; in just 5 cases dronabinol (Marinol) was taken by prescription. About half of the 128 participants of the survey (52.4%) had used cannabis as a recreational drug before the onset of their illness. To date 14.3% took cannabis orally, 49.2% by inhalation and in 36.5% of cases both application modes were used. 72.2% of the patients stated the symptoms of their illness to have 'much improved' after cannabis ingestion, 23.4% stated to have 'slightly improved', 4.8% experienced 'no change' and 1.6% described that their symptoms got 'worse'. Being asked for the satisfaction with their therapeutic use of cannabis 60.8% stated to be 'very satisfied', 24.0% 'satisfied', 11.2% 'partly satisfied' and 4.0% were 'not satisfied'. 70.8% experienced no side effects, 26.4% described 'moderate' and 3.3% 'strong' side effects. 84.1% of patients have not felt any need for dose escalation during the last 3 months, 11.0% had to increase their cannabis dose 'moderately' and 4.8% 'strongly' in order to maintain the therapeutic effects. Thus, this survey demonstrates a successful use of cannabis products for the treatment of a multitude of various illnesses and symptoms. This use was usually accompanied only by slight and in general acceptable side effects. Because the patient group responding to this survey is presumably highly selected, no conclusions can be drawn about the quantity of wanted and unwanted effects of the medicinal use of the hemp plant for particular indications. Copyright Copyright 1999 S. Karger GmbH, Freiburg

PMID: 10575286 [PubMed - indexed for MEDLINE]

Therapeutic aspects of cannabis and cannabinoids.

Therapeutic aspects of cannabis and cannabinoids.

Br J Psychiatry. 2001 Feb;178:107-15

Authors: Robson P

BACKGROUND: Review commissioned in 1996 by the Department of Health (DOH). AIMS: Assess therapeutic profile of cannabis and cannabinoids. METHOD: Medline search, references supplied by DOH and others, and personal communications. RESULTS AND CONCLUSIONS: Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.

PMID: 11157423 [PubMed - indexed for MEDLINE]

Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice.

Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice.

Epilepsia. 2001 Mar;42(3):321-7

Authors: Lambert DM, Vandevoorde S, Diependaele G, Govaerts SJ, Robert AR

PURPOSE: The purpose of this study was to evaluate in mice the anticonvulsant potential of N-palmitoylethanolamide, a putative endocannabinoid that accumulates in the body during inflammatory processes. METHODS: N-palmitoylethanolamide was injected intraperitoneally (i.p.) in mice and evaluated for anticonvulsant activity [in maximal electroshock seizure (MES) and chemical-induced convulsions] and for neurologic impairment (rotorod). It was compared with anandamide and with different palmitic acid analogues as well as with reference anticonvulsants (AEDs) injected under the same conditions. RESULTS: The MES test showed, after i.p. administration to mice, that N-palmitoy]ethanolamide had an median effective dose (ED50) value comparable to that of phenytoin (PHT; 8.9 and 9.2 mg/kg, respectively). In the subcutaneous pentylenetetrazol test and in the 3-mercaptropropionic acid test, it was effective only against tonic convulsions. N-palmitoylethanolamide was devoid of neurologic impairment < or = 250 mg/kg, yielding a high protective index. CONCLUSIONS: N-palmitoylethanolamide, an endogenous compound with antiinflammatory and analgesic activities, is a potent AED in mice. Its precise mechanism of action remains to be elucidated.

PMID: 11442148 [PubMed - indexed for MEDLINE]

Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide.

Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide.

EMBO J. 2001 Dec 17;20(24):7033-40

Authors: Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P

Low-voltage-activated or T-type Ca(2+) channels (T-channels) are widely expressed, especially in the central nervous system where they contribute to pacemaker activities and are involved in the pathogenesis of epilepsy. Proper elucidation of their cellular functions has been hampered by the lack of selective pharmacology as well as the absence of generic endogenous regulations. We report here that both cloned (alpha(1G), alpha(1H) and alpha(1I) subunits) and native T-channels are blocked by the endogenous cannabinoid, anandamide. Anandamide, known to exert its physiological effects through cannabinoid receptors, inhibits T-currents independently from the activation of CB1/CB2 receptors, G-proteins, phospholipases and protein kinase pathways. Anandamide appears to be the first endogenous ligand acting directly on T-channels at submicromolar concentrations. Block of anandamide membrane transport by AM404 prevents T-current inhibition, suggesting that anandamide acts intracellularly. Anandamide preferentially binds and stabilizes T-channels in the inactivated state and is responsible for a significant decrease of T-currents associated with neuronal firing activities. Our data demonstrate that anandamide inhibition of T-channels can regulate neuronal excitability and account for CB receptor-independent effects of this signaling molecule.

PMID: 11742980 [PubMed - indexed for MEDLINE]

Psychostimulants and epilepsy.

Psychostimulants and epilepsy.

Epilepsia. 2002;43 Suppl 2:28-31

Authors: Zagnoni PG, Albano C

PURPOSE: The aim of this article is to review the literature on the effects of psychostimulants in epileptic subjects in order to reach a consensus statement regarding the use or abuse of these substances. METHODS: Psychostimulant substances have been considered the drugs that share the ability to produce excitation of the CNS leading to convulsions. The stimulation may be at cortical, brainstem, or spinal levels. In this article, the following cortical stimulants are analyzed and discussed: cocaine, amphetamine and related agents, caffeine, cannabinoids, and psychedelic drugs. This review is based on research done using pharmacological textbooks and Medline. RESULTS: The use of cocaine is associated with the occurrence of seizures. The reported frequency varies from 1% to 40% of addicted subjects, based on the typology of the considered study. Amphetamines and related drugs rarely induce epileptic seizures at therapeutic doses, but seizures may occur after the first dosing. Caffeine at high doses may induce epileptic seizures because of its adenosine receptor-antagonizing properties. Marijuana, at variance with other psychostimulants, owing to its serotonin-mediated anticonvulsant action, could have a medical use for the treatment of epilepsy. Psychedelic compounds rarely induce epileptic seizures, but the most common clinical CNS complication after ingestion of ecstasy is the occurrence of seizures. CONCLUSIONS: The use of psychostimulants, except for marijuana, can induce single or multiple seizures in healthy subjects.

