Biomedical subjects

J Bargas

Publications and source records attributed to J Bargas.

At least 19 recordsLinked to original sources

PubMed2003

Spontaneous voltage oscillations in striatal projection neurons in a rat corticostriatal slice.

In a rat corticostriatal slice, brief, suprathreshold, repetitive cortical stimulation evoked long-lasting plateau potentials in neostriatal neurons. Plateau potentials were often followed by spontaneous voltage transitions between two preferred membrane potentials. While the induction of plateau potentials was disrupted by non-NMDA and NMDA glutamate receptor antagonists, the maintenance of spontaneous voltage transitions was only blocked by NMDA receptor and L-type Ca2+ channel antagonists. The frequency and duration of depolarized events, resembling up-states described in vivo, were increased by NMDA and L-type Ca2+ channel agonists as well as by GABAA receptor and K+ channel antagonists. NMDA created a region of negative slope conductance and a positive slope crossing indicative of membrane bistability in the current-voltage relationship. NMDA-induced bistability was partially blocked by L-type Ca2+ channel antagonists. Although evoked by synaptic stimulation, plateau potentials and voltage oscillations could not be evoked by somatic current injection--suggesting a dendritic origin. These data show that NMDA and L-type Ca2+ conductances of spiny neurons are capable of rendering them bistable. This may help to support prolonged depolarizations and voltage oscillations under certain conditions.

2-Amino-5-phosphonovalerate↗

PubMed2002

Paired pulse facilitation is turned into paired pulse depression in hippocampal slices after epilepsy induced by 4-aminopyridine in vivo.

Modifications in synaptic plasticity seem to play a key role in the origin and persistence of epilepsy. 4-Aminopyridine (4-AP) induces intense and long lasting epileptic seizures and neurodegeneration when applied into the hippocampus in vivo, effects that seem to be mediated by overactivation of glutamate receptors due to the enhancement of glutamate release from nerve endings. We have studied presynaptic modifications of CA1 responses, using the paired pulse paradigm, in hippocampal slices obtained from 4-AP-treated rats killed during epileptic activity (ex vivo). The paired pulse facilitation (PPF) observed in control slices with interstimulus intervals of 10-30 ms was changed into paired pulse depression (PPD) after 100 microM 4-AP added in vitro. A strikingly similar change was observed in the ex vivo slices even though 4-AP was no longer present in the tissue. We conclude that the facilitation of glutamate release induced by 4-AP becomes chronic after a transient exposure to the drug. This suggests that the facilitated neurotransmitter release induced by 4-AP triggers a more permanent plastic change that may be responsible for the persistence of epilepsy.

4-Aminopyridine↗

PubMed2002

Somatostatin modulates Ca2+ currents in neostriatal neurons.

Somatostatin is synthesized and released by aspiny interneurons of the neostriatum. This work investigates the actions of somatostatin on rat neostriatal neurons of medium size (ca. 6 pF). Somatostatin (1 microM) reduces both calcium action potentials (20 mM tetraethylammonium) by ca. 24% and calcium currents by ca. 35%, in all cells tested. This action was produced in the presence of tetrodotoxin and in dissociated cells and was blocked by cyclo(-7-aminoheptanoyl-phe-d-try-lys-O-benzyl-thr) acetate (CPP-1), a somatostatin receptor antagonist. Except for nitrendipine (5 microM), several calcium channel antagonists, 1 microM omega-conotoxin GVIA, 400 nM omega-agatoxin TK, and 1 microM omega-conotoxin MVIIC, partially occluded somatostatin action. According to the calcium channel types known to be blocked by these antagonists, P/Q-type channels appeared to be the channels mainly modulated by somatostatin, followed by N-type channels. Since these channel types generate the afterhyperpolarizing potential in spiny neurons, we investigated the action of somatostatin on this event. Somatostatin reduces the amplitude of the afterhyperpolarizing potential by ca. 39%. This action is occluded by omega-agatoxin TK and omega-conotoxin MVIIC but not by omega-conotoxin GVIA or nicardipine. Thus, the action of somatostatin on the afterhyperpolarizing potential is mainly mediated by P/Q-type calcium channels. The block of the slow afterhyperpolarizing potential made most neurons exhibit an irregular firing mode, suggesting that ion currents other than calcium may also be affected by somatostatin. We conclude that somatostatin exerts a direct postsynaptic effect on neostriatal neurons via the activation of somatostatin receptors. This action affects non-L-type calcium channels and therefore modifies the afterhyperpolarizing potential and the firing pattern. It is proposed that somatostatin and its analogues may have profound effects on the motor functions controlled by the basal ganglia.

