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PubMed2004

Long-term characterization of firing dynamics of spontaneous bursts in cultured neural networks.

Extracellular action potentials were recorded from developing dissociated rat neocortical networks continuously for up to 49 days in vitro using planar multielectrode arrays. Spontaneous neuronal activity emerged toward the end of the first week in vitro and from then on exhibited periods of elevated firing rates, lasting for a few days up to weeks, which were largely uncorrelated among different recording sites. On a time scale of seconds to minutes, network activity typically displayed an ongoing repetition of distinctive firing patterns, including short episodes of synchronous firing at many sites (network bursts). Network bursts were highly variable in their individual spatio-temporal firing patterns but showed a remarkably stable underlying probabilistic structure (obtained by summing consecutive bursts) on a time scale of hours. On still longer time scales, network bursts evolved gradually, with a significant broadening (to about 2 s) in the third week in vitro, followed by a drastic shortening after about one month in vitro. Bursts at this age were characterized by highly synchronized onsets reaching peak firing levels within less than ca. 60 ms. This pattern persisted for the rest of the culture period. Throughout the recording period, active sites showed highly persistent temporal relationships within network bursts. These longitudinal recordings of network firing have, thus, brought to light a reproducible pattern of complex changes in spontaneous firing dynamics of bursts during the development of isolated cortical neurons into synaptically interconnected networks.

Action Potentials↗

PubMed1998

Anemone toxin (ATX II)-induced increase in persistent sodium current: effects on the firing properties of rat neocortical pyramidal neurones.

1. The experiments were performed on sensorimotor cortex using current-clamp intracellular recordings in layer V pyramidal neurones and whole-cell voltage-clamp recordings in dissociated pyramidal neurones. The intracellularly recorded neurones were classified on the basis of their firing characteristics as intrinsically bursting (IB) and regular spiking (RS). The RS neurones were further subdivided into adapting (RSAD) or non-adapting (RSNA), depending on the presence or absence of spike frequency adaptation. Since burst firing in neocortical pyramidal neurones has previously been suggested to depend on the persistent fraction of Na+ current (INa, p), pharmacological manipulations with drugs affecting INa inactivation have been employed. 2. ATX II, a toxin derived from Anemonia sulcata, selectively inhibited INa fast inactivation in dissociated neurones. In current-clamp experiments on neocortical slices, ATX II enhanced the naturally occurring burst firing in IB neurones and revealed the ability of RSNA neurones to discharge in bursts, whereas in RSAD neurones it increased firing frequency, without inducing burst discharges. During the ATX II effect, in all the three neuronal subclasses, episodes of a metastable condition occurred, characterized by long-lasting depolarizing shifts, triggered by action potentials, which were attributed to a peak in the toxin-induced inhibition of INa inactivation. The ATX II effect on IB and RSNA neurones was compared with that induced by veratridine and iodoacetamide. Veratridine induced a small increase in the INa and a large shift to the left in the voltage dependence of INa activation. Accordingly, its major effect on firing characteristics was the induction of prolonged tonic discharges, associated with burst facilitation less pronounced than that induced by ATX II. The alkylating agent iodoacetamide was able to induce a selective small increase in the INa,p, with a similar but less pronounced effect than ATX II on firing behaviour. 3. The present results show that pharmacological manipulations capable of slowing down INa inactivation significantly enhance burst behaviour in IB neurones and promote burst firing in otherwise non-bursting RSNA neurones. We suggest that IB and, to a lesser extent, RSNA neurones are endowed with a relatively large fraction of INa,p which, in physiological conditions, is sufficient to sustain bursting in IB but not in RSNA neurones.

Alkylating Agents↗

PubMed1998

Ensemble firing of muscle afferents recorded during normal locomotion in cats.