PMID: 11903480 [PubMed - indexed for MEDLINE]

Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature.

Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature.

J Palliat Care. 2002;18(2):111-22

Authors: Bagshaw SM, Hagen NA

PMID: 12164099 [PubMed - indexed for MEDLINE]

Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.

Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.

Eur J Pharmacol. 2002 Oct 11;452(3):295-301

Authors: Wallace MJ, Martin BR, DeLorenzo RJ

The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB(1) receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED(50)=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-hydroxy-2'-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED(50)=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB(1) receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P< or =0.01, Fisher exact test), indicating a cannabinoid CB(1) receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB(1) receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC(50)=14.27 mA) compared to vehicle-treated animals (CC(50)=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB(1) receptor as a major endogenous site of seizure modulation.

PMID: 12359270 [PubMed - indexed for MEDLINE]

Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

Neuropharmacology. 2003 Jul;45(1):116-21

Authors: Nakatsuka T, Chen HX, Roper SN, Gu JG

In spite of their popular uses as recreational drugs and their potential therapeutic uses, little direct information has been obtained about the synaptic effects of cannabinoids in the human brain. In the present study, patch-clamp recordings were performed on granule cells of the human dentate gyrus and the effects of cannabinoid receptor-1 (CB1) activation on inhibitory synaptic activity were examined. Activation of CB1 receptors by WIN55212-2 significantly suppressed both frequency and amplitude of spontaneous inhibitory synaptic currents (IPSCs) to about 50% of control. The suppressive effects were completely abolished in the presence of the CB1 receptor antagonist, AM251. WIN55212-2 also suppressed evoked IPSCs. However, neither frequency nor amplitude of miniature IPSCs were affected by WIN55212-2. These results provide electrophysiological evidence for the role of CB1 receptors in modulating inhibitory activity in human dentate gyrus.

PMID: 12814664 [PubMed - indexed for MEDLINE]

Hedonic-specific activity in piriform cortex during odor imagery mimics that during odor perception.

Hedonic-specific activity in piriform cortex during odor imagery mimics that during odor perception.

J Neurophysiol. 2007 Oct 3;

Authors: Bensafi M, Sobel N, Khan RM

Whereas it is known that visual imagery is accompanied by activity in visual cortical areas, including primary visual cortex, whether olfactory imagery exists remains controversial. Here we asked whether cue-dependent olfactory imagery was similarly accompanied by activity in olfactory cortex, and in particular whether hedonic-specific patterns of activity evident in olfactory perception would also be present during olfactory imagery. We used functional magnetic resonance imaging to measure activity in subjects who alternated between smelling and imagining pleasant and unpleasant odors. Activity induced by imagining odors mimicked that induced by perceiving real odorants, not only in the particular brain regions activated, but also in its hedonic-specific pattern. For both real and imagined odors, unpleasant stimuli induced greater activity than pleasant stimuli in the left frontal portion of piriform cortex and left insula. These findings combine with findings from other modalities to suggest activation of primary sensory cortical structures during mental imagery of sensory events.

PMID: 17913994 [PubMed - as supplied by publisher]

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Neuroimage. 2007 Sep 14;

Authors: Ciumas C, Lindström P, Bernard A, Savic I

Metabolic and neuro-receptor abnormalities within the extrafocal limbic circuits are established in mesial temporal lobe epilepsy (MTLE). However, very little is known about how these circuits process external stimuli. We tested whether odor activation can help delineate limbic functional disintegration in MTLE, and measured cerebral blood flow with PET during birhinal smelling of familiar and unfamiliar odors, using smelling of odorless air as the baseline condition. Patients with MTLE (13 left-sided, 10 right-sided) and 21 controls were investigated. In addition to odor activation, the analysis included functional connectivity, using right and left piriform cortex as seed regions. Healthy controls activated the amygdala, piriform, anterior insular, and cingulate cortices on both sides. Smelling of familiar odors engaged, in addition, the right parahippocampus, and the left Brodmann Area (BA) 44, 45, 47. Patients failed to activate the amygdala, piriform and the anterior insular cortex in the epileptogenic hemisphere. Furthermore, those with left MTLE did not activate the left BA 44, 45 and 47 with familiar odors, which they perceived as less familiar than controls. Congruent with the activation data each seed region was in patients functionally disconnected with the contralateral amygdala+piriform+insular cortex. The functional disintegration in patients exceeded the reduced activation, and included the contralateral temporal neocortex, and in subjects with right MTLE also the right orbitofrontal cortex. Imaging of odor perception may be used to delineate functional disintegration of the limbic networks in MTLE. It shows an altered response in several regions, which may underlie some interictal behavioral problems associated with this condition.

PMID: 17951077 [PubMed - as supplied by publisher]

Thursday 15 November 2007

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

J Neurosci. 2007 Sep 12;27(37):9866-73

Authors: Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C

Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) receptor-mediated postsynaptic events, indicating a perturbed Cl- homeostasis. We assessed possible contributions of changes in expression of the potassium-chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium-sodium-chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA(A) reversal potentials and suppressed interictal activity. Changes in Cl- transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

PMID: 17855601 [PubMed - indexed for MEDLINE]

Chaos, brain and divided consciousness.

