Development and Serotonergic Modulation of NMDA Bursting in Rat Trigeminal Motoneurons

2002 ◽  
Vol 87 (3) ◽  
pp. 1318-1328 ◽  
Author(s):  
Chie-Fang Hsiao ◽  
Nanping Wu ◽  
Michael S. Levine ◽  
Scott H. Chandler
Keyword(s):  
Membrane Potential ◽  
Nmda Receptor ◽  
Voltage Clamp ◽  
Input Resistance ◽  
Burst Discharge ◽  
Bath Application ◽  
Voltage Clamp Analysis ◽  
Voltage Dependent ◽  
Trigeminal Motoneurons ◽  
Bursting Activity

The development of N-methyl-d-aspartate (NMDA)-induced burst discharge in rat trigeminal motoneurons (TMNs) between postnatal days P1 and P10 was examined using whole cell patch-clamp recording methods in brain slices. Bath application of NMDA (50 μM) induced a Mg2+-dependent rhythmical bursting activity starting around P8. Prior to the onset of bursting, the membrane potential depolarized and the input resistance increased. Hyperpolarization of the membrane potential with extrinsic current demonstrated a narrow window of membrane potential where maintained rhythmical burst discharge was evident. In P1–P4 neurons, NMDA application produced membrane depolarization and a minimal change in input resistance, but no burst activity at any membrane potential. Voltage-clamp analysis indicated that the bursting activity was related to the presence or absence of a voltage-dependent Mg2+ block and induction of a negative slope conductance (NSC) region in the I NMDA- V relationship. Regardless of age, reduction of extracellular Mg2+ from 1 mM to 30 μM enhanced I NMDA at voltages negative to −60 mV. However, in 1 mM Mg2+, P1–P4 neurons were devoid of a prominent NSC region compared with P8–P10 neurons, suggesting that the efficacy of depolarization in unblocking the NMDA receptors increased with age. NMDA bursting was not dependent on calcium influx through voltage-gated calcium channels (VGCC) but did require a minimal concentration of Ca2+ in the bath. Intracellular bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid application suppressed burst discharge completely, suggesting that intracellular Ca2+ directly, or via second-messenger systems, regulates NMDA receptor activity and bursting. Interestingly, NMDA bursting could be induced in P1–P4 neurons by simultaneous bath application of serotonin (5-HT, 10 μM), which by itself did not produce bursting, suggesting an “enabling” role for 5-HT. Voltage-clamp analysis demonstrated that the NMDA/5-HT bursting resulted from induction of an NSC in the I-Vrelationship of total membrane current. 5-HT by itself produced no such effect. The mechanisms for this effect were due to an enhancement of the NSC region of the I NMDA- V relationship and reduction of a presumed leak current by 5-HT. These data indicate that NMDA bursting in trigeminal motoneurons is developmentally regulated and subject to neuromessenger modulation. Control of the Mg2+ sensitivity of the NMDA receptor and voltage-dependent block by neuromessengers could be an effective means to control the efficacy of glutamatergic synaptic drive to motoneurons during rhythmical oral-motor activity at early postnatal ages.

Single-electrode voltage-clamp analysis of the N-methyl-D-aspartate component of synaptic responses in neocortical slices from children with intractable epilepsy

1992 ◽  
Vol 67 (1) ◽  
pp. 84-93 ◽  
Author(s):  
J. P. Wuarin ◽  
W. J. Peacock ◽  
F. E. Dudek
Keyword(s):  
Electrical Stimulation ◽  
Membrane Potential ◽  
Nmda Receptor ◽  
Voltage Clamp ◽  
Intractable Epilepsy ◽  
Perfusion Solution ◽  
Electrode Voltage ◽  
Voltage Dependent ◽  
Abnormal Tissue ◽  
Synaptic Responses

