CAN in nigra

A calcium-activated nonselective cation conductance underlies the plateau potential in rat substantia nigra GABAergic neurons.

Related Articles

A calcium-activated nonselective cation conductance underlies the plateau potential in rat substantia nigra GABAergic neurons.

J Neurosci. 2007 Jun 13;27(24):6531-41

Authors: Lee CR, Tepper JM

Plateau potentials can be elicited in nigral GABAergic neurons by injection of 500 ms depolarizing current pulses from hyperpolarized holding potentials in whole-cell recordings in vitro. In approximately one-third of these neurons, plateau potentials were observed under control conditions and could be elicited in the remaining neurons after blocking potassium conductances. Application of the L-type calcium channel agonist Bay K 8644 or activation of NMDA receptors enhanced plateau potentials observed under control conditions and caused a plateau to be elicited in neurons not exhibiting it previously. The plateau potential was abolished in calcium-free buffer, as well as by nickel or cadmium. The L-type calcium channel blockers nimodipine and nifedipine abolished the plateau potential observed under control conditions but did not affect plateaus unmasked by tetraethylammonium. Plateau potentials observed under control conditions as well as those observed in the presence of Bay K 8644, NMDA, or tetraethylammonium were abolished in low-sodium buffer and by the calcium-activated nonselective cation conductance blocker flufenamic acid. These data suggest that nigral plateau potentials are mediated by a calcium-activated nonselective cation conductance (I(CAN)) that is activated by calcium entry predominantly through L-type calcium channels. In many nigral neurons, I(CAN) is masked by tetraethylammonium-sensitive potassium conductances, but plateaus can be evoked after increasing calcium conductances. The I(CAN)-mediated plateau potential in nigral GABAergic neurons likely affects the way these neurons integrate input and may represent a mechanism contributing to the rhythmic firing of these neurons seen in pathological conditions such as Parkinson's disease.

PMID: 17567814 [PubMed - in process]

MEA and cultures - controlling bursting

Network dynamics and synchronous activity in cultured cortical neurons.

Related Articles

Network dynamics and synchronous activity in cultured cortical neurons.

Int J Neural Syst. 2007 Apr;17(2):87-103

Authors: Chiappalone M, Vato A, Berdondini L, Koudelka-Hep M, Martinoia S

Neurons extracted from specific areas of the Central Nervous System (CNS), such as the hippocampus, the cortex and the spinal cord, can be cultured in vitro and coupled with a micro-electrode array (MEA) for months. After a few days, neurons connect each other with functionally active synapses, forming a random network and displaying spontaneous electrophysiological activity. In spite of their simplified level of organization, they represent an useful framework to study general information processing properties and specific basic learning mechanisms in the nervous system. These experimental preparations show patterns of collective rhythmic activity characterized by burst and spike firing. The patterns of electrophysiological activity may change as a consequence of external stimulation (i.e., chemical and/or electrical inputs) and by partly modifying the "randomness" of the network architecture (i.e., confining neuronal sub-populations in clusters with micro-machined barriers). In particular we investigated how the spontaneous rhythmic and synchronous activity can be modulated or drastically changed by focal electrical stimulation, pharmacological manipulation and network segregation. Our results show that burst firing and global synchronization can be enhanced or reduced; and that the degree of synchronous activity in the network can be characterized by simple parameters such as cross-correlation on burst events.

PMID: 17565505 [PubMed - in process]

Cannabinoids and neuropathic pain

Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain.

Related Articles

Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain.

Eur J Pharmacol. 2007 May 22;

Authors: Guindon J, Desroches J, Dani M, Beaulieu P

The antinociceptive effects of WIN55,212-2, a synthetic cannabinoid, were evaluated in the model of partial sciatic nerve ligation after daily subcutaneous administration of 0.1 mg/kg a week before and two weeks after surgery. Mechanical allodynia and thermal hyperalgesia were evaluated in 46 rats allocated to receive: (1) Vehicle (before surgery)-Vehicle (after surgery); (2) Vehicle-WIN55,212-2; (3) WIN55,212-2-Vehicle; (4) WIN55,212-2-WIN55,212-2; (5) AM251+vehicle; (6) AM251+WIN55,212-2; (7) AM630+vehicle; (8) AM630+WIN55,212-2; (9) Sham receiving vehicle; and (10) Sham receiving WIN55,212-2. The decreased in mechanical allodynia and thermal hyperalgesia by WIN55,212-2 was significantly greater when it was administered during one week before surgery. In conclusion, pre-emptive use of cannabinoids produced greater antinociceptive effects in a model of neuropathic pain and this effect is mediated by cannabinoid CB(1) and CB(2) receptors.