Chaos, brain and divided consciousness.

Acta Univ Carol Med Monogr. 2007;153:9-80

Authors: Bob P

Modern trends in psychology and cognitive neuroscience suggest that applications of nonlinear dynamics, chaos and self-organization seem to be particularly important for research of some fundamental problems regarding mind-brain relationship. Relevant problems among others are formations of memories during alterations of mental states and nature of a barrier that divides mental states, and leads to the process called dissociation. This process is related to a formation of groups of neurons which often synchronize their firing patterns in a unique spatial maner. Central theme of this study is the relationship between level of moving and oscilating mental processes and their neurophysiological substrate. This opens a question about principles of organization of conscious experiences and how these experiences arise in the brain. Chaotic self-organization provides a unique theoretical and experimental tool for deeper understanding of dissociative phenomena and enables to study how dissociative phenomena can be linked to epileptiform discharges which are related to various forms of psychological and somatic manifestations. Organizing principles that constitute human consciousness and other mental phenomena from this point of view may be described by analysis and reconstruction of underlying dynamics of psychological or psychophysiological measures. These nonlinear methods in this study were used for analysis of characteristic changes in EEG and bilateral electrodermal activity (EDA) during reliving of dissociated traumatic and stressful memories and during psychopathological states. Analysis confirms a possible role of chaotic transitions in the processing of dissociated memory. Supportive finding for a possible chaotic process related to dissociation found in this study represent also significant relationship of dissociation, epileptiform discharges measured by typical psychopathological manifestations and characteristic laterality changes in bilateral EDA in patients with schizophrenia and depression. Increased level of psychopathological symptoms indicates close relationship to the right-left EDA asymmetry and asymmetry of information entropy calculated by non-linear recurrence quantification analysis of EDA records. Because epileptiform activity has specific chaotic behaviour and calculated information entropy from EDA records reflects the complexity of the deterministic structure in the system there is a relevant assumption that unilaterally increased complexity may produce interhemispheric disbalance and increased chaoticity which hypothetically may serve as a dynamic source of epileptiform discharges related to trauma induced kindling mechanism. Specific form of chaotic inner organization which cannot be explained only as a consequence of external causality support also psychophysiological data that lead to the so-called self-organizing theory of dreaming by Kahn and Hobson. This study suggests that self-organizing theory of dreaming is particularly important with respect to problem of memory formation and processing during dissociative states characteristic for dreams. Recent data and also findings of this study support the research utility of chaos theory in psychology and neuroscience, and also its conceptual view of dynamic ordering factors and self-organization underlying psychological processes and brain physiology.

PMID: 17867519 [PubMed - indexed for MEDLINE]

Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus.

Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus.

J Neurosci. 2007 Oct 3;27(40):10674-84

Authors: Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG

Status epilepticus (SE), an unremitting seizure, is known to cause a variety of traumatic responses including delayed neuronal death and later cognitive decline. Although excitotoxicity has been implicated in this delayed process, the cellular mechanisms are unclear. Because our previous brain slice studies have shown that chemically induced epileptiform activity can lead to elevated astrocytic Ca2+ signaling and because these signals are able to induce the release of the excitotoxic transmitter glutamate from these glia, we asked whether astrocytes are activated during status epilepticus and whether they contribute to delayed neuronal death in vivo. Using two-photon microscopy in vivo, we show that status epilepticus enhances astrocytic Ca2+ signals for 3 d and that the period of elevated glial Ca2+ signaling is correlated with the period of delayed neuronal death. To ask whether astrocytes contribute to delayed neuronal death, we first administered antagonists which inhibit gliotransmission: MPEP [2-methyl-6-(phenylethynyl)pyridine], a metabotropic glutamate receptor 5 antagonist that blocks astrocytic Ca2+ signals in vivo, and ifenprodil, an NMDA receptor antagonist that reduces the actions of glial-derived glutamate. Administration of these antagonists after SE provided significant neuronal protection raising the potential for a glial contribution to neuronal death. To test this glial hypothesis directly, we loaded Ca2+ chelators selectively into astrocytes after status epilepticus. We demonstrate that the selective attenuation of glial Ca2+ signals leads to neuronal protection. These observations support neurotoxic roles for astrocytic gliotransmission in pathological conditions and identify this process as a novel therapeutic target.

PMID: 17913901 [PubMed - in process]

A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy.

A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy.

Epilepsy Behav. 2007 Oct 11;

Authors: Kossoff EH, Los JG, Boatman DF

Benign rolandic epilepsy (BRE) and Landau-Kleffner syndrome (LKS) are similar epilepsy syndromes with sleep-accentuated epileptiform activity, sporadic seizures, and language dysfunction. Levetiracetam has been associated with improved language function in LKS and seizure reduction in BRE. We hypothesized levetiracetam would improve language function in children with BRE. A pilot study was performed with six children (aged 6-12) with BRE and evidence of impaired auditory comprehension and verbal memory. Children were transitioned from their current anticonvulsant to 40 mg/kg/day levetiracetam over a 2-week period and retested at 6 months. At 6 months, three of four children with baseline auditory comprehension impairments performed normally (P=0.06), and five had improved auditory verbal memory (P=0.08). Seizures improved in five, decreasing from 2.7 to 1.0 seizure per 6 months (P=0.11). Results from this pilot study suggest that levetiracetam may have a beneficial effect on language in children with BRE.

PMID: 17936689 [PubMed - as supplied by publisher]

Inhibitory interneurons in the piriform cortex.

Inhibitory interneurons in the piriform cortex.