1. Synaptic transmission mediated by the N-methyl-D-aspartate (NMDA)-receptor type was studied in neocortex from children undergoing surgical treatment for intractable epilepsy. Intracellular recordings from pyramidal cells were obtained in slices of neocortical tissue by use of microelectrodes. Synaptic responses were induced by electrical stimulation and studied with current-clamp and single-electrode voltage-clamp techniques. The NMDA-receptor-mediated component of the synaptic responses was isolated by addition of 10 microM bicuculline and 30 microM 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX) in the perfusion solution. 2. In the presence of bicuculline and CNQX, electrical stimulation evoked an excitatory postsynaptic potential (EPSP) in every recorded cell. The amplitude of this EPSP increased when membrane potential was depolarized with injected current. 3. All cells studied in voltage clamp were recorded with microelectrodes containing Cs+ and QX 314. To avoid contamination of the responses from voltage-dependent Ca2+ conductances, membrane potential was held at depolarized potentials until Ca2+ spiking inactivated completely. The evoked excitatory postsynaptic currents (EPSCs) measured at resting membrane potential ranged from 100 to 400 pA. The NMDA receptor-selective antagonist DL-2-amino-5-phosphonopentanoic acid (AP-5) reversibly decreased the current amplitude by 60% for 10 microM and 80% for 30 microM. 4. The current-voltage (I-V) relation showed a region of negative slope conductance between -100 and -20 mV. The largest currents (-250 to -900 pA) were recorded in the range of -45 to -20 mV and reversed between -10 and +10 mV. Removing Mg2+ from the perfusion solution decreased the negativity of the slope, which is consistent with a reduction in the voltage-dependent Mg2+ block of the NMDA-receptor channel. 5. The I-V plots obtained from cells recorded in the most abnormal tissue were averaged and compared with those from the least abnormal tissue. No significant difference was found between these two groups. The averaged plots from the youngest patients (8 and 10 mo old) and those from the oldest (5-15 yr old) patients were also compared, and the results from these two groups were not significantly different.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of ouabain on background and voltage-dependent currents in canine colonic myocytes

1990 ◽  
Vol 259 (3) ◽  
pp. C402-C408 ◽  
Author(s):  
E. P. Burke ◽  
K. M. Sanders
Keyword(s):  
Membrane Potential ◽  
Potential Gradient ◽  
Circular Muscle ◽  
Input Resistance ◽  
Pump Current ◽  
Muscle Layer ◽  
Membrane Properties ◽  
Resting Potential ◽  
Voltage Dependent ◽  
In Cells

Previous studies have suggested that the membrane potential gradient across the circular muscle layer of the canine proximal colon is due to a gradient in the contribution of the Na(+)-K(+)-ATPase. Cells at the submucosal border generate approximately 35 mV of pump potential, whereas at the myenteric border the pump contributes very little to resting potential. Results from experiments in intact muscles in which the pump is blocked are somewhat difficult to interpret because of possible effects of pump inhibitors on membrane conductances. Therefore, we studied isolated colonic myocytes to test the effects of ouabain on passive membrane properties and voltage-dependent currents. Ouabain (10(-5) M) depolarized cells and decreased input resistance from 0.487 +/- 0.060 to 0.292 +/- 0.040 G omega. The decrease in resistance was attributed to an increase in K+ conductance. Studies were also performed to measure the ouabain-dependent current. At 37 degrees C, in cells dialyzed with 19 mM intracellular Na+ concentration [( Na+]i), ouabain caused an inward current averaging 71.06 +/- 7.49 pA, which was attributed to blockade of pump current. At 24 degrees C or in cells dialyzed with low [Na+]i (11 mM), ouabain caused little change in holding current. With the input resistance of colonic cells, pump current appears capable of generating at least 35 mV. Thus an electrogenic Na+ pump could contribute significantly to membrane potential.

Input Resistance, Time Constants, and Spike Initiation

1998 ◽  
Author(s):  
Christof Koch
Keyword(s):  
Membrane Potential ◽  
Time Constant ◽  
Action Potentials ◽  
Input Resistance ◽  
Current Injection ◽  
Membrane Conductances ◽  
Voltage Dependent ◽  
Dc Component ◽  
Definition Of ◽  
A Current