PMID: 17555742 [PubMed - as supplied by publisher]

New cannabinoid ligands

Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors.

Related Articles

Design, synthesis, binding, and molecular modeling studies of new potent ligands of cannabinoid receptors.

Bioorg Med Chem. 2007 May 31;

Authors: Brizzi A, Cascio MG, Brizzi V, Bisogno T, Dinatolo MT, Martinelli A, Tuccinardi T, Di Marzo V

In our ongoing program aimed at the design, synthesis, and biological evaluation of novel cannabinoid receptor ligands derived from olivetol and hexyl-resorcinol, we have designed a structural model for new derivatives on the basis of a previous study. Here we report the synthesis, binding, and molecular modeling studies of new potent compounds with high affinity toward CB(1) and CB(2) receptors. Compounds with amidic 'heads' with alkyloxy chains varying in length from 8 to 12 carbon atoms showed nanomolar affinity for both receptors, depending on the type of aromatic backbone. Two of the new compounds, although not very potent, exhibit selectivity for CB(1) receptors (CB(1)/CB(2)=0.07 and 0.08, respectively). Molecular modeling studies fitted this new class of cannabinoid ligands into a CB(1) receptor model, and the qualitative analysis of the results was in general agreement with the CB(1) affinity constants observed experimentally for these derivatives.

PMID: 17561406 [PubMed - as supplied by publisher]

Cannabinoids and taste

Role of cortical cannabinoid CB1 receptor in conditioned taste aversion memory.

Related Articles

Role of cortical cannabinoid CB1 receptor in conditioned taste aversion memory.

Eur J Neurosci. 2007 Jun;25(11):3417-21

Authors: Kobilo T, Hazvi S, Dudai Y

The brain endocannabinoid system has been shown to play a role in memory, though the extent to which this role generalizes over different types and processes of memory is not yet determined. Here we show that the cannabinoid receptor 1 (CB1) plays differential roles in acquisition, extinction and reconsolidation of conditioned taste aversion (CTA) memory in the rat insular cortex, which contains the taste cortex. Activation of the CB1 receptor in the insular cortex inhibits acquisition and reconsolidation but not extinction, whereas blockade of the CB1 receptor promotes memory and blocks extinction of CTA, while having no apparent effect on reconsolidation. The CB1 ligands used in this study were incapable of substituting the unconditioned stimulus in CTA training. All in all, the data raise the possibility that the state of activity of the CB1 receptor in the insular cortex contributes to the encoding of hedonic valence that enters into association with taste items.

PMID: 17553010 [PubMed - in process]

OB and PC innervation

Changes in the connections of the main olfactory bulb after mitral cell selective neurodegeneration.

Related Articles

Changes in the connections of the main olfactory bulb after mitral cell selective neurodegeneration.

J Neurosci Res. 2007 Jun 5;

Authors: Recio JS, Weruaga E, Gómez C, Valero J, Briñón JG, Alonso JR

The connections of the main olfactory bulb (OB) of the mouse were studied with iontophoretic injections of biotinylated dextran amine. To sort efferences from mitral cells and tufted cells, the Purkinje cell degeneration (PCD) mouse was used. This mutant animal undergoes a specific neurodegeneration of mitral cells, whereas tufted cells do not degenerate. The unilateral tracer injections used were small and confined largely to the OB of both PCD and control mice at P120. Seven days after tracer injection, the efferences from the OB and the centrifugal afferences from secondary olfactory structures to it were studied. Although there is a large overlap of their target fields, mitral cell axons innervated more caudal regions of the olfactory cortex than tufted cell axons, thus providing definitive evidence of the differential projections of olfactory output neurons. Additionally, an important increase in retrogradely-labeled neurons was detected in the ipsilateral anterior olfactory nucleus of the mutant animals. This was not observed in any other secondary olfactory structure, suggesting a strengthening of the centrifugal input to the OB from that central area after mitral cell loss. Moreover, we recorded a complete loss of bilaterality in the olfactory connections of the PCD mice due to degeneration of the anterior commissure. These results point to an important reorganization of this essential olfactory circuit between the anterior olfactory nucleus and the OB, and hint at a transsynaptic level of plasticity not considered previously in literature. (c) 2007 Wiley-Liss, Inc.