1. The main purpose of this study was to collate population data on the firing characteristics of muscle afferents recorded chronically during normal stepping in cats. 2. Ensemble firing profiles of forty-seven muscle spindle and tendon organ afferents were compiled from stored data. The relationships between the firing profiles and the displacement and force signals were analysed with the help of mathematical models of the response characteristics of spindle primary and secondary afferents and tendon organs. 3. Whereas the firing of hamstring spindle afferents could be predicted with reasonable accuracy from the length and velocity signals alone, the firing profiles of triceps surae spindle afferents deviated from the predicted profiles, particularly during electromyogram (EMG) activity. This indicated that the components of fusimotor action linked to extrafusal muscle activity were significant in triceps surae, possibly because this muscle is more strongly recruited in the cat step cycle. 4. From the limited data available, it was not possible to identify the 'best' or most general mathematical function to predict spindle secondary firing. In the two triceps surae spindle secondary units studied, firing was well predicted by using the simplest possible model, rate proportional to displacement, whereas in the hamstring spindle secondary data, a more complex linear transfer function was needed. The results of modelling the spindle secondary data were consistent with a modest amount of phasic, static fusimotor action linked to EMG activity. 5. The averaged ensemble of tendon organ afferent activity from the triceps surae gave predictions of whole-muscle force that agreed well with separate triceps force measurements in normal cat locomotion. This supports the idea that ensembles of tendon organ afferents signal whole-muscle force. 6. Our overall conclusion is that to a first approximation, large muscle afferents in the cat hindlimb signal muscle velocity, muscle length and muscle force, at least in movements of the speed and amplitude seen in locomotion.

Animals↗

PubMed2004

Two different Ca2+-dependent inhibitory mechanisms of spontaneous firing by glutamate in dopamine neurons.

The excitatory neurotransmitter, glutamate, generates a characteristic burst-pause type of firing in midbrain dopamine neurons in association with the reward behavior, but the cellular mechanism by which glutamate generates these bursts is unknown. Here, we show that the bursts in spontaneously firing dopamine neurons can be generated by the combinative actions of the brief stimulatory and the subsequent Ca(2+)-dependent inhibitory signals in response to glutamate stimulation. The two Ca(2+)-dependent firing-extinction signals are activated by different glutamate receptors. Although the activation of metabotropic glutamate receptors rapidly stopped the enhanced firing through the Ca(2+) release from intracellular stores, the activation of NMDA and AMPA/kainate receptors abolished the firing immediately after termination of the stimulation due to the Ca(2+) accumulation in the cell. These two Ca(2+)-dependent inhibitory mechanisms appear to participate in the generation of characteristic bursts in dopamine neurons by controlling the maximum firing number of single bursts and the duration of post-firing pauses.

Action Potentials↗

PubMed2006

Analysis of a soldered wire burnt in a fire.

Fire investigators frequently encounter electrical wires with melted ends at fire scenes, which can provide useful information on the cause and development of the fire even when the melted ends result from the fires. A bead on a melted end of a wire was found in the area of origin of a massive fire that lasted for nearly a whole day, devastating a factory. The bead appeared to be the end of a wire soldered to a terminal. X-ray analysis showed that the bead is a tin-copper alloy. Although regular tin-lead solder was used in the factory, lead was not detected. This contradictory result stood in the way of fire investigation. Therefore, an unused wire soldered with tin-lead solder was heated in an electric furnace at 500 degrees C for 3 h for further examination. X-ray analysis of this wire showed that copper can be alloyed with tin while losing lead in a long-term heat in a fire.

Journal Article↗

PubMed1989

Bistable firing properties of soleus motor units in unrestrained rats.

EMG recordings from single motor units in the soleus muscle were performed in alert unrestrained rats. A cuff electrode around the tibial nerve and subcutaneously placed electrodes in the foot permitted stimulation of afferent fibres. The movements of the rat and the simultaneous EMG activity were displayed together on a video monitor. Most motor units were tonically active for extended periods during quiet standing. During tonic discharge, maintained shifts between stable low (8-12 Hz; quartiles) and high (16-22.8 Hz) frequency ranges were initiated by short-lasting synaptic excitation of the motoneuron pool by stimulation of Ia afferents, or inhibition by stimulation of skin afferents. The shifts were not related to gross limb movements. This phenomenon is referred to as a bistable firing pattern. Bistable firing also occurred spontaneously during quiet standing. Typically the firing frequency shifted between a low (9-12.5 Hz) and a high (20-24.5 Hz) mode. During recordings of simultaneous activity in two units, spontaneous and stimulus-induced frequency jumps causing maintained changes in firing frequency were regularly seen to occur in one unit, while the frequency in the second unit was unchanged or only phasically influenced. These results demonstrate for the first time a bistable firing pattern during postural activity in the intact animal. The firing pattern closely resembles the bistable behaviour described in spinal motoneurons in reduced preparations, where it is due to the presence of a plateau potential. This suggests that the bistable firing is unexplained by plateau potentials also in the intact animal.