This chapter represents somewhat of a tephnical interlude. Having introduced the reader to both simplified and more complex compartmental single neuron models, we need to revisit terrain with which we are already somewhat familiar. In the following pages we reevaluate two important concepts we defined in the first few chapters: the somatic input resistance and the neuronal time constant. For passive systems, both are simple enough variables: Rin is the change in somatic membrane potential in response to a small sustained current injection divided by the amplitude of the current injection, while τm is the slowest time constant associated with the exponential charging or discharging of the neuronal membrane in response to a current pulse or step. However, because neurons express nonstationary and nonlinear membrane conductances, the measurement and interpretation of these two variables in active structures is not as straightforward as before. Having obtained a more sophisticated understanding of these issues, we will turn toward the question of the existence of a current, voltage, or charge threshold at which a biophysical faithful model of a cell triggers action potentials. We conclude with recent work that suggests how concepts from the subthreshold domain, like the input resistance or the average membrane potential, could be extended to the case in which the cell is discharging a stream of action potentials. This chapter is mainly for the cognoscendi or for those of us that need to make sense of experimental data by comparing therp to theoretical models that usually fail to reflect reality adequately. In Sec. 3.4, we defined Kii (f) for passive cable structures as the voltage change at location i in response to a sinusoidal current injection of frequency f at the same location. Its dc component is also referred to as input resistance or Rin. Three difficulties render this definition of input resistance problematic in real cells: (1) most membranes, in particular at the soma, show voltage-dependent nonlinearities, (2) the associated ionic membrane conductances are time dependent and (3) instrumental aspects, such as the effect of the impedance of the recording electrode on Rin, add uncertainty to the measuring process.

Anoxia-induced LTP of isolated NMDA receptor-mediated synaptic responses

1993 ◽  
Vol 69 (5) ◽  
pp. 1774-1778 ◽  
Author(s):  
V. Crepel ◽  
C. Hammond ◽  
K. Krnjevic ◽  
P. Chinestra ◽  
Y. Ben-Ari
Keyword(s):  
Nmda Receptor ◽  
Neuronal Death ◽  
Hippocampal Neurons ◽  
Input Resistance ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Bath Application ◽  
Synaptic Responses

1. The effects of an anoxic-aglycemic episode (1-3 min) on the pharmacologically isolated N-methyl-D-aspartate (NMDA)-mediated responses were examined in CA1 pyramidal hippocampal neurons in vitro. 2. An anoxic-aglycemic episode induced a long term potentiation (LTP) of the NMDA receptor-mediated field excitatory post-synoptic potentials (EPSPs). This LTP, referred to as anoxic LTP, was observed in the presence of 1) a normal Mg2+ concentration [+40.1 +/- 5% (mean +/- SE)], 2) a low Mg2+ concentration (+52.2 +/- 10%), or 3) a Mg2+ free (+49 +/- 11%), 1 h after anoxia. 3. Bath application of D-2-amino-5-phosphonovaleric acid (D-APV, 20 microM, 15-21 min) before, during, and after the anoxic-aglycemic episode, which transiently blocked the synaptic NMDA receptor mediated response, prevented the induction of anoxic LTP. 4. The intracellularly recorded NMDA receptor-mediated EPSP was also persistently potentiated by anoxia-aglycemia (+47 +/- 4%). This potentiation was not associated with changes in membrane potential or input resistance. 5. These findings provide the first evidence that an anoxic-aglycemic episode induces an LTP of NMDA receptor-mediated responses. This potentiation may participate in the cascade of events that lead to delayed neuronal death.

Voltage-clamp analysis of a Ca2+- and voltage-dependent chloride conductance in cultured mouse spinal neurons

1986 ◽  
Vol 55 (6) ◽  
pp. 1115-1135 ◽  
Author(s):  
D. G. Owen ◽  
M. Segal ◽  
J. L. Barker
Keyword(s):  
Voltage Clamp ◽  
Reversal Potential ◽  
Gamma Aminobutyric Acid ◽  
Spinal Neurons ◽  
Exponential Process ◽  
Voltage Clamp Analysis ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Ca 50 ◽  
O 10