Action Potentials↗

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↗

PubMed2001

Modeling functions of striatal dopamine modulation in learning and planning.

The activity of midbrain dopamine neurons is strikingly similar to the reward prediction error of temporal difference reinforcement learning models. Experimental evidence and simulation studies suggest that dopamine neuron activity serves as an effective reinforcement signal for learning of sensorimotor associations in striatal matrisomes. In the current study, we simulate dopamine neuron activity with the extended temporal difference model of Pavlovian learning and examine the influences of this signal on medium spiny neurons in striatal matrisomes. The modeled influences include transient membrane effects of dopamine D(1) receptor activation, dopamine-dependent long-term adaptations of corticostriatal transmission, and effects of dopamine on rhythmic fluctuations of the membrane potential between an elevated "up-state" and a hyperpolarized "down-state". The most dominant activity in the striatal matrisomes is assumed to elicit behaviors via projections from the basal ganglia to the thalamus and the cortex. This "standard model" performs successfully when tested for sensorimotor learning and goal-directed behavior (planning). To investigate the contributions of our model assumptions to learning and planning, we test the performance of several model variants that lack one of these mechanisms. These simulations show that the adaptation of the dopamine-like signal is necessary for sensorimotor learning and planning. Sensorimotor learning requires dopamine-dependent long-term adaptation of corticostriatal transmission. Lack of dopamine-like novelty responses decreases the number of exploratory acts, which impairs planning capabilities. The model loses its planning capabilities if the dopamine-like signal is simulated with the original temporal difference model, because the original temporal difference model does not form novel associative chains. Transient membrane effects of the dopamine-like signal on striatal firing substantially shorten the reaction time in the planning task. The capability for planning is improved by influences of dopamine on the durations of membrane potential fluctuations and by manipulations that prolong the reaction time of the model. These results suggest that responses of dopamine neurons to conditioned stimuli contribute to sensorimotor reward learning, novelty responses of dopamine neurons stimulate exploration, and transient dopamine membrane effects are important for planning.

Animals↗

PubMed2001

Hippocampal hyperexcitability induced by GABA withdrawal is due to down-regulation of GABA(A) receptors.

The sudden interruption of an intracortical instillation of exogenous gamma-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABA(A) receptor agonists. This work reports a quantitative analysis of GW-induced hyperexcitability produced in the hippocampus in vitro. GW produced a left-ward displacement of the input/output (I/O) function, suggesting that the postsynaptic component is predominant to explain the hyperexcitability. A decrease in the inhibitory efficacy of the GABA(A) receptor agonist, muscimol, confirmed that inhibition was impaired. Binding saturation experiments demonstrated a decrease in [(3)H]-muscimol binding after GABA withdrawal showing a close correlation with the development of hyperexcitability. All these modifications coursed without changes in receptor affinity (K(D)) for muscimol or bicuculline as demonstrated by both binding studies and Schild analysis. It is concluded that, in the CA1 region of the hippocampus, it is the number of functional GABA(A) receptors, and not the affinity of the receptor, what is decreased during GW-induced hyperexcitability.

Animals↗

PubMed2000

D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade.

In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.

Action Potentials↗

PubMed2000

GABAergic presynaptic inhibition of rat neostriatal afferents is mediated by Q-type Ca(2+) channels.

Population spikes associated with the paired pulse facilitation paradigm have been successfully used to measure presynaptic inhibition in several systems. In the present work, this paradigm was used to evaluate the action of baclofen on neostriatal glutamatergic transmission. Baclofen enhanced synaptic facilitation with an EC(50)=0.57 microM and a maximal effect of 457%. Selective antagonists for N-, P- and Q-type Ca(2+)-channels enhanced paired pulse facilitation; suggesting that these channel types participate in the release of transmitter. Nevertheless, neither 1 microM omega-conotoxin GVIA, nor 20 nM omega-agatoxinTK occluded the action of baclofen. Baclofen's action was occluded only by 400 nM omega-agatoxinTK. These data suggest that Q-type Ca(2+)-channels mediate gamma-aminobutyric acid(B) presynaptic inhibition of neostriatal afferents.

Animals↗

PubMed2000

Ca2+ channels that activate Ca2+-dependent K+ currents in neostriatal neurons.