Action Potentials↗

PubMed1968

Firing patterns of gastrocnemius motor units in the decerebrate cat.

1. The patterns of medial gastrocnemius (MG) motor unit firing in response to MG muscle stretch have been studied in decerebrate cats, using intracellular recording techniques. In most of the units, the motoneurone axonal conduction velocity and cell input resistance were measured, and the maximum amplitude and wave form of the group Ia composite EPSP evoked by MG nerve stimulation were determined. The mechanical properties of the muscle unit portion of each motor unit were also studied.2. Motor unit firing patterns were classified into two groups, ;tonic' and ;phasic'. With few exceptions, tonic motor units showed sustained firing throughout MG stretches of varying duration, while most phasic units did not fire at all to the same stimulus. Tetanization of the afferents did not convert any of the previously phasic units to tonic firing.3. MG motor units in this study were divided into three groups on the basis of the muscle unit twitch properties. Units with short twitch time to peak values (< 35 msec) were subdivided into two groups according to twitch tension output: (a) type F, with twitch tension > 1.5 g, and (b) type F(*), with twitch tension < 1.5 g. Units with slow twitch time to peak (> 35 msec) were classified as type S.4. The presence or absence of tonic firing during sustained MG stretch was found to be significantly related to the following factors: (a) the motor unit twitch type, in that tonic firing was observed in 100% of type S, 70% of type F(*), and only 10% of type F units; (b) the apparent motoneurone size, in that tonic units tended to have higher cell input resistance values and slower axonal conduction velocities than phasic units; and (c) the density and spatial organization of the group Ia synaptic input, in that the MG monosynaptic EPSPs found in tonic motor units tended to be both larger in amplitude and longer in duration than those found in phasic units.5. The intrinsic properties of MG motor units, the characteristics of the group Ia synaptic input to the motoneurones and the unit firing patterns elicited by MG muscle stretch appear to be mutually interrelated, forming a pattern of motor units within the MG pool which is analogous to the pattern thought to characterize the motor units belonging to ;slow' and ;fast' muscles. In most respects this pattern of MG motor units appears to be a continuum without clearly separable subgroups.

Action Potentials↗

PubMed1974

The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones.

1. In anaesthetized rabbits, preoptic single unit activity was recorded while preoptic, spinal cord and skin temperatures were independently manipulated.2. The units that were insensitive to preoptic temperature were characterized by low firing rates and also by a very low incidence of extrahypothalamic thermosensitivity.3. Thirty-seven units having positive coefficients to preoptic temperature were tested for their response to spinal or skin temperature. Of these, twenty-two units responded to extrahypothalamic temperature, seventeen with positive thermal coefficients. In addition, the incidence of extrahypothalamic thermosensitivity generally increased among the higher firing units.4. Twenty-two units had negative coefficients for preoptic temperature and were tested for their extrahypothalamic thermosensitivities. Of these, sixteen units had dual thermosensitivities, ten with negative coefficients for the extrahypothalamic temperatures. In addition, there was no correlation between the incidence of extrahypothalamic thermosensitivity and the level of firing rate.5. In the units having positive coefficients for preoptic temperature, an increased firing rate, due to extrahypothalamic temperature, generally resulted in a decreased preoptic thermosensitivity. Conversely, a decreased firing rate usually resulted in an increased preoptic thermosensitivity.6. In the units having negative coefficients for preoptic temperature, an increased firing rate, due to extrahypothalamic temperature, usually increased the preoptic thermosensitivity; while a decreased firing rate tended to decrease the sensitivity to preoptic temperature.

Action Potentials↗

PubMed1974

The effect of firing rate on preoptic neuronal thermosensitivity.

1. In anaesthetized rabbits, preoptic single units were recorded having positive or negative thermal coefficients (impulses/sec. degrees C) for changes in preoptic temperature.2. A population of forty-two positive coefficient units was divided into four groups based on their level of firing rate at 38 degrees C. In each group, the average thermoresponse curve was determined by averaging the firing rates of the units at 1 degrees C intervals over the 33-43 degrees C range of preoptic temperatures.3. A population of twenty-six negative coefficient units was divided into three groups based on their firing rates at 38 degrees C. Similar average thermoresponse curves were determined for each group.4. As the level of firing rate increased in the positive coefficient units, the preoptic thermosensitivity progressively decreased at temperatures above 39 degrees C, but generally increased at temperatures below 39 degrees C.5. In the negative coefficient units, preoptic thermosensitivity generally increased (especially above 39 degrees C) as the firing rate at 38 degrees C increased.6. The results indicate that in positive coefficient units the level of firing rate determines the temperature range in which units are most thermosensitive. This range reflects whether a neurone is more likely to function in heat-loss or heat-production responses.7. Since peripheral thermal input affects the level of firing rate of positive coefficient units, a neuronal model is suggested to explain the role of peripheral and central thermal signals in temperature regulation.