Current and voltage-clamp recordings were made at room temperature from cultured mouse spinal neurons using conventional two-electrode voltage-clamp techniques and electrodes filled with either 3 M KCl, 3 M CsCl, or 3 M Cs2SO4. In the presence of tetraethylammonium and tetrodotoxin, “fast” (rapidly rising and falling) action potentials (FAP) of variable duration were recorded in most neurons. “Slow” (slowly rising and falling) depolarizing potentials (SDP) occurred in 23% of the cells, when using KCl-filled electrodes, and in 82% of the cells with CsCl-filled electrodes. The SDP was frequently preceded by an FAP, although in some cells activation of the SDP occurred before the FAP threshold was reached and in a graded fashion. Both the FAP and SDP were abolished by Cd2+ and other Ca2+ antagonists. In cells exhibiting SDPs, voltage-clamp analysis revealed a sustained (noninactivating) inward current (Isin) during depolarizing steps to potentials more positive than -45 mV. Repolarizing steps resulted in slowly decaying inward tail currents (Itail). Both Isin and Itail were abolished in solutions nominally free of Cao2+, or containing Ca2+-channel antagonists. Bao2+ did not support Isin. The data indicated a U-shaped activation curve for Isin, peaking at about -10 mV. Activation of Isin occurred exponentially with a time constant of approximately 140 ms at -23 mV, becoming faster at more depolarized potentials (ca. 50 ms at -2 mV). Deactivation was slow, giving rise to tail currents lasting seconds. In some cases deactivation could be described by a single exponential process, although frequently the kinetics were more complex. Deactivation was faster at hyperpolarized potentials and sensitive to extracellular ([Ca2+]o), duration of activating voltage steps, and the degree of activation of Isin. Using CsCl-filled electrodes, the reversal potential (Erev) for Isin was -1.7 mV (SEM 3.5 mV, n = 20). Erev always corresponded to the reversal potential for gamma-aminobutyric acid-evoked currents in the same cell. In experiments in which Cs2SO4-filled electrodes were used, Erev was estimated to be -44 mV (SEM 2.3 mV, n = 9). Neither complete substitution of Nao+ with choline ions nor elevation of [K+]o 10-fold significantly affected the estimated Erev. However, substitution of Cl0- with isethionate or methanesulphonate increased the amplitude of inward currents (recorded with CsCl-filled electrodes) and shifted Erev to more depolarized potentials. The results indicate that Cl- are the primary charge carriers for this current and that Cai2+ is required for its activation, leading us to identify it as ICl(Ca).(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Depletion and accumulation of potassium in the extracellular clefts of cardiac Purkinje fibers during voltage clamp hyperpolarization and depolarization: experiments in sodium-free bathing media.

1977 ◽  
Vol 70 (2) ◽  
pp. 149-169 ◽  
Author(s):  
C M Baumgarten ◽  
G Isenberg ◽  
T F McDonald ◽  
R E Ten Eick
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Driving Force ◽  
Time Course ◽  
Potassium Concentration ◽  
Outward Current ◽  
Voltage Step ◽  
Purkinje Fibers ◽  
Cardiac Purkinje Fibers ◽  
Voltage Dependent

Voltage clamp hyperpolarization and depolarization result in currents consistent with depletion and accumulation of potassium in the extracellular clefts o cardiac Purkinje fibers exposed to sodium-free solutions. Upon hyperpolarization, an inward current that decreased with time (id) was observed. The time course of tail currents could not be explained by a conductance exhibiting voltage-dependent kinetics. The effect of exposure to cesium, changes in bathing media potassium concentration and osmolarity, and the behavior of membrane potential after hyperpolarizing pulses are all consistent with depletion of potassium upon hyperpolarization. A declining outward current was observed upon depolarization. Increasing the bathing media potassium concentration reduced the magnitude of this current. After voltage clamp depolarizations, membrane potential transiently became more positive. These findings suggest that accumulation of potassium occurs upon depolarization. The results indicate that changes in ionic driving force may be easily and rapidly induced. Consequently, conclusions based on the assumption that driving force remains constant during the course of a voltage step may be in error.

Calcium-dependent plateau potentials in a crab stomatogastric ganglion motor neuron. I. Calcium current and its modulation by serotonin

1995 ◽  
Vol 74 (5) ◽  
pp. 1929-1937 ◽  
Author(s):  
B. Zhang ◽  
R. M. Harris-Warrick
Keyword(s):  
Motor Neuron ◽  
Voltage Clamp ◽  
Physiological Role ◽  
Input Resistance ◽  
Stomatogastric Ganglion ◽  
Channel Blockers ◽  
Plateau Potentials ◽  
Cancer Borealis ◽  
Calcium Dependent ◽  
Voltage Dependent