Clin Exp Pharmacol Physiol. 2007 Oct;34(10):1064-9

Authors: Suzuki N, Bekkers JM

1. The piriform cortex (PC) is the largest subdivision of the olfactory cortex and the first cortical destination of olfactory information. Despite the relatively simple anatomy of the PC and its obvious appeal as a model system for the study of cortical sensory processing, there are many outstanding questions about its basic cell physiology. In the present article, we review what is known about GABAergic inhibitory interneurons in the PC. 2. The GABA-containing neurons in the PC are morphologically diverse, ranging from small neurogliaform cells to large multipolar forms. Some of these classes are distributed across all three main layers of the PC, whereas others have a more restricted laminar expression. 3. Distinct and overlapping populations of GABAergic basket cells in Layers II and III of the PC express different combinations of calcium-binding proteins and neuropeptides. Few Layer I interneurons express any of the molecular markers so far examined. 4. The intrinsic firing properties of one or two types of putative PC interneurons have been measured and inhibitory post-synaptic responses have been recorded in PC pyramidal cells following extracellular stimulation. However, little is known about the physiology of the subtypes of interneurons identified. 5. In view of the likely importance of PC interneurons in olfactory learning, olfactory coding and epileptogenesis, further investigation of their properties is likely to be highly informative.

PMID: 17714095 [PubMed - indexed for MEDLINE]

Early Telencephalic Migration Topographically Converging in the Olfactory Cortex.

Early Telencephalic Migration Topographically Converging in the Olfactory Cortex.

Cereb Cortex. 2007 Sep 17;

Authors: García-Moreno F, López-Mascaraque L, de Carlos JA

Neurons that participate in the olfactory system arise in different areas of the developing mouse telencephalon. The generation of these different cell populations and their tangential migration into the olfactory cortex (OC) was tracked by tracer injection and in toto embryo culture. Cells originating in the dorsal lateral ganglionic eminence (LGE) migrate tangentially along the anteroposterior axis to settle in the piriform cortex (PC). Those originating in the ventral domain of this structure occupy the thickness of the olfactory tubercle (OT), whereas cells from the rostral LGE migrate tangentially into the most anterior telencephalon, at the level of the prospective olfactory bulb (pOB). Neurons from the dorsal telencephalon migrate ventrally, bordering the PC, toward olfactory structures. Two cell populations migrate tangentially from the rostromedial telencephalic wall to the OT and the PC, passing through the ventromedial and dorsolateral face of the telencephalon. Some cells from the germinative area of the rostral telencephalon, at the level of the septoeminential sulcus, migrate rostrally to the pOB or caudally to the OC. Thus, we demonstrate multiple telencephalic origins for the first olfactory neurons and each population following different migratory routes to colonize the OC according to an accurate topographic map.

PMID: 17878174 [PubMed - as supplied by publisher]

Distinct effects of anterior pyriform cortex and the lateral hypothalamus lesions on protein intake in rats.

Distinct effects of anterior pyriform cortex and the lateral hypothalamus lesions on protein intake in rats.

J Med Invest. 2007 Aug;54(3-4):255-60

Authors: Nakao R, Ozaki E, Hasegawa M, Kondo A, Uezu K, Hirasaka K, Nikawa T, Kishi K

Several specific locations in brain, including pyriform cortex and hypothalamus, are associated with regulation of food intake. Although lesions of these locations significantly alter food intake, their involvement in the selection of macronutrients is not well characterized. In this study, we examined distinct effects of anterior pyriform cortex (APC) and lateral hypothalamus (LH) lesions on protein intake in rats. The APC or LH of male adult rats were lesioned by treatment with kainic acid, and the rats were then given free access to two kinds of casein diets containing high (60%) and low (5%) protein. Total energy content of these diets was kept constant by changing the carbohydrate content. Following the APC lesions, body weight and food intake decreased, but returned to control levels on day 13 and day 4, respectively. APC lesions did not change the ratio of protein intake. In contrast, LH lesions disturbed body weight gain and the selection of a high protein diet for at least two weeks, although food intake returned to control levels by day 2. Our results suggest that LH, but not APC, may play an important role in the selection of protein intake in rats.

PMID: 17878674 [PubMed - indexed for MEDLINE]

Muscarinic receptor activation modulates granule cell excitability and potentiates inhibition onto mitral cells in the rat olfactory bulb.

Muscarinic receptor activation modulates granule cell excitability and potentiates inhibition onto mitral cells in the rat olfactory bulb.

J Neurosci. 2007 Oct 10;27(41):10969-81

Authors: Pressler RT, Inoue T, Strowbridge BW

The olfactory bulb is a second-order brain region that connects sensory neurons with cortical areas. However, the olfactory bulb does not appear to play a simple relay role and is subject instead to extensive local and extrinsic synaptic influences. Prime among the external, or centrifugal, inputs is the dense cholinergic innervation from the basal forebrain, which terminates in both the granule cell and plexiform layers. Cholinergic inputs to the bulb have been implicated in olfactory working memory tasks in rodents and may be related to olfactory deficits reported in people with neurodegenerative disorders that involve basal forebrain neurons. In this study, we use whole-cell recordings from acute rat slices to demonstrate that one function of this input is to potentiate the excitability of GABAergic granule cells and thereby modulate inhibitory drive onto mitral cells. This increase in granule cell excitability is mediated by a concomitant decrease in the normal afterhyperpolarization response and augmentation of an afterdepolarization, both triggered by pirenzepine-sensitive M1 receptors. The afterdepolarization was dependent on elevations in intracellular calcium and appeared to be mediated by a calcium-activated nonselective cation current (I(CAN)). Near firing threshold, depolarizing inputs could evoke quasipersistent firing characterized by irregular discharges that lasted, on average, for 2 min. In addition to regulating the excitability of the primary interneuronal subtype in the bulb, M1 receptors regulate the degree of adaptation that occurs during repetitive sniffing-like inputs and may therefore play a critical role in regulating short-term plasticity in the olfactory system.

