Biomedical subjects

J C Pineda

Publications and source records attributed to J C Pineda.

8 recordsLinked to original sources

PubMed2005

Dopamine prevents muscarinic-induced decrease of glutamate release in the auditory cortex.

Acetylcholine and dopamine are simultaneously released in the cortex at the occurrence of novel stimuli. In addition to a series of excitatory effects, acetylcholine decreases the release of glutamate acting on presynaptic muscarinic receptors. By recording evoked excitatory postsynaptic currents in layers II/III neurons of the auditory cortex, we found that activation of muscarinic receptors by oxotremorine reduces the amplitude of glutamatergic current (A(oxo)/A(ctr) = 0.53 +/- 0.17) in the absence but not in the presence of dopamine (A(oxo)/A(ctr) = 0.89 +/- 0.12 in 20 microM dopamine). These data suggested that an excessive sensitivity to dopamine, such as postulated in schizophrenia, could prevent the decrease of glutamate release associated with the activation of cholinergic corticopetal nuclei. Thus, a possible mechanism of action of antipsychotic drugs could be through a depression of the glutamatergic signal in the auditory cortex. We tested the capability of haloperidol, clozapine and lamotrigine to affect glutamatergic synaptic currents and their muscarinic modulation. We found that antipsychotics not only work as dopamine receptor antagonists in re-establishing muscarinic modulation, but also directly depress glutamatergic currents. These results suggest that presynaptic modulation of glutamate release can account for a dual route of action of antipsychotic drugs.

Animals↗

PubMed2001

High-affinity inhibition of glutamate release from corticostriatal synapses by omega-agatoxin TK.

To know which Ca(2+) channel type is the most important for neurotransmitter release at corticostriatal synapses of the rat, we tested Ca(2+) channel antagonists on the paired pulse ratio. omega-Agatoxin TK was the most effective Ca(2+) channel antagonist (IC(50)=127 nM; maximal effect=211% (with >1 microM) and Hill coefficient=1.2), suggesting a single site of action and a Q-type channel profile. Corresponding parameters for Cd(2+) were 13 microM, 178% and 1.2. The block of L-type Ca(2+) channels had little impact on transmission, but we also tested facilitation of L-type Ca(2+) channels. The L-type Ca(2+) channel agonist, s-(-)-1,4 dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine carboxylic acid methyl ester (Bay K 8644 (5 microM)), produced a 45% reduction of the paired pulse ratio, suggesting that even if L-type channels do not participate in the release process, they may participate in its modulation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1999

Different Ca2+ source for slow AHP in completely adapting and repetitive firing pyramidal neurons.

Intracellular recordings in an in vitro neocortical slice preparation from immature rats were used to investigate the Ca2 source for slow afterhyperpolarization (sAHP) generation in pyramidal neurons that exhibit complete spike frequency adaptation (CA neurons). In pyramidal neurons that maintain repetitive firing for long periods of time (RF neurons), N-, P- and Q-type Ca2+ channels supply Ca2+ for sAHP generation. In CA neurons, the sAHP was reduced by only 50% by the combination of antagonists for these Ca2+ channel types and L-type channels. Ryanodine and dantrolene, blockers of Ca2(+)-induced Ca2+ release, reduced the sAHP by approximately 45% in CA neurons, but caused no reduction of the sAHP in RF neurons. Dantrolene application caused CA neurons to fire throughout a 1s suprathreshold current injection (as do RF neurons).

Action Potentials↗

PubMed1999

Ca2+-activated outward currents in neostriatal neurons.

Whole-cell voltage-clamp recordings of outward currents were obtained from acutely dissociated neurons of the rat neostriatum in conditions in which inward Ca2+ current was not blocked and intracellular Ca2+ concentration was lightly buffered. Na+ currents were blocked with tetrodotoxin. In this situation, about 53 +/- 4% (mean +/- S.E.M.; n = 18) of the outward current evoked by a depolarization to 0 mV was sensitive to 400 microM Cd2+. A similar percentage was sensitive to high concentrations of intracellular chelators or to extracellular Ca2+ reduction (<500 microM); 35+/-4% (n=25) of the outward current was sensitive to 3.0 mM 4-aminopyridine. Most of the remaining current was blocked by 10 mM tetraethylammonium. The results suggest that about half of the outward current is activated by Ca2+ entry in the present conditions. The peptidic toxins charybdotoxin, iberotoxin and apamin confirmed these results, since 34 +/- 5% (n = 14), 29 5% (n= 14) and 28 +/- 6% (n=9) of the outward current was blocked by these peptides, respectively. The effects of charybdotoxin and iberotoxin added to that of apamin, but their effects largely occluded each other. There was additional Cd2+ block after the effect of any combination of toxins. Therefore, it is concluded that Ca2+-activated outward currents in neostriatal neurons comprise several components, including small and large conductance types. In addition, the present experiments demonstrate that Ca2+-activated K+ currents are a very important component of the outward current activated by depolarization in neostriatal neurons.

4-Aminopyridine↗

PubMed1998

Specificity in the interaction of HVA Ca2+ channel types with Ca2+-dependent AHPs and firing behavior in neocortical pyramidal neurons.