Action Potentials↗

PubMed1978

Further observations on back-firing in the motor nerve fibres of a muscle during twitch contractions.

1. The tension developed by a muscle in response to a single supramaximal nerve volley is often the sum of two contractions, the second resulting from re-excitation of some nerve terminals during the first contraction. Re-excitation or back-firing can be prevented if the muscle nerve is stimulated twice with the second volley arriving in the muscle at a time when muscle fibres are still refractory following the first volley (Brown & Matthews, 1960). 2. Back-firing has been studied here in the medial gastrocnemius muscle of the spinal cat and responses have been recorded, either representing the summed activity of the muscle's motor supply or discharges of single functional motor axons. 3. When stimulating at a distance from the muscle, the second of two shocks is effective in suppressing back-firing over a narrower range of stimulus intervals than when stimulating close to the muscle. 4. The amount of back-firing can be reduced by stretching the muscle. At a length corresponding to the optimum for a twitch little if any back-firing remains. 5. Measurements of threshold to electrical stimulation of single functional motor axons suggests that low threshold axons are more likely to show back-firing. In the majority of cases, most or all of the motor units in the muscle have to be active before back-firing can be observed.

Animals↗

PubMed1981

The effects of digital nerve stimulation on the firing of motor units in human first dorsal interosseous muscle.

1. The effect of cutaneous stimulation on the firing of single motor units has been studied during voluntary contractions in human first dorsal interosseous muscle. 2. Electrical stimulation of the index finger at 3 x threshold for perception reduced the firing rate of most units recruited at voluntary contraction strengths less than 1.5 N and increased the firing rate of all units recruited at contraction strengths greater than 1.5 N. The firing rate of all slow twitch units (contraction time greater than 75 msec) was reduced. The behaviour of fast twitch units was mixed but at this stimulus strength all units recruited at contraction strengths greater than 1.5 N had their firing rate increased. 3. Tested at different stimulus strengths, the stronger the stimulus the more the firing rate of low threshold units was reduced. The firing rate of units recruited at high contraction strength was increased by weak stimuli but reduced by strong stimuli. 4. It is concluded that stimulation of the index finger shifts the weighting of synaptic input associated with a voluntary contraction to favour the activity of the more powerful fast twitch motor units in first dorsal interosseous muscle.

Action Potentials↗

PubMed1983

Relation between shapes of post-synaptic potentials and changes in firing probability of cat motoneurones.