PMID: 17928438 [PubMed - indexed for MEDLINE]

Friday 26 October 2007

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Conf Proc IEEE Eng Med Biol Soc. 2005;2:2134-7

Authors: Li X, Zhou W, Liu M, Luo Q

Spontaneous firing play an important role in development of neuronal network. Activity-dependent modification of synaptic efficacy is widely recognized as a cellular basis of learning, memory, and development plasticity. Little is known of the activity-dependent modification of the synchronized spontaneous firing of the hippocampal networks. Long-term recording of spontaneous activity in cultured hippocampal neuronal networks was carried out using substrates containing multi-electrode array (MEA). Spontaneous uncorrelated firing appeared within a week and transformed progressively into synchronized pattern. During the development, these synchronized firings became into oscillation pattern and the synchronization has little change. By paired stimulation from adjacent electrodes in the network, the synchronized firing form a larger network burst. These results suggest that synchronized spontaneous spikes show the development of neuronal network and electronical stimulation could change the development.

PMID: 17282651 [PubMed - in process]

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Conf Proc IEEE Eng Med Biol Soc. 2005;1:141-4

Authors: Suhail Y, Oweiss K

We describe multiresolution Bayesian tests for spike detection in multielectrode recordings. We derive results for single channel and multi electrode data, and show that the use of the array model substantially improves the detection performance. The effect of signal and noise spatial correlation characteristics is also discussed. Our approach focuses on blind signal detection without any assumptions about the underlying signal parameters. It is therefore suitable for chronic recordings with electrode arrays where typically temporal and spatial nonstationarity of the extracellular waveforms complicates the estimation of the true action potential.

PMID: 17282131 [PubMed - in process]

Modeling the Nonlinear Dynamic Interactions of the Lateral and the Medial Perforant Path of the Hippocampal Dentate Gyrus.

Modeling the Nonlinear Dynamic Interactions of the Lateral and the Medial Perforant Path of the Hippocampal Dentate Gyrus.

Conf Proc IEEE Eng Med Biol Soc. 2006;1:5539-5542

Authors: Dimoka A, Courellis SH, Marmarelis VZ, Berger TW

We present a new method to characterize the nonlinearities resulting from the co-activity of two pathways that converge on a common postsynaptic element. We investigated the nonlinear dynamic interactions between the lateral perforant pathway (LPP) and the medial perforant pathway (MPP) of the hippocampal dentate gyms, and the effects of these cross-pathway interactions on granule cell output. A third order Volterra-Poisson modeling approach was implemented to capture the interactions between the two pathways. The kernels presented pathway specific signatures as they capture the nonlinear dynamics of each pathway individually in the form of self-kernels, and the nonlinear interactions between the two pathways in the form of cross-kernels. Data were collected in-vitro from acute slices of adult rats via a multi-electrode array recording system. The stimuli were dual-site random impulse trains with Poisson distributed inter-impulse intervals. The recorded responses from the granule cells were population spikes, simplified as discrete impulses with variable amplitudes. Our results indicated that the third order nonlinear interactions between the LPP and the MPP needs to be included in the model in order to achieve adequate predictive accuracy and indicate that this approach can be generalized to complex interactions between distinct inputs to the same set of neurons.

PMID: 17946313 [PubMed - as supplied by publisher]

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Neuroimage. 2007 Sep 14;

Authors: Ciumas C, Lindström P, Bernard A, Savic I

PMID: 17951077 [PubMed - as supplied by publisher]

Rhythmic Spontaneous Activity in the Piriform Cortex.

Rhythmic Spontaneous Activity in the Piriform Cortex.

Cereb Cortex. 2007 Oct 8;

Authors: Sanchez-Vives MV, Descalzo VF, Reig R, Figueroa NA, Compte A, Gallego R

Slow spontaneous rhythmic activity is generated and propagates in neocortical slices when bathed in an artificial cerebrospinal fluid with ionic concentrations similar to the ones in vivo. This activity is extraordinarily similar to the activation of the cortex in physiological conditions (e.g., slow-wave sleep), thus representing a unique in vitro model to understand how cortical networks maintain and control ongoing activity. Here we have characterized the activity generated in the olfactory or piriform cortex and endopiriform nucleus (piriform network). Because these structures are prone to generate epileptic discharges, it seems critical to understand how they generate and regulate their physiological rhythmic activity. The piriform network gave rise to rhythmic spontaneous activity consisting of a succession of up and down states at an average frequency of 1.8 Hz, qualitatively similar to the corresponding neocortical activity. This activity originated in the deep layers of the piriform network, which displayed higher excitability and denser connectivity. A remarkable difference with neocortical activity was the speed of horizontal propagation (114 mm/s), one order of magnitude faster in the piriform network. Properties of the piriform cortex subserving fast horizontal propagation may underlie the higher vulnerability of this area to epileptic seizures.

PMID: 17925296 [PubMed - as supplied by publisher]

Neuromodulation by Glutamate and Acetylcholine can Change Circuit Dynamics by Regulating the Relative Influence of Afferent Input and Excitatory Feedback.

Neuromodulation by Glutamate and Acetylcholine can Change Circuit Dynamics by Regulating the Relative Influence of Afferent Input and Excitatory Feedback.