It is demonstrated that not all voltage-gated calcium channel types expressed in neostriatal projection neurons (L, N, P, Q and R) contribute equally to the activation of calcium-dependent potassium currents. Previous work made clear that different calcium channel types contribute with a similar amount of current to whole-cell calcium current in neostriatal neurons. It has also been shown that spiny neurons possess both "big" and "small" types of calcium-dependent potassium currents and that activation of such currents relies on calcium entry through voltage-gated calcium channels. In the present work it was investigated whether all calcium channel types equally activate calcium-dependent potassium currents. Thus, the action of organic calcium channel antagonists was investigated on the calcium-activated outward current. Transient potassium currents were reduced by 4-aminopyridine and sodium currents were blocked by tetrodotoxin. It was found that neither 30 nM omega-Agatoxin-TK, a blocker of P-type channels, nor 200 nM calciseptine or 5 microM nitrendipine, blockers of L-type channels, were able to significantly reduce the outward current. In contrast, 400 nM omega-Agatoxin-TK, which at this concentration is able to block Q-type channels, and 1 microM omega-Conotoxin GVIA, a blocker of N-type channels, both reduced outward current by about 50%. These antagonists given together, or 500 nM omega-Conotoxin MVIIC, a blocker of N- and P/Q-type channels, reduced outward current by 70%. In addition, the N- and P/Q-type channel blockers preferentially reduce the afterhyperpolarization recorded intracellularly. The results show that calcium-dependent potassium channels in neostriatal neurons are preferentially activated by calcium entry through N- and Q-type channels in these conditions.

Animals↗

PubMed2000

Neocortical hyperexcitability after GABA withdrawal in vitro.

The sharp interruption of the intracortical instillation of exogenous gamma-aminobutyric acid (GABA), generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal last several days or weeks. The present work reports that GABA withdrawal-induced hyperexcitability can be produced in vitro: a sudden withdrawal of GABA (5 mM; 120 min) or benzodiazepine (60 microM flunitrazepam) from the superfusion, induced a gradual increase in the amplitude of the evoked population spike (PS) recorded on neocortical slices. PS enhancement reached 150% above the control value 2.5 h after GABA withdrawal. GABA withdrawal-induced hyperexcitability was facilitated by progesterone. PS enhancement induced by GABA withdrawal was associated with an impairment of GABA transmission occurring before epileptiform discharges were fully established. Paired pulse inhibition and evoked [3H]-GABA release appear decreased; suggesting that cortical hyperexcitability as a result of GABA withdrawal involves pre-synaptic changes. Specific muscimol binding decreased during GABA superfusion but recovered after GABA withdrawal. However, the sensitivity of the post-synaptic response to 3alpha-OH-5alpha-pregnan-20-one or allopregnanolone (alloP) was enhanced after GABA withdrawal, suggesting a functional change in the GABA(A) receptors. The changes described may be the cellular correlates of the withdrawal syndromes appearing after interruption of the administration of GABA(A) receptor agonists.

Animals↗

PubMed1999

Muscarinic presynaptic inhibition of neostriatal glutamatergic afferents is mediated by Q-type Ca2+ channels.

Cholinergic presynaptic inhibition was investigated on neostriatal glutamatergic transmission. Paired pulse facilitation (PPF) of orthodromic population spikes (PS) were used to construct a concentration-response relationship for muscarine on presynaptic inhibition. Muscarine had an effect proportional to its extracellular concentration with an EC50 (mean +/- standard estimation error) of: 2.5 +/- 1.5 nM, and a maximal effect (saturation) of 245 +/- 16%. Several peptidic toxins against some voltage-gated Ca2+-channels increased PPF indicating that the Ca2+-channels they block participate in transmitter release. However, neither 1 microM omega-conotoxin GVIA, a specific blocker of N-type Ca2+-channels, nor 10-30 nM omega-agatoxinTK, a selective blocker of P-type Ca2+-channels, were able to occlude muscarine's effect on presynaptic inhibition. Nevertheless, 100-400 nM omega-agatoxinTK occluded muscarine's action on PPF in a dose-dependent manner. These results are consistent with Q-type Ca2+-channels mediating muscarinic presynaptic inhibition of neostriatal afferents.

Afferent Pathways↗

PubMed1999

Cholinergic modulation of neostriatal output: a functional antagonism between different types of muscarinic receptors.

It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits.

Acetylcholine↗

PubMed1999

Action of substance P (neurokinin-1) receptor activation on rat neostriatal projection neurons.