1. The shapes of post-synaptic potentials (p.s.p.s) in cat motoneurones were compared with the time course of changes in firing probability during repetitive firing. Excitatory and inhibitory post-synaptic potentials (e.p.s.p.s and i.p.s.p.s) were evoked by electrical stimulation of peripheral nerve filaments. With the motoneurone quiescent, the shape of each p.s.p. was obtained by compiling post-stimulus averages of the membrane potential. Depolarizing current was then injected to evoke repetitive firing, and the post-stimulus time histogram of motoneurone spikes was obtained; this histogram reveals the primary features (peak and/or trough) of the cross-correlogram between stimulus and spike trains. The time course of the correlogram features produced by each p.s.p. was compared with the p.s.p. shape and its temporal derivative.2. E.p.s.p.s of different sizes (0.15-3.1 mV, mean 0.75 mV) and shapes were investigated. The primary correlogram peak began, on the average, 0.48 msec after onset of the e.p.s.p., and reached a maximum 0.29 msec before the summit of the e.p.s.p; in many cases the correlogram peak was followed by a trough, in which firing rate fell below base-line rate. The height of the correlogram peak with respect to base-line firing rate increased in proportion to both the amplitude of the e.p.s.p.s and the magnitude of their rising slope (in these data, amplitude and rising slope also covaried).3. The mean half-width of the correlogram peaks (0.65+/-0.28 msec (S.D.)) agreed better with the average half-width of the e.p.s.p. derivatives (0.55+/-0.33 msec) than with the half-width of the e.p.s.p.s (4.31+/-1.50 msec). The shape of the primary correlogram peak produced by simple e.p.s.p.s often resembled the temporal derivative of the e.p.s.p. rise. For larger e.p.s.p.s, the shape of the correlogram peak closely matched the e.p.s.p. derivative, while smaller e.p.s.p.s in appreciable synaptic noise often generated correlogram peaks somewhat wider than their derivatives. On the other hand, the match between the correlogram trough that followed the peak and the negative slope of the e.p.s.p. was better for the small e.p.s.p.s than for the large e.p.s.p.s; for large e.p.s.p.s the drop in firing rate during the trough was typically limited at zero. These relations were tested further by comparing the integral of the correlogram with the time course of the e.p.s.p. For large e.p.s.p.s, the correlogram integral matched the rising phase of the e.p.s.p. quite well, although it underestimated the rate of decline of the e.p.s.p.4. Complex e.p.s.p.s with distinct components during their rising phase often produced correlogram peaks that did not accurately reflect the features in their temporal derivative. Temporal summation of large e.p.s.p.s and summation of their derivatives was linear, but the resulting correlogram peaks did not add linearly; the second correlogram peak was often smaller than the first. However, when small e.p.s.p.s were summed, the correlogram peaks more closely matched the e.p.s.p. derivatives.5. Compound i.p.s.p.s produced primary correlogram troughs followed by a shallow compensatory peak. The width of the trough extended through the peak of the i.p.s.p., well into the falling phase of the i.p.s.p. During the trough the firing rate usually dropped to zero. Thus, the primary correlogram features produced by large i.p.s.p.s did not resemble any linear combination of the shape of the i.p.s.p. and/or its temporal derivative. Moreover, the integral of the correlogram did not resemble the i.p.s.p.6. The major observations are consistent with a motoneurone model in which a membrane potential ramp approaches a voltage threshold for spike initiation. Near threshold, e.p.s.p.s superimposed on the ramp advance the occurrence of spikes to their rising phase, producing a correlogram peak resembling their temporal derivative. Synaptic noise would increase the probability of sampling the peak of the e.p.s.p., leading to wider correlogram peaks. I.p.s.p.s would delay the occurrence of spikes to their falling phase.

Action Potentials↗

PubMed1993

Electrophysiology of guinea-pig supraoptic neurones: role of a hyperpolarization-activated cation current in phasic firing.

1. Immunocytochemically identified magnocellular neurosecretory cells (MNCs) in the guinea-pig supraoptic nucleus (SON) were studied using the in vitro intracellular recording technique. Cells were identified as containing arginine vasopressin (AVP) or oxytocin (OT) following recordings made with biocytin-filled electrodes. Both AVP and OT MNCs demonstrated a fusiform or pyramidal shape (15-20 microns by 26-39 microns), with two to three processes. There were no significant differences in the proportion of AVP and OT cells in the retrochiasmatic (caudal) versus the rostral slices. 2. No significant differences in passive membrane properties were observed between AVP and OT cells, except that AVP cells exhibited a significantly broader action potential width (1.51 +/- 0.1 ms, n = 11) than did OT cells (1.01 +/- 0.08 ms, n = 7). 3. Firing patterns were recorded for 100 MNCs, 41% of which fired in a phasic manner (repeated clustering of action potentials into bursts). Of the seventy-seven cells which were immunocytochemically identified, only AVP-containing MNCs displayed phasic firing. Phasic firing occurred only in MNCs demonstrating a depolarizing potential which followed hyperpolarizing after-potentials (HAPs). The presence of the depolarizing potential was not always associated with phasic firing, however, as both OT cells and non-phasic AVP cells sometimes exhibited a depolarizing potential. 4. In 160 MNCs examined for the presence of the time-dependent inward rectification (TDR in current clamp, or Ih in voltage clamp), a significant difference in the proportion of cells expressing the Ih was observed in the two cell types. The Ih was expressed in forty-five of fifty-four AVP MNCs (83%) and in six of fifteen OT MNCs (40%). No significant association was found with firing pattern. 5. The Ih exhibited properties similar to those found in other CNS and peripheral tissues. It appeared on steps to potentials more hyperpolarized than -65 mV. It was augmented by raising the extracellular potassium concentration, blocked by 2 mM CsCl, and insensitive to 100-500 microM BaCl2. Activation followed a single exponential, and the time constant of activation was voltage dependent. 6. The adenylate cyclase activator forskolin increased the Ih and shifted its activation curve to more depolarized levels. In cells recorded for several hours, the Ih varied in amplitude, suggesting intrinsic modulation, possibly by intracellular second messenger systems. The Ih in guinea-pig SON MNCs appears to serve an excitatory role, bringing cells closer to firing threshold.