Mol Neurobiol. 2007 Oct;36(2):184-200

Authors: Giocomo LM, Hasselmo ME

Substances such as acetylcholine and glutamate act as both neurotransmitters and neuromodulators. As neuromodulators, they change neural information processing by regulating synaptic transmitter release, altering baseline membrane potential and spiking activity, and modifying long-term synaptic plasticity. Slice physiology research has demonstrated that many neuromodulators differentially modulate afferent, incoming information compared to intrinsic and recurrent processing in cortical structures such as piriform cortex, neocortex, and the hippocampus. The enhancement of afferent (external) pathways versus the suppression at recurrent (internal) pathways could cause cortical dynamics to switch between a predominant influence of external stimulation to a predominant influence of internal recall. Modulation of afferent versus intrinsic processing could contribute to the role of neuromodulators in regulating attention, learning, and memory effects in behavior.

PMID: 17952661 [PubMed - in process]

The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

Neuron. 2006 Aug 17;51(4):455-66

Authors: Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B

Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.

PMID: 16908411 [PubMed - indexed for MEDLINE]

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.

Neurosci Lett. 2007 Jan 3;411(1):11-6

Authors: Deshpande LS, Sombati S, Blair RE, Carter DS, Martin BR, DeLorenzo RJ

Status epilepticus (SE) is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 microM) or AM251 (1 microM) to "epileptic" neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges.

PMID: 17110038 [PubMed - indexed for MEDLINE]

Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

Med Hypotheses. 2007;68(4):920-1

Authors: Cortesi M, Fusar-Poli P

PMID: 17112679 [PubMed - indexed for MEDLINE]

Endocannabinoids block status epilepticus in cultured hippocampal neurons.

Endocannabinoids block status epilepticus in cultured hippocampal neurons.

Eur J Pharmacol. 2007 Mar 8;558(1-3):52-9

Authors: Deshpande LS, Blair RE, Ziobro JM, Sombati S, Martin BR, DeLorenzo RJ

Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg(2+) hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC(50) of 145+/-4.15 nM and 1.68+/-0.19 microM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB(1) receptor since they were blocked by the cannabinoid CB(1) receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus.

PMID: 17174949 [PubMed - indexed for MEDLINE]

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

J Neurosci. 2007 Jan 3;27(1):46-58

Authors: Chen K, Neu A, Howard AL, Földy C, Echegoyen J, Hilgenberg L, Smith M, Mackie K, Soltesz I

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

PMID: 17202471 [PubMed - indexed for MEDLINE]

Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus.

Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus.

Exp Neurol. 2007 Apr;204(2):705-13

Authors: Deshpande LS, Blair RE, Nagarkatti N, Sombati S, Martin BR, DeLorenzo RJ

Status epilepticus (SE) is a life-threatening neurological disorder associated with a significant morbidity and mortality. Benzodiazepines are the initial drugs of choice for the treatment of SE. Despite aggressive treatment, over 40% of SE cases are refractory to the initial treatment with two or more medications. It would be a major advance in the clinical management of SE to identify novel anticonvulsant agents that do not lose their ability to treat SE with increasing seizure duration. Cannabinoids have recently been demonstrated to regulate seizure activity in brain. However, it remains to be seen whether they develop pharmacoresistance upon prolonged SE. In this study, we used low Mg(2+) to induce SE in hippocampal neuronal cultures and in agreement with animal models and human SE confirm the development of resistance to benzodiazepine with increasing durations of SE. Thus, lorazepam (1 microM) was effective in blocking low Mg(2+) induced high-frequency spiking for up to 30 min into SE. However, by 1 h and 2 h of SE onset it was only 10-15% effective in suppressing SE. In contrast, the cannabinoid type-1 (CB1) receptor agonist, WIN 55,212-2 (1 microM) in a CB1 receptor-dependent manner completely abolished SE at all the time points tested even out to 2 h after SE onset, a condition where resistance developed to lorazepam. Thus, the use of cannabinoids in the treatment of SE may offer a unique approach to controlling SE without the development of pharmacoresistance observed with conventional treatments.

PMID: 17289026 [PubMed - indexed for MEDLINE]

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

Biochem Pharmacol. 2004 Nov 1;68(9):1691-8

Authors: Lutz B

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

PMID: 15450934 [PubMed - indexed for MEDLINE]

Altering cannabinoid signaling during development disrupts neuronal activity.

Altering cannabinoid signaling during development disrupts neuronal activity.

Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9388-93

Authors: Bernard C, Milh M, Morozov YM, Ben-Ari Y, Freund TF, Gozlan H

In adult cortical tissue, recruitment of GABAergic inhibition prevents the progression of synchronous population discharges to epileptic activity. However, at early developmental stages, GABA is excitatory and thus unable to fulfill this role. Here, we report that retrograde signaling involving endocannabinoids is responsible for the homeostatic control of synaptic transmission and the resulting network patterns in the immature hippocampus. Blockade of cannabinoid type 1 (CB1) receptor led to epileptic discharges, whereas overactivation of CB1 reduced network activity in vivo. Endocannabinoid signaling thus is able to keep population discharge patterns within a narrow physiological time window, balancing between epilepsy on one side and sparse activity on the other, which may result in impaired developmental plasticity. Disturbing this delicate balance during pregnancy in either direction, e.g., with marijuana as a CB1 agonist or with an antagonist marketed as an antiobesity drug, can have profound consequences for brain maturation even in human embryos.

PMID: 15964987 [PubMed - indexed for MEDLINE]

Alternative therapies for seizures: promises and dangers.

Alternative therapies for seizures: promises and dangers.

Semin Neurol. 2007 Sep;27(4):325-30

Authors: Sirven JI

Complementary and alternative medicine (CAM) is increasingly being used for a multitude of medical problems, one of them being seizures. This article discusses the prevalence of CAM use for seizures and epilepsy. Evidence-based data regarding CAM for epilepsy are presented as well as potential safety concerns regarding ephedra and cannabis use.