Intracellular recordings and organic and inorganic Ca2+ channel blockers were used in a neocortical brain slice preparation to test whether high-voltage-activated (HVA) Ca2+ channels are differentially coupled to Ca2+-dependent afterhyperpolarizations (AHPs) in sensorimotor neocortical pyramidal neurons. For the most part, spike repolarization was not Ca2+ dependent in these cells, although the final phase of repolarization (after the fast AHP) was sensitive to block of N-type current. Between 30 and 60% of the medium afterhyperpolarization (mAHP) and between approximately 80 and 90% of the slow AHP (sAHP) were Ca2+ dependent. Based on the effects of specific organic Ca2+ channel blockers (dihydropyridines, omega-conotoxin GVIA, omega-agatoxin IVA, and omega-conotoxin MVIIC), the sAHP is coupled to N-, P-, and Q-type currents. P-type currents were coupled to the mAHP. L-type current was not involved in the generation of either AHP but (with other HVA currents) contributes to the inward currents that regulate interspike intervals during repetitive firing. These data suggest different functional consequences for modulation of Ca2+ current subtypes.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Muscarinic receptors modulate the afterhyperpolarizing potential in neostriatal neurons.

The actions of carbachol were studied on the firing response of neostriatal neurons recorded intracellularly from in vitro slice preparations of the rat brain. Carbachol (1-10 microM) reversibly reduced the afterhyperpolarization in neostriatal neurons. This effect was accompanied by an increase in both firing frequency and input resistance in the subthreshold voltage range. Atropine (1-10 microM) reversibly blocked carbachol effects, suggesting muscarinic receptor modulation. Pirenzepine (up to 1 microM), but not AF-DX 384 (10 microM) or gallamine (30 microM), blocked the effects of carbachol on the afterhyperpolarization. The protein kinase C activator, phorbol 12,13 dibutyrate, but not the inactive phorbol ester, 4 alpha-phorbol 12-myristate 13-acetate, mimicked carbachol effects. The results suggest that muscarinic receptors, probably of the M1 type, regulate neostriatal excitability by modulating afterhyperpolarization.

Action Potentials↗

PubMed1994

Patterns of excitatory and inhibitory synaptic transmission in the rat neostriatum as revealed by 4-AP.

1. Synaptic potentials induced by 4-aminopyridine (4-AP) were recorded intracellularly from rat neostriatal neurons in an in vitro slice preparation. EC50 for this 4-AP action was approximately 120 microM. The threshold for activation of synaptic potentials was 5 microM. 2. 4-AP-induced synaptic potentials appeared stochastically. Most were blocked by 1 microM tetrodotoxin or 400 microM Cd2+. Therefore they reflect a release of neurotransmitters dependent on both Ca2+ entry to the terminals and action potential firing. 3. Bicuculline (BIC) (< or = 10 microM), a gamma-aminobuturic acid-A (GABAA) antagonist, blocked about half of the 4-AP-induced synaptic potentials. This suggests that intrinsic inhibitory connections within the neostriatum are activated by 4-AP administration. 4. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; < or = 10 microM) plus D-2-amino-5-phosphonovaleric acid (D-APV; < or = 100 microM) blocked most of the BIC-resistant 4-AP-induced synaptic potentials. This suggests that 4-AP induced release of glutamate (GLU) from extrinsic glutamatergic afferents. As most glutamatergic afferents are extrinsic, these afferents then would be able to fire spikes and release transmitter for several hours after they are cut from their somata. 5. If CNQX plus D-APV were administered before BIC, neostriatal neurons responded in different ways. In one half of the neurons, all induced synaptic potentials were blocked. This suggests that most GABAergic intrinsic connections between neostriatal neurons are activated indirectly by 4-AP. 4-AP would first activate extrinsic glutamatergic afferents and these in turn would activate GABAergic intrinsic neurons and connections. 6. In the remaining half of the recorded neurons, administration of CNQX plus D-APV blocked most, but not all of the 4-AP-induced synaptic potentials. The synaptic potentials that remained had a characteristic pattern: they were high amplitude, rhythmic, bursts of synaptic potentials. They were blocked by BIC (5 microM) but not by mecamylamine (> 10 microM). This suggests that these bursts of synaptic potentials were GABAergic and generated by intrinsic neurons. Therefore these neurons would not innervate all neostriatal neurons equally but just a subset of them. 7. Records from an identified aspiny neostriatal interneuron, obtained from the same preparation, are shown. This interneuron fired in bursts and its morphologically and physiologically similar to the recently described, fast spiking, parvalbumin immunoreactive, GABAergic, aspiny interneuron is functional in the slice preparation.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗

PubMed1992

Charybdotoxin and apamin sensitivity of the calcium-dependent repolarization and the afterhyperpolarization in neostriatal neurons.

1. Intracellular recordings from neostriatal neurons in an in vitro slice preparation of the rat brain were used to analyze the pharmacological sensitivity of the action potential (AP) repolarization and the afterhyperpolarization (AHP) that follows a single action potential. The interspike voltage trajectory and the AHP could be divided into two main parts: a fast component lasting a few milliseconds and better observed during a train of spikes, and a slow component lasting approximately 250 ms and that comprises the main portion of the AHP. In some cells, a slow (up to 1 s) component of low amplitude was also detected. 2. Single APs were elicited at two imposed membrane potentials (around -60 and around -80 mV). The AP amplitude was larger, the repolarization rate was faster, and the duration was shorter when spikes were evoked at -80 mV. When measured from the -60 mV holding potential, the afterpotential was an AHP with peak amplitude of -5 mV. The afterpotential became a delayed depolarization (DD) at -80 mV. 3. Firing frequency adaptation was voltage sensitive. The firing of APs induced by long intracellular current pulses from a holding potential of -80 mV exhibited only a slow-frequency adaptation (time constant of seconds). However, at -60 mV, an initial and faster frequency adaptation was evident (time constant of tens of milliseconds). 4. The Ca2+ channel blocker Cd2+ retarded AP repolarization rate. This effect correlated with a significant block of the fast and slow components of the AHP. In contrast, Ni2+ had no significant effects on the same parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