Action Potentials↗

PubMed2002

Measurement of excitability of tonically firing neurones tested in a variable-threshold model motoneurone.

A new measure of excitability of tonically firing neurones termed the 'estimated potential' (EP) was tested on a model motoneurone (MN) with a voltage-dependent threshold; the threshold followed the noisy membrane potential with an exponential delay. First, the model MN's after-hyperpolarisation (AHP) was deduced from its interval histogram for tonic firing, using a recently described transform. This provided a 'distance-to-threshold' measure which underestimated the AHP's absolute size but had the same time course, thereby providing the time constant of the AHP's decay of conductance. The 'estimated potential' was then obtained from the classical 'firing index' (no. of responses/no. of stimuli) by using the estimated AHP to create a fixed threshold 'daughter' model MN to mimic its variable threshold parent and reproduce its input-output non-linearities. The EP gave a linear measure of the parent's stimulus-evoked depolarisation for firing indices up to about 60 %, corresponding to depolarisations of three to four times the noise S.D. The EP was scaled in units of voltage whose absolute value will usually be unknown for real neurones, since it depended upon the details of the parent model. The EP's virtue is that, within its range, combining stimuli gives arithmetical addition and subtraction, thereby improving on the firing index which scales sigmoidally with the input. Moreover, with weak stimuli, the EP for a given input did not change on varying the parent model's firing rate. The estimated 'distance-to-threshold' AHP did not, however, give an accurate measure of the recovery of excitability following a spike during tonic firing. Excitability then depends upon the 'survivors' trajectory' giving the mean membrane potential, relative to threshold, of those intervals which have 'survived' up to the time in question rather than upon the AHP per se; the survivors' mean is more hyperpolarised because spiking preferentially eliminates trajectories with noise-induced depolarisation.

Animals↗

PubMed2003

ATP modulates intracellular Ca2+ and firing rate through a P2Y1 purinoceptor in cane toad pacemaker cells.

The effect of extracellular ATP (10-100 microM) on intracellular Ca2+ concentration ([Ca2+]i) and firing rate has been studied in single pacemaker cells isolated from the sinus venosus of cane toads. In spontaneously firing cells, ATP initially increased peak [Ca2+]i by 43 +/- 5 %, increased diastolic [Ca2+]i by 20 + 3 % and increased the firing rate by 58 +/- 8 %. These early effects were followed by a late phase in which both the peak [Ca2+]i and the firing rate declined. Adenosine, and UTP (respectively, P1- and P2Y2,4,6-selective agonists) caused no significant change in [Ca2+]i or firing rate, while alphabeta-methylene ATP (a P2X1,3 agonist) caused a small increase in firing rate but no changes in [Ca2+]i. In contrast the P2Y1-selective agonist 2-MesADP (1 microM) mimicked the biphasic effects of ATP and these effects were inhibited by the purinoceptor antagonists suramin and PPADS and by the P2Y1-selective antagonist MRS 2179. Immunohistochemistry established that P2Y1 purinoceptors were present on the cell surface. Western blotting analysis demonstrated that the P2Y1 antibody recognised a 57 kDa protein. After sarcoplasmic reticulum Ca2+ release was prevented with caffeine or ryanodine, ATP no longer had any effect on [Ca2+]i or firing rate. Furthermore, the SR Ca2+ store content was decreased during the late phase of 2-MesADP application. The effect of ATP was coupled to phospholipase C (PLC) activity because the PLC inhibitor U-73122 eliminated the effects of ATP. Our study shows that in toad pacemaker cells, the biphasic effects of ATP on pacemaker activity are mainly through P2Y1 purinoceptors, which are able to modulate Ca2+ release from the SR Ca2+ store.

Adenosine Diphosphate↗

PubMed2006

The effects of long chain-length n-alcohols on the firing frequency of dopaminergic neurons of the ventral tegmental area.