PMID: 17701869 [PubMed - in process]

[Therapeutic use of cannabinoids in neurology]

[Therapeutic use of cannabinoids in neurology]

Schmerz. 2003 Oct;17(5):367-73

Authors: Schwenkreis P, Tegenthoff M

This review gives insight into the potential therapeutical role of cannabinoids in neurology. Preclinical data are presented which could give a rationale for the clinical use of cannabinoids in the fields of multiple sclerosis, spasticity, epilepsy, movement disorders, and neuroprotection after traumatic head injury or ischemic stroke. Besides, clinical data (case reports, open-label and randomised controlled studies) dealing with the therapeutical use of cannabinoids in these fields are reported and discussed. At present, clinical data are insufficient to recommend the use of cannabinoids in any neurological disease as standard therapy. Several questions still have to be answered (which cannabinoid? which way of administration? stimulation of endogenous cannabinoids? separation between desired and undesired effects?), and controlled studies are still needed to clarify the potential therapeutical role of cannabinoids in neurology.

PMID: 14513344 [PubMed - indexed for MEDLINE]

Delta9-tetrahydrocannabinol and epilepsy in the photosensitive baboon, Papio papio.

Delta9-tetrahydrocannabinol and epilepsy in the photosensitive baboon, Papio papio.

Epilepsia. 1974 Jun;15(2):255-64

Authors: Meldrum BS, Fariello RG, Puil EA, Derouaux M, Naquet R

PMID: 4525183 [PubMed - indexed for MEDLINE]

Anticonvulsant effects of cannabinoids in mice: drug interactions within cannabinoids and cannabinoid interactions with phenytoin.

Anticonvulsant effects of cannabinoids in mice: drug interactions within cannabinoids and cannabinoid interactions with phenytoin.

Psychopharmacologia. 1974 Jul 11;37(3):255-64

Authors: Chesher GB, Jackson DM

PMID: 4850601 [PubMed - indexed for MEDLINE]

Letter: Cannabidiol and electroencephalographic epileptic activity.

Letter: Cannabidiol and electroencephalographic epileptic activity.

JAMA. 1974 Dec 23-30;230(12):1635

Authors: Perez-Reyes M, Wingfield M

PMID: 4612180 [PubMed - indexed for MEDLINE]

The pharmacology of the cannabinoid system-a question of efficacy and selectivity.

The pharmacology of the cannabinoid system-a question of efficacy and selectivity.

Mol Neurobiol. 2007 Aug;36(1):15-25

Authors: Fowler CJ

Our knowledge of the function of the cannabinoid system in the body has been aided by the availability of pharmacological agents that affect its function. This has been achieved by the design of agents that either directly interact with the receptor (agonists and antagonist/inverse agonists) and agents that indirectly modulate the receptor output by changing the levels of the endogenous cannabinoids (endocannabinoids). In this review, examples of the most commonly used receptor agonists, antagonists/inverse agonists, and indirectly acting agents (anandamide uptake inhibitors, fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors) are given, with particular focus upon their selectivity and, in the case of the directly acting compounds, efficacy. Finally, the links between the endocannabinoid and cyclooxygenase pathways are explored, in particular, with respect to agents whose primary function is to inhibit cyclooxygenase activity, but which also interact with the endocannabinoid system.

PMID: 17952646 [PubMed - in process]

Cannabinoid CB(2) Receptor-Mediated Anti-nociception in Models of Acute and Chronic Pain.

Cannabinoid CB(2) Receptor-Mediated Anti-nociception in Models of Acute and Chronic Pain.

Mol Neurobiol. 2007 Aug;36(1):26-35

Authors: Jhaveri MD, Sagar DR, Elmes SJ, Kendall DA, Chapman V

The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action.

PMID: 17952647 [PubMed - in process]

Cannabinoids and gliomas.

Cannabinoids and gliomas.

Mol Neurobiol. 2007 Aug;36(1):60-7

Authors: Velasco G, Carracedo A, Blázquez C, Lorente M, Aguado T, Haro A, Sánchez C, Galve-Roperh I, Guzmán M

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances-the endocannabinoids-that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

PMID: 17952650 [PubMed - in process]

The endocannabinoid system and Alzheimer's disease.

The endocannabinoid system and Alzheimer's disease.

Mol Neurobiol. 2007 Aug;36(1):75-81

Authors: Benito C, Núñez E, Pazos MR, Tolón RM, Romero J

The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB(1) type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB(2) cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer's disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.

PMID: 17952652 [PubMed - in process]

Cannabinoids in eating disorders and obesity.

Cannabinoids in eating disorders and obesity.

Mol Neurobiol. 2007 Aug;36(1):113-28

Authors: Arias Horcajadas F

Cannabinoid system is a crucial mechanism in regulating food intake and energy metabolism. It is involved in central and peripheral mechanisms regulating such behavior, interacting with many other signaling systems with a role in metabolic regulation. Cannabinoid agonists promote food intake, and soon a cannabinoid antagonist, rimonabant, will be marketed for the treatment of obesity. It not only causes weight loss, but also alleviates metabolic syndrome. We present a review of current knowledge on this subject, along with data from our own research: genetic studies on this system in eating disorders and obesity and studies locating cannabinoid receptors in areas related to food intake. Such studies suggest cannabinoid hyperactivity in obesity, and this excessive activity may have prognostic implications.

PMID: 17952656 [PubMed - in process]

Cannabinoid-based medicines for neurological disorders-clinical evidence.

Cannabinoid-based medicines for neurological disorders-clinical evidence.

Mol Neurobiol. 2007 Aug;36(1):129-36

Authors: Wright S

Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex(R) (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.

PMID: 17952657 [PubMed - in process]

Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.

Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.

J Neurochem. 2007 Oct 22;

Authors: Sáez-Cassanelli JL, Fontanella GH, Delgado-García JM, Carrión AM

Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the kappa-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a kappa-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.