1. Using current- and voltage-clamp techniques, we examined the biophysical properties of a voltage-dependent Ca2+ current and its physiological role in plateau potential generation in the dorsal gastric (DG) motor neuron of the stomatogastric ganglion in the crab, Cancer borealis. 2. Stimulation of one of a set of identified serotonergic/cholinergic mechanosensory cells, the gastropyloric receptor (GPR) cells, induced plateau potentials in DG. A brief pressure application of serotonin (5-HT) closely mimicked the effect of the GPR cells. The 5-HT-evoked plateau in DG was not blocked by the sodium channel blocker, tetrodotoxin (TTX), or a combination of TTX with potassium channel blockers, including tetraethylammonium (TEA) and 4-aminopyridine (4-AP), and the Ih blocker, CsCl. The 5-HT-evoked plateau was eliminated by the Ca2+ channel blockers Co2+ and Cd2+, suggesting that Ca2+ entry is essential for plateau potentials in DG. During the plateau, we observed a 30% decrease in input resistance. 3. When sodium and potassium currents were blocked pharmacologically, injection of suprathreshold depolarizing current evoked all-or-none plateau-like responses lasting several seconds, even in the absence of 5-HT. This response was blocked by Ca2+ channel blockers, further supporting a role for Ca2+ in plateau generation. 5-HT significantly prolonged the duration of this plateau. 4. We isolated a voltage-dependent Ca2+ current in voltage-clamped DG neurons. This current was analyzed with the use of either Ca2+ or Ba2+ as the charge carrier after other currents had been maximally blocked with extracellular TTX, TEA, 4-AP, and CsCl and intracellular loading with Cs+ and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The Ca2+ current was detectable at -45 mV, peaked at -15 mV, and was estimated to reverse at +45 mV. Co2+ and Cd2+ effectively blocked the Ca2+ current. 5. The voltage dependence of activation of the Ca2+ current was quantantitively analyzed by fitting the voltage-conductance relation with a third power Boltzmann relation. The maximum conductance (gA), half-activation voltage (VA) for individual gating steps, and the slope steepness (k) were 0.19 +/- 0.02 (SE) microS, -36.5 +/- 2.0 mV, and 4.4 +/- 1.4 mV/e-fold, respectively. 6. 5-HT significantly potentiated the gA by approximately 42% without affecting VA and k. 7. We conclude from our current- and voltage-clamp results that a voltage-dependent Ca2+ current plays an important role in generating plateau potentials in the DG neuron. Enhancement of the voltage-dependent Ca2+ current by 5-HT is one of the mechanisms for 5-HT-evoked plateau potentials.

An Intrinsic Oscillation in Interneurons of the Rat Lateral Geniculate Nucleus

1999 ◽  
Vol 81 (2) ◽  
pp. 702-711 ◽  
Author(s):  
J. Julius Zhu ◽  
William W. Lytton ◽  
Jin-Tang Xue ◽  
Daniel J. Uhlrich
Keyword(s):  
Membrane Potential ◽  
Lateral Geniculate Nucleus ◽  
Action Potentials ◽  
Optic Tract ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Lateral Geniculate ◽  
Bath Application ◽  
Voltage Dependent ◽  
Intrinsic Oscillation

Intrinsic oscillation in interneurons of the rat lateral geniculate nucleus. By using the whole cell patch recording technique in vitro, we examined the voltage-dependent firing patterns of 69 interneurons in the rat dorsal lateral geniculate nucleus (LGN). When held at a hyperpolarized membrane potential, all interneurons responded with a burst of action potentials. In 48 interneurons, larger current pulses produced a bursting oscillation. When relatively depolarized, some interneurons produced a tonic train of action potentials in response to a depolarizing current pulse. However, most interneurons produced only oscillations, regardless of polarization level. The oscillation was insensitive to the bath application of a combination of blockers to excitatory and inhibitory synaptic transmission, including 30 μM 6,7-dinitroquinoxaline-2,3-dione, 100 μM (±)-2-amino-5-phosphonopentanoic acid, 20 μM bicuculline, and 2 mM saclofen, suggesting an intrinsic event. The frequency of the oscillation in interneurons was dependent on the intensity of the injection current. Increasing current intensity increased the oscillation frequency. The maximal frequency of the oscillation was 5–15 Hz for most cells, with some ambiguity caused by the difficulty of precisely defining a transition from oscillatory to regular firing behavior. In contrast, the interneuron oscillation was little affected by preceding depolarizing and hyperpolarizing pulses. In addition to being elicited by depolarizing current injections, the oscillation could also be initiated by electrical stimulation of the optic tract when the interneurons were held at a depolarized membrane potential. This suggests that interneurons may be recruited into thalamic oscillations by synaptic inputs. These results indicate that interneurons may play a larger role in thalamic oscillations than was previously thought.