Substance P (SP) acts as a neurotransmitter in the neostriatum through the axon collaterals of spiny projection neurons. However, possible direct or indirect actions of SP on the neostriatal output neurons have not been described. Targets of SP terminals within the neostriatum include interneurons, spiny neurons, afferent fibers and boutons. SP induces the release of both dopamine (DA) and acetylcholine (ACh). Since some postsynaptic actions of both DA and ACh on spiny neurons are known, we asked if activation of neostriatal NK1-class receptors is able to reproduce them. The SP NK1-receptor agonist, GR73632 (1 microM), had both excitatory and inhibitory actions on virtually all spiny neurons tested at resting potential. The excitatory action was blocked by atropine and coursed with an increase in firing rate and input resistance (R(N)). The inhibitory action was blocked by haloperidol and coursed with a reduction in firing rate and R(N). Therefore, the release of both DA and ACh induced by NK1-receptor activation modulates indirectly the excitability of the projection neurons. SP facilitates the actions of these transmitters on the spiny neuron. A residual excitatory response to the NK1-receptor agonist was observed in 30% of a sample of neurons tested in the presence of both haloperidol and atropine. The increase in R(N) that accompanied this response could be observed in the presence of 1 microM TTX or 100 microM Cd2+, suggesting a direct effect. Double labeling showed that only SP-immunoreactive neurons were facilitated by NK1-receptor activation in these conditions.

Animals↗

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

Effects of NaCl removal on osmolyte fluxes and regulatory volume decrease in cultured astrocytes.

Cultured cerebellar astrocytes exhibit regulatory volume decrease (RVD) after anisosmotic swelling by extrusion of potassium (K), chloride (Cl), and organic osmolytes. The volume decay curve after swelling in 50% hyposmotic solutions has a first-order rate constant k min(-1) of 0.18 and 70% cell volume recovery is attained after 15 min. Replacing NaCl in the hyposmotic medium by sugars and polyalcohols markedly accelerated RVD increasing k to 0.37-0.39 min(-1) and full recovery in 3-5 min. NaCl removal increased (80%) K efflux (measured as 86Rb), delayed the inactivation of Cl efflux (measured as 125I) and enhanced taurine and D-aspartate release by 25%. These effects appear due to NaCl removal rather than to specific actions of the organic molecules. Replacing Na by other cations or Cl by gluconate increased k to 0.22 min(-1) and 0.26 min(-1), respectively, and 86Rb efflux by 4-23% and 39, respectively. It is concluded that the electrochemical gradient after NaCl removal increasing the K driving force, delaying the equilibrium of Cl and increasing amino acid efflux, accounts for the observed RVD acceleration. Other consequences of NaCl removal possibly modulating the K efflux pathway include changes in the surface charge screening, decreased ion strength, a rise in [Ca]i and a decrease in intracellular Na.

Amino Acids↗

PubMed1998

Ca2+-channels involved in neostriatal glutamatergic transmission.

The actions of peptidic toxins that work as Ca2+-channel antagonists were investigated on neostriatal glutamatergic transmission. Both intracellularly recorded excitatory postsynaptic potentials (EPSPs) and extracellularly recorded population spikes (PS) evoked by afferent stimulation were evaluated in the presence of 10 microM bicuculline. Percentage of block (mean +/- SEM; n = 4) for these events (EPSP and PS, respectively) was: omega-AgTxIVA (100-200 nM): 35 +/- 2 and 54 +/- 4%; omega-CgTxGVIA (1 microM): 37 +/- 3 and 63 +/- 6%; omega-CgTxMVIIC (500 nM): 40 +/- 4 and 50 +/- 2%; and calciseptine (500 nM): 5 +/- 4 and 9 +/- 6%. When given together, toxins had additive effects. The calciseptine effects were nonsignificant. The toxins were also tested on Ca2+-dependent random synaptic responses induced by 100 microM 4-AP. Each toxin reduced the frequency of spontaneous EPSPs by more than 60% (n = 2). The summed actions of individual toxins yields more than 100% block (superadditivity); suggesting that several terminals may possess more than one channel type. The reduction in frequency was not accompanied by a reduction in amplitude confirming that toxins' actions were presynaptic. It is concluded that at least three different Ca2+-channel subtypes are involved in glutamate release in neostriatal afferents: N-type, P/Q-type, and a type resistant to the toxins used. The L-type Ca2+-channel had little, if any, participation.

4-Aminopyridine↗

PubMed1998

Passive properties of neostriatal neurons during potassium conductance blockade.