The dopaminergic neurons of the ventral tegmental area (DA VTA neurons) have been implicated in the reinforcing properties of drugs of abuse, including ethanol (ethyl alcohol). Ethanol increases the spontaneous firing frequency of DA VTA neurons in vitro, in both brain slices and acutely dissociated neurons, and also in vivo. In many systems, longer n-alkyl alcohols have a more potent effect than ethanol, and the potency is a function of the number of carbons in the alkyl chain. We studied n-alcohols of chain length 1 (methanol) to 5 (pentanol) on the firing rate of DA VTA neurons in brain slice preparations. All of the alcohols studied produced increases in the spontaneous firing frequency in DA VTA neurons; as the chain length increased, lower concentrations of the alcohols were needed to produce the same percentage increase in firing. With very high concentrations of all the alcohols except methanol, we observed apparent depolarization block of firing. In addition, trichloroethanol (TCE), the active metabolite of chloral hydrate, increased the firing frequency of DA VTA neurons, and the EC(40) (concentration to produce a 40% increase in firing rate) of TCE was below that of ethanol. These studies indicate that excitation of VTA dopamine neurons by n-alcohols is related to the chain length of the carbons. This is likely to be a characteristic of the ethanol-sensitive element of DA VTA neurons and may be useful in identifying the element of the membrane that is responsible for ethanol-induced excitation.

Alcohols↗

PubMed2004

Differences between accumbens core and shell neurons exhibiting phasic firing patterns related to drug-seeking behavior during a discriminative-stimulus task.

The habit-forming effects of abused drugs depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens (NAcc). To examine whether different NAcc subterritories (core and medial shell) exhibit a differential distribution of neurons showing phasic firing patterns correlated with drug-seeking behavior, rats were trained to self-administer cocaine, and activity of single NAcc neurons was recorded. In the presence of a discriminative-stimulus (S(D)) tone, a single lever press produced an intravenous infusion of cocaine (0.35 mg/kg), terminated the tone, and started an intertone interval ranging from 3 to 6 min. Lever presses during this intertone interval had no programmed consequences. In addition to evaluating neuronal firing patterns associated with cocaine-reinforced presses, we also evaluated firing patterns associated with unreinforced lever presses to allow interpretation of firing free of factors other than the instrumental response (such as tone-off and onset of the pump signaling drug infusion). Core neurons exhibited a greater change in firing than medial shell neurons both in the seconds preceding the reinforced and unreinforced lever press response and in the seconds following the unreinforced response. Core and medial shell neurons exhibited similar changes in firing during the seconds following the cocaine-reinforced press. The differential distribution of neurons exhibiting phasic changes in firing preceding the lever press suggests that the physiological activity of core neurons may play a greater role than that of medial shell neurons in processes related to the execution of conditioned drug-seeking responses.

Action Potentials↗

PubMed2004

Role of ionotropic glutamatergic and GABAergic inputs on the firing activity of neurons in the external pallidum in awake monkeys.

The neurons in the external segment of the pallidum (GPe) in awake animals maintain a high level of firing activity. The level and pattern of the activity change with the development of basal ganglia disorders including parkinsonism and hemiballism. The GPe projects to most of the nuclei in the basal ganglia. Thus exploring the mechanisms controlling the firing activity is essential for understanding basal ganglia function in normal and pathological conditions. To explore the role of ionotropic glutamatergic and GABAergic inputs to the GPe, unit recordings combined with local injections of receptor antagonists were performed in awake monkeys. Observations on the effects of local application of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate antagonist 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo[f]quinoxaline-7-sulfonamide, the N-methyl-D-aspartic acid (NMDA) antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, and the GABAA antagonist gabazine as well as the effects of muscimol blockade of the subthalamic nucleus on the spontaneous firing rate, firing patterns, and cortical stimulation induced responses in the GPe suggested the following: sustained glutamatergic and GABAergic inputs control the level of the spontaneous firing of GPe neurons; both AMPA/kainate and NMDA receptors are activated by glutamatergic inputs; some GPe neurons receive glutamatergic inputs originating from areas other than the subthalamic nucleus; no GPe neurons became silent after a combined application of glutamate and GABA antagonists, suggesting that GPe neurons have intrinsic properties or nonionotropic glutamatergic tonic inputs that sustain a fast oscillatory firing or a combination of a fast and a slow oscillatory firing in GPe neurons.

Animals↗