PMID: 17551987 [PubMed - as supplied by publisher]

Adenosine, kindling and PC

The role of adenosine A(1) and A(2A) receptors of entorhinal cortex on piriform cortex kindled seizures in rats.

Related Articles

The role of adenosine A(1) and A(2A) receptors of entorhinal cortex on piriform cortex kindled seizures in rats.

Pharmacol Res. 2007 May 1;

Authors: Hosseinmardi N, Mirnajafi-Zadeh J, Fathollahi Y, Shahabi P

In this research the role of adenosine A(1) and A(2A) receptors of the entorhinal cortex on piriform cortex kindled seizures was investigated. In piriform cortex kindled rats, N(6)-cyclohexyladenosine (CHA), a selective A(1) receptor agonist, 1,3-dimethyl-8 cyclopenthylxanthine (CPT), a selective A(1) receptor antagonist, CGS21680 hydrochloride (CGS), a selective A(2A) receptor agonist and ZM241385 (ZM), a selective A(2A) receptor antagonist were injected into the entorhinal cortex bilaterally. Five minutes later, animals were stimulated and seizure parameters were recorded. CHA (10 and 100muM) decreased the afterdischarge duration (ADD), stage 5 seizure duration (S5D), and seizure duration (SD), and increased the latency to stage 4 of the seizure (S4L) significantly. Bilateral microinjection of CPT (100muM) increased ADD, S(5)D, and SD, and reduced S(4)L significantly. Pretreatment of animals with CPT (50muM) before CHA (100muM), reduced the effect of CHA on seizure parameters. On the other hand, CGS (1mM) increased only ADD. Bilateral microinjection of ZM had no effect on seizure parameters. However, pretreatment of animals with ZM (200muM) before CGS (1mM), eliminated the excitatory effect of CGS on seizure parameters. These results suggest that activation of A(1) receptors of the entorhinal cortex has an anticonvulsant, but activation of A(2A) receptors of this region has a proconvulsive effect on piriform cortex kindled seizures.

PMID: 17548208 [PubMed - as supplied by publisher]

Zn and Cav2.3

Z2+ sensitivity of high- and low-voltage activated calcium channels.

Related Articles

Z2+ sensitivity of high- and low-voltage activated calcium channels.

Biophys J. 2007 May 25;

Authors: Sun HS, Hui K, Lee DW, Feng ZP

The essential cation zinc (Z(2+)) blocks voltage-dependent calcium channels (VDCCs) in several cell types, which exhibit different sensitivities to Z(2+). The specificity of the Z(2+) effect on VDCC subtypes has not been systematically investigated. In this study, we used a transient protein expression system to determine the Z(2+) effect on low- and high-voltage activated channels. We found that in Ba(2+), the IC50 value of Z(2+) was alpha1 subunit-dependent with lowest for CaV1.2, and highest for CaV3.1; the sensitivity of the channels to Z(2+) was approximately ranked as CaV1.2 > CaV3.2 > CaV2.3 > CaV2.2 = CaV 2.1 >/= CaV3.3 = CaV3.1. Although the CaV2.2 and CaV3.1 channels had similar IC50 for Zn(2+) in Ba(2+), the CaV2.2, but not CaV3.1 channels, had ~10 fold higher IC50 to Zn(2+) in Ca(2+). The reduced sensitivity of CaV2.2 channels to Zn(2+) in Ca(2+) was partially reversed by disrupting a putative EF-hand motif located external to the selectivity filter EEEE locus. Thus, our findings support the notion that the Zn(2+) block, mediated by multiple mechanisms, may depend on conformational changes surrounding the alpha1 pore regions. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of zinc on various Ca(2+) channel subtypes.

PMID: 17526568 [PubMed - as supplied by publisher]

Cerebellum plasticity

Linking synaptic plasticity and spike output at excitatory and inhibitory synapses onto cerebellar Purkinje cells.

Related Articles

Linking synaptic plasticity and spike output at excitatory and inhibitory synapses onto cerebellar Purkinje cells.

