Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids.

Potentiation of electrical and chemical synaptic transmission mediated by endocannabinoids.

Neuron. 2007 Dec 20;56(6):1034-47

Authors: Cachope R, Mackie K, Triller A, O'Brien J, Pereda AE

Endocannabinoids are well established as inhibitors of chemical synaptic transmission via presynaptic activation of the cannabinoid type 1 receptor (CB(1)R). Contrasting this notion, we show that dendritic release of endocannabinoids mediates potentiation of synaptic transmission at mixed (electrical and chemical) synaptic contacts on the goldfish Mauthner cell. Remarkably, the observed enhancement was not restricted to the glutamatergic component of the synaptic response but also included a parallel increase in electrical transmission. This effect involved the activation of CB(1) receptors and was indirectly mediated via the release of dopamine from nearby varicosities, which in turn led to potentiation of the synaptic response via a cAMP-dependent protein kinase-mediated postsynaptic mechanism. Thus, endocannabinoid release can potentiate synaptic transmission, and its functional roles include the regulation of gap junction-mediated electrical synapses. Similar interactions between endocannabinoid and dopaminergic systems may be widespread and potentially relevant for the motor and rewarding effects of cannabis derivatives.

PMID: 18093525 [PubMed - in process]

Prolonged CNS hyperexcitability in mice after a single exposure to delta-9-tetrahydrocannabinol.

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Prolonged CNS hyperexcitability in mice after a single exposure to delta-9-tetrahydrocannabinol.

Neuropharmacology. 1986 Apr;25(4):441-6

Authors: Karler R, Calder LD, Turkanis SA

A single exposure to delta-9-tetrahydrocannabinol (THC) resulted in a "rebound" hyperexcitability in the CNS in mice, which was assessed in terms of the susceptibility of the CNS to electrically-induced convulsions. The magnitude of the hyperexcitability was dose-related (25-150 mg/kg, i.p.), as measured 24 hr after treatment. The time-course study of the effect indicated a peak-effect at 24 hr after administration of the drug, with a duration of the effect for as long as 196 hr. The time course of the rebound hyperexcitability to THC was compared to that for phenobarbital, which peaked at 48 hr after administration of the drug and returned to the control value by 96 hr. Tolerance developed rapidly to the motor-toxic effect of THC, but after 23 days of daily treatment there was no evidence of tolerance to the rebound hyperexcitability. The functional significance of the hyperexcitable state was assessed in two tests; electrical kindling to minimal convulsions was enhanced, even when the kindling procedure was initiated 120 hr after exposure to the drug; and the anticonvulsant activity of phenytoin was blocked when mice were treated with the anticonvulsant 96 hr after a single exposure to THC. The results suggest that the rebound response from a single exposure to THC represents a functionally significant prolonged increase in excitability of the CNS.

PMID: 3012403 [PubMed - indexed for MEDLINE]

Different cannabinoids exhibit different pharmacological and toxicological properties.

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Different cannabinoids exhibit different pharmacological and toxicological properties.

NIDA Res Monogr. 1987;79:96-107

Authors: Karler R, Turkanis SA

PMID: 3125482 [PubMed - indexed for MEDLINE]

Structure-anticonvulsant activity relationships of cannabidiol analogs.

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Structure-anticonvulsant activity relationships of cannabidiol analogs.

NIDA Res Monogr. 1987;79:48-58

Authors: Martin AR, Consroe P, Kane VV, Shah V, Singh V, Lander N, Mechoulam R, Srebnik M

Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.

PMID: 3125480 [PubMed - indexed for MEDLINE]

Anticonvulsant and neurotoxic effects of tetrahydrocannabinol stereoisomers.

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Anticonvulsant and neurotoxic effects of tetrahydrocannabinol stereoisomers.

NIDA Res Monogr. 1987;79:59-66

Authors: Consroe P, Mechoulam R

Enantiomers of delta-6-tetrahydrocannabinol (THC), delta-6-THC-1'', 1''-dimethylheptyl (DMHP), and 7-OH-delta-6-THC-1'',1''-DMHP were assessed for their ability to block audiogenic seizures in genetically epilepsy-prone rats. The stereoisomers were evaluated also for their ability to produce differential neurotoxicity in the rat rotorod (ROT) paradigm. Potency comparisons among the compounds revealed modest to profound stereoselectivity for anticonvulsant and neurotoxic activities, a general increase in both activities with the DMHP and 7-OH modifications of delta-6-THC, and some favorable separation between anticonvulsant and neurotoxic activities with selected THC analogs.

PMID: 2830538 [PubMed - indexed for MEDLINE]

Marijuana use and the risk of new onset seizures.

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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]

The autism-epilepsy connection.

The autism-epilepsy connection.

Epilepsia. 2007;48 Suppl 9:33-5

Authors: Levisohn PM

The high prevalence of epilepsy in children with autism supports a neurobiologic etiology for autism. It remains unclear whether seizures and epileptiform activity on the EEG are causative or comorbid. It is also uncertain if focal epileptiform EEG abnormalities may be associated with stable cognitive impairment. Even less clear is whether these EEG abnormalities can result in the combination of language and social dysfunction seen in autistic spectrum disorders.

PMID: 18047599 [PubMed - in process]

Effect of different patterns of low-frequency stimulation on piriform cortex kindled seizures.

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Effect of different patterns of low-frequency stimulation on piriform cortex kindled seizures.