PMID: 17953671 [PubMed - as supplied by publisher]

Expression and Function of CB(1) Receptor in the Rat Striatum: Localization and Effects on D(1) and D(2) Dopamine Receptor-Mediated Motor Behaviors.

Expression and Function of CB(1) Receptor in the Rat Striatum: Localization and Effects on D(1) and D(2) Dopamine Receptor-Mediated Motor Behaviors.

Neuropsychopharmacology. 2007 Oct 24;

Authors: Martín AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, Rodriguez de Fonseca F, Moratalla R

Cannabinoid CB(1) receptors are densely expressed on striatal projection neurons expressing dopamine D(1) or D(2) receptors. However, the specific neuronal distribution of CB(1) receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D(2) receptors, but it is not clear if endocannabinoids also modulate D(1) receptor-mediated motor behavior. In the present study, we show that cannabinoid CB(1) receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D(1) receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D(2) receptors. We explored the functional relevance of the interaction between dopamine D(1) and D(2) receptors and cannabinoid CB(1) receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D(1) receptor-mediated grooming and D(2) receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D(1) receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D(1) receptor-mediated behaviors in addition to its previously described effect on dopamine D(2) receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D(1) receptor knockout mice, demonstrating its dependence on D(1) receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D(1) and D(2) receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.Neuropsychopharmacology advance online publication, 24 October 2007; doi:10.1038/sj.npp.1301558.

PMID: 17957223 [PubMed - as supplied by publisher]

A neutral CB1 receptor antagonist reduces weight gain in rat.

A neutral CB1 receptor antagonist reduces weight gain in rat.

Am J Physiol Regul Integr Comp Physiol. 2007 Oct 24;

Authors: Chambers AP, Vemuri VK, Peng Y, Wood JT, Olzewska T, Pittman QJ, Makriyannis A, Sharkey KA

Cannabinoid (CB) 1 receptor inverse agonists inhibit food intake in animals and humans, but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain and emesis. Neutral antagonist and binding properties were confirmed in HEK293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80+/-0.44nM) in competitive binding assays with the CB1/2 agonist [(3)H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg kg(-1)) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg kg(-1)), a highly anorectic dose of AM4113 (10 mg kg(-1)) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans they could be developed into a new class of anti-obesity agents. Key words: Cannabinoid receptor, Food intake, inverse agonist, obesity, emesis.

PMID: 17959701 [PubMed - as supplied by publisher]

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Modulation of pain transmission by G-protein-coupled receptors.

Modulation of pain transmission by G-protein-coupled receptors.

Pharmacol Ther. 2007 Sep 22;

Authors: Pan HL, Wu ZZ, Zhou HY, Chen SR, Zhang HM, Li DP

The heterotrimeric G-protein-coupled receptors (GPCR) represent the largest and most diverse family of cell surface receptors and proteins. GPCR are widely distributed in the peripheral and central nervous systems and are one of the most important therapeutic targets in pain medicine. GPCR are present on the plasma membrane of neurons and their terminals along the nociceptive pathways and are closely associated with the modulation of pain transmission. GPCR that can produce analgesia upon activation include opioid, cannabinoid, alpha(2)-adrenergic, muscarinic acetylcholine, gamma-aminobutyric acid(B) (GABA(B)), groups II and III metabotropic glutamate, and somatostatin receptors. Recent studies have led to a better understanding of the role of these GPCR in the regulation of pain transmission. Here, we review the current knowledge about the cellular and molecular mechanisms that underlie the analgesic actions of GPCR agonists, with a focus on their effects on ion channels expressed on nociceptive sensory neurons and on synaptic transmission at the spinal cord level.

PMID: 17959251 [PubMed - as supplied by publisher]

Saturday 6 October 2007

Organotypic slice culture of the hypothalamic paraventricular nucleus of rat.

Organotypic slice culture of the hypothalamic paraventricular nucleus of rat.

J Vet Sci. 2007 Mar;8(1):15-20

Authors: Cho ES, Lee SY, Park JY, Hong SG, Ryu PD

Organotypic slice cultures have been developed as an alternative to acute brain slices because the neuronal viability and synaptic connectivity in these cultures can be preserved well for a prolonged period of time. This study evaluated a stationary organotypic slice culture developed for the hypothalamic paraventricular nucleus (PVN) of rat. The results showed that the slice cultures maintain the typical shape of the nucleus, the immunocytochemical signals for oxytocin, vasopressin, and corticotropin-releasing hormone, and the electrophysiological properties of PVN neurons for up to 3 weeks in vitro. The PVN neurons in the culture expressed the green fluorescent protein gene that had been delivered by the adenoviral vectors. The results indicate that the cultured slices preserve the properties of the PVN neurons, and can be used in longterm studies on these neurons in vitro.

PMID: 17322769 [PubMed - indexed for MEDLINE]

Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol.

Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol.

Neuropharmacology. 2005 Dec;49(8):1101-9

Authors: Verty AN, McGregor IS, Mallet PE

BACKGROUND/AIMS: The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB(1) cannabinoid receptors mediate food intake, it is not clear whether PVN CB(1) receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Delta(9)-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. METHODS: After being habituated to the test environment and injection procedure, sated rats were injected with SR 141716 (0.03-3.0 microg, Experiment 1) alone or in combination with THC (5.0 microg, Experiment 2) into the PVN. Food intake and locomotor activity then were recorded for 120 min. RESULTS: Intra-PVN administration of THC produced a significant increase in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB(1) receptors alone is insufficient to reduce baseline feeding behaviour under these conditions.

PMID: 16098995 [PubMed - indexed for MEDLINE]

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