Voltage recordings from neostriatal projection neurons were obtained using in vitro intracellular techniques before and during K+-conductance blockade. Neurons were stained with the biocytin technique. Somatic surface area (AS) was determined by both whole-cell recordings in isolated somata and by measuring stained somata recorded in slices. Dendritic measurements were done in reconstructed neurons. Average determinations of dendritic (AD) and neuronal (AN) surface areas coincided with previously reported anatomical data. Thus: As approximately 6.5 x 10(-6) cm2; AD approximately 1.9 x 10(-4) cm2; AN approximately AD + AS approximately 2 x 10(-4) cm2; AD/AS approximately 30. Measurements were done before and after superfusion with K+-conductance blockers (K+-blockers). Cells whose neuronal morphology was not obviously distorted by K+-blockade were chosen for the present study. Electrotonic transients were matched to a somatic shunt equivalent cylinder model adjusted with the generalized correction factor (Fdga) that constrains the parameters for neuronal anatomy. Neuronal input resistance (RN; mean +/- SEM) increased when it was corrected for somatic shunt, from 49 +/- 2 Momega (n = 80) to 179 +/- 7 Momega (n = 32). A difference was also obtained between the slowest time constant, tau0 = 16 +/- 0.9 ms (n = 49), and the dendritic membrane time constant, taumD = 33 +/- 1.6 ms (n = 36). When these electrophysiological measurements were used to calculate AN, the value obtained was similar to the anatomical measurements. Combining anatomical and electrophysiological data, somatic and dendritic input resistances were determined: RD = 182 +/- 7 Momega; Rs (with shunt) = 74 +/- 4 Momega (n = 32). The generalized correction factor, Fdga = 0.91 +/- 0.007 (n = 10), implied a short effective electrotonic length for dendrites: LD = 0.46 +/- 0.014 (n = 32). Saturating concentrations of the K+-blockers tetraethylammonium, Cs+, and Ba2+ increased RN and induced charging curves well fitted by single exponential functions in 56% of neostriatal neurons. Ba2+ greatly decreased the somatic shunt (n = 5): (RN = 216 +/- 21 Momega, tau0 = 46 +/- 2 ms, RD = 239 +/- 25 Momega, and RS = 3.2 +/- 0.5 Gomega), rendering values similar to those obtained with whole-cell recordings (e.g., RN approximately 198 Momega, RS approximately 2.62 Gomega) (n = 52). Cs+ (n = 5) had less effect on the somatic shunt (RN = 115 +/- 19 Momega, tau0 = 49 +/- 13 ms, RS = 161 +/- 8 Momega), although dendritic conductance was equally blocked (RD = 261 +/- 16 Momega). The Cs+-sensitive conductance exhibited inward rectifying properties not displayed by the Ba2+-sensitive conductance, suggesting that Cs+ preferentially acted upon inward rectifier conductances. In contrast, Ba2+ significantly acted upon linear conductances making up the somatic shunt. This suggests a differential action of different K+-blockers on the somato-dendritic membrane, implying a differential distribution of membrane conductances. Another action of K+-blockers, in about 40% of the cells, was to induce dye and probably electrical coupling between neighboring neurons.

Animals↗

PubMed1998

3-Alpha-chloro-imperialine, a potent blocker of cholinergic presynaptic modulation of glutamatergic afferents in the rat neostriatum.

Cortico-thalamic glutamatergic afferents control neuronal activity in the neostriatum. Cholinergic interneurons modulate the activity of medium spiny neurons through both pre- and post-synaptic actions via the activation of muscarinic receptors. The muscarinic pre-synaptic modulation was analyzed electrophysiologically. The transmitter release, induced by 4-AP, was studied and the block of paired pulse facilitation (PPF) by different muscarinic receptor antagonists was analyzed. The GABA(A) antagonist bicuculline isolated the glutamatergic transmission. Muscarinic agonists decreased the frequency of random synaptic potentials induced by 4-AP in about 60% of the cases without changes in input resistance (RN) of the post-synaptic neuron or in the mean amplitude of the synaptic events; indicating a presynaptic action. The administration of both 1 microM carbachol or 20 nM muscarine increased PPF. Muscarinic receptor antagonists blocked this action with a potency order: 3-alpha-chloroimperialine > 4-DAMP>>AFDX-116 > or = gallamine >> pirenzepine. The IC50's for the first three antagonists were (nM): 0.65, 1.1, and 3.0. Their respective Hill coefficients were: 1.9, 1.4, and 1.3. 3-alpha-Chloroimperialine reduced the PPF almost completely. The M3 and the M2 muscarinic receptor antagonists 4-DAMP and AFDX-116, given at saturating concentrations, consistently blocked only a part of the PPF but had additive effects when given together. These data are consistent with the existence of both M2 and M3 muscarinic receptors in striatal glutamatergic afferents.

4-Aminopyridine↗