Neurosci Lett. 2007 Oct 2;425(3):162-6

Authors: Ghorbani P, Mohammad-Zadeh M, Mirnajafi-Zadeh J, Fathollahi Y

Low-frequency stimulation (LFS) is an antiepileptic and antiepileptogenic electrical stimulation. In this study the effect of changes in some LFS (1Hz, monophasic square wave) parameters (intensity, pulse duration and train duration) on piriform cortex kindled seizures was investigated both in fully kindled rats and during kindling acquisition. In fully kindled animals, application of different patterns of LFS immediately before kindling stimulation had no significant effect on seizure parameters. However, daily (15 min) application of LFS (0.1 ms pulse duration at intensity equal to after-discharge threshold (ADT) and 1 ms pulse duration at intensity equal to 1/4 ADT) during inter-seizure interval of 7 days significantly reduced the stage 5 duration of the next kindled seizure. Application of the same two LFS protocols for 3 days and 2 weeks had no effect on seizure parameters. The effect of LFS was also tested using different paradigms during kindling acquisition. When LFS (0.1 and 1 ms pulse duration, intensity equal to ADT and 1/4 ADT) was delivered daily after each kindling stimulation, it could significantly decrease after-discharge duration in various days during kindling development. In this experiment, only LFS with 0.1 ms pulse duration and intensity equal to ADT significantly delayed the appearance of seizure stages 1 and 2. According to obtained results, it may be concluded that in fully kindled rats application of different patterns of LFS before kindling stimulation has no anticonvulsant effect, but it can exert an inhibitory effect when applied during an inter-seizure interval of 7 days. In addition, LFS has antiepileptogenic effect during kindling acquisition. These effects depend on the applied LFS parameters (e.g. intensity, pulse duration and train duration).

PMID: 17868994 [PubMed - indexed for MEDLINE]

A Novel Role for Extracellular Signal-Regulated Kinase in Maintaining Long-Term Memory-Relevant Excitability Changes.

A Novel Role for Extracellular Signal-Regulated Kinase in Maintaining Long-Term Memory-Relevant Excitability Changes.

J Neurosci. 2007 Nov 14;27(46):12584-12589

Authors: Cohen-Matsliah SI, Brosh I, Rosenblum K, Barkai E

Pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats show enhanced intrinsic neuronal excitability that lasts for several days after learning. Such enhanced intrinsic excitability is mediated by long-term reduction in the postburst afterhyperpolarization (AHP), which is generated by repetitive spike firing. AHP reduction is attributable to decreased conductance of a calcium-dependent potassium current, the sI(AHP). We have previously shown that such learning-induced AHP reduction is maintained by PKC activation. However, the molecular machinery underlying such long-lasting modulation of intrinsic excitability is yet to be fully described. Here we examine whether the extracellular signal-regulated kinase I/II (ERKI/II) pathway, which is known to be crucial in learning, memory, and synaptic plasticity processes, is instrumental for the long-term maintenance of learning-induced AHP reduction. PD98059 or UO126, which selectively block MEK, the upstream kinase of ERK, increased the AHP in neurons from trained rats but not in neurons from naive and pseudo-trained rats. Consequently, the differences in AHP amplitude and neuronal adaptation between neurons from trained rats and controls were abolished. This effect was not mediated by modulation of basic membrane properties. In accordance with its effect on neuronal excitability, the level of activated ERK in the membranal fraction was significantly higher in piriform cortex samples taken from trained rats. In addition, the PKC activator OAG (1-oleoyl-20acety-sn-glycerol), which was shown to reduce the AHP in neurons from control rats, had no effect on these neurons in the presence of PD98059. Our data show that ERK has a key role in maintaining long-lasting learning-induced enhancement of neuronal excitability.

PMID: 18003837 [PubMed - as supplied by publisher]

Cellular and subcellular localization of Kir2.1 subunits in neurons and glia in piriform cortex with implications for K(+) spatial buffering.

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Cellular and subcellular localization of Kir2.1 subunits in neurons and glia in piriform cortex with implications for K(+) spatial buffering.

J Comp Neurol. 2007 Dec 12;506(5):877-893

Authors: Howe MW, Feig SL, Osting SM, Haberly LB

Potassium channels of the Kir2 family are widely expressed in neurons and glia, where they form strong inwardly rectifying channels. Existing functional hypotheses for these channels in neurons are based on the weak outward conductance, whereas the leading hypothesis for glia, that they promote potassium spatial buffering, is based on inward conductance. Although the spatial buffering hypothesis has been confirmed for Müller glia in retina, many aspects of Kir2 channels that will be required for understanding their functional roles in neurons and other forms of glia have received little or no study. Particularly striking is the paucity of data regarding their cellular and subcellular localization. We address this gap for Kir2.1-containing channels by using light and electron microscopic immunocytochemistry. The analysis was of piriform cortex, a highly epileptogenic area of cerebral cortex, where pyramidal cells have K(+)-selective strong inward rectification like that observed in Müller cells, where Kir2.1 is the dominant Kir2 subunit. Pyramidal cells in adult piriform cortex also lack I(h), the mixed Na(+)-K(+) current that mediates a slower form of strong inward rectification in large pyramidal cells in neocortex and hippocampus. The experiments demonstrated surface expression of Kir2.1-containing channels in astrocytes and in multiple populations of pyramidal and nonpyramidal cells. Findings for astrocytes were not consistent with predictions for K(+) spatial buffering over substantial distance. However, findings for pyramidal cells suggest that they could be a conduit for spatially buffering K(+) when it is highly elevated during seizure. J. Comp. Neurol. 506:877-893, 2008. (c) 2007 Wiley-Liss, Inc.

PMID: 18076085 [PubMed - as supplied by publisher]