J Neurosci. 2007 May 23;27(21):5559-70

Authors: Mittmann W, Häusser M

Understanding the relationship between synaptic plasticity and neuronal output is essential if we are to understand how plasticity is encoded in neural circuits. In the cerebellar cortex, motor learning is thought to be implemented by long-term depression (LTD) of excitatory parallel fiber (PF) to Purkinje cell synapses triggered by climbing fiber (CF) input. However, theories of motor learning generally neglect the contribution of plasticity of inhibitory inputs to Purkinje cells. Here we describe how CF-induced plasticity of both excitatory and inhibitory inputs is reflected in Purkinje cell spike output. We show that coactivation of the CF with PF input and interneuron input leads not only to LTD of PF synapses but also to comparable, "balanced" LTD of evoked inhibitory inputs. These two forms of plasticity have opposite effects on the spike output of Purkinje cells, with the number and timing of spikes sensitively reflecting the degree of plasticity. We used dynamic clamp to evaluate plasticity-induced changes in spike responses to sequences of excitation and feedforward inhibition of varied relative and absolute amplitude. Balanced LTD of both excitatory and inhibitory components decreased the net spike output of Purkinje cells only for inputs with small inhibitory components, whereas for inputs with a larger proportion of feedforward inhibition CF-triggered LTD resulted in an increase in the net spike output. Thus, the net effect of CF-triggered plasticity on Purkinje cell output depends on the balance of excitation and feedforward inhibition and can paradoxically increase cerebellar output, contrary to current theories of cerebellar motor learning.

PMID: 17522301 [PubMed - in process]

Neuronal correlations with hyperphagia and cannabinoids

Cannabinoid-induced hyperphagia: Correlation with inhibition of proopiomelanocortin neurons?

Related Articles

Cannabinoid-induced hyperphagia: Correlation with inhibition of proopiomelanocortin neurons?

Physiol Behav. 2007 Apr 29;

Authors: Ho J, Cox JM, Wagner EJ

We tested the hypothesis that cannabinoids modulate feeding in male guinea pigs, and correlated cannabinoid-induced changes in feeding behavior with alterations in glutamatergic synaptic currents impinging upon proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. Feeding experiments were performed as follows: after a three-day acclimation period, animals were weighed and injected with either the CB1 receptor agonist WIN 55,212-2 (1 mg/kg, s.c.), antagonist AM251 (3 mg/kg, s.c.) or their cremophore/ethanol/saline vehicle (1:1:18; 1 ml/kg, s.c.) each day for seven days. WIN 55,212-2 increased, whereas AM251 decreased, the rate of cumulative food intake. The agonist effect was manifest primarily by increases in meal frequency and the amount of food eaten per meal. By contrast, the antagonist effect was associated with decreases in meal frequency, duration and weight loss. For the electrophysiological experiments, we performed whole-cell patch-clamp recordings from POMC neurons in hypothalamic slices. WIN 55,212-2 decreased the amplitude of evoked, glutamatergic excitatory postsynaptic currents (eEPSCs) and increased the S2:S1 ratio. Conversely, AM251 increased eEPSC amplitude per se, and blocked the inhibitory effects of the agonist. WIN 55,212-2 also decreased miniature EPSC (mEPSC) frequency; whereas AM251 increased mEPSC frequency per se, and again blocked the inhibitory effect of the agonist. A subpopulation of cells exhibited an agonist-induced outward current, which was blocked by AM251, associated with increased conductance and reversed polarity near the Nernst equilibrium potential for K(+). These data demonstrate that cannabinoids regulate appetite in the guinea pig in part through both presynaptic and postsynaptic actions on anorexigenic POMC neurons.

PMID: 17532014 [PubMed - as supplied by publisher]

CB1 and spike timing

Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity.

Related Articles

Coactivation of pre- and postsynaptic signaling mechanisms determines cell-specific spike-timing-dependent plasticity.

Neuron. 2007 Apr 19;54(2):291-301

Authors: Tzounopoulos T, Rubio ME, Keen JE, Trussell LO

Synapses may undergo long-term increases or decreases in synaptic strength dependent on critical differences in the timing between pre-and postsynaptic activity. Such spike-timing-dependent plasticity (STDP) follows rules that govern how patterns of neural activity induce changes in synaptic strength. Synaptic plasticity in the dorsal cochlear nucleus (DCN) follows Hebbian and anti-Hebbian patterns in a cell-specific manner. Here we show that these opposing responses to synaptic activity result from differential expression of two signaling pathways. Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling underlies Hebbian postsynaptic LTP in principal cells. By contrast, in interneurons, a temporally precise anti-Hebbian synaptic spike-timing rule results from the combined effects of postsynaptic CaMKII-dependent LTP and endocannabinoid-dependent presynaptic LTD. Cell specificity in the circuit arises from selective targeting of presynaptic CB1 receptors in different axonal terminals. Hence, pre- and postsynaptic sites of expression determine both the sign and timing requirements of long-term plasticity in interneurons.

PMID: 17442249 [PubMed - indexed for MEDLINE]