Voltage and beat dependence of Ca2+ transient in feline ventricular myocytes

1989 ◽  
Vol 257 (3) ◽  
pp. H746-H759 ◽  
Author(s):  
W. H. duBell ◽  
S. R. Houser
Keyword(s):  
Steady State ◽  
Membrane Potential ◽  
Sarcoplasmic Reticulum ◽  
Voltage Clamp ◽  
Ventricular Myocytes ◽  
Rest Period ◽  
Voltage Dependent ◽  
Early Peak ◽  
Comparable Magnitude ◽  
Voltage Relationship

The positive contractile staircase after a period of rest is attributable to a positive staircase in the magnitude of the Ca2+ transient. The present study used voltage-clamp techniques and the fluorescent Ca2+ indicator, indo-1, to examine the effects of membrane potential, the duration of depolarization, and the slow inward Ca2+ current (Isi) in the regulation of the magnitude of the steady-state Ca2+ transient and the development of the steady state during the positive staircase. In the steady state, the Ca2+ transient was greatest at +10 mV, the potential at which Isi was also the greatest. However, the Isi-voltage relationship was much more bell-shaped than the Ca2+ transient-voltage relationship. The magnitude and duration of the steady-state Ca2+ transient was not affected by pulse durations as short as 25 ms. However, prolonged voltage pulses were essential to maintain the steady state. The development of the positive staircase was very voltage dependent. After a rest period, a positive staircase was seen when voltage-clamp drives were done to +30 mV but not when done to -10 mV, potentials that elicit Isi of comparable magnitude. These results support the idea that the early peak of Isi can act as a trigger for release of Ca2+ from the sarcoplasmic reticulum. However, sarcoplasmic reticulum Ca2+ loading is dependent on prolonged depolarization and may be mediated through Na+-Ca2+ exchange.

Blockade of SK-Type Ca2+-Activated K+Channels Uncovers a Ca2+-Dependent Slow Afterdepolarization in Nigral Dopamine Neurons

1999 ◽  
Vol 81 (3) ◽  
pp. 977-984 ◽  
Author(s):  
Han Xian Ping ◽  
Paul D. Shepard
Keyword(s):  
Brain Slices ◽  
Dopamine Neurons ◽  
Voltage Response ◽  
Current Clamp ◽  
Electrode Current ◽  
Current Pulses ◽  
Bath Application ◽  
Voltage Dependent ◽  
Bursting Activity ◽  
Slow Depolarization

Blockade of SK-type Ca2+-activated K+ channels uncovers a Ca2+-dependent slow afterdepolarization in nigral dopamine neurons. Sharp electrode current-clamp recording techniques were used to characterize the response of nigral dopamine (DA)-containing neurons in rat brain slices to injected current pulses applied in the presence of TTX (2 μM) and under conditions in which apamin-sensitive Ca2+-activated K+ channels were blocked. Addition of apamin (100–300 nM) to perfusion solutions containing TTX blocked the pacemaker oscillation in membrane voltage evoked by depolarizing current pulses and revealed an afterdepolarization (ADP) that appeared as a shoulder on the falling phase of the voltage response. ADP were preceded by a ramp-shaped slow depolarization and followed by an apamin-insensitive hyperpolarizing afterpotential (HAP). Although ADPs were observed in all apamin-treated cells, the duration of the response varied considerably between individual neurons and was strongly potentiated by the addition of TEA (2–3 mM). In the presence of TTX, TEA, and apamin, optimal stimulus parameters (0.1 nA, 200-ms duration at −55 to −68 mV) evoked ADP ranging from 80 to 1,020 ms in duration (355.3 ± 56.5 ms, n = 16). Both the ramp-shaped slow depolarization and the ensuing ADP were markedly voltage dependent but appeared to be mediated by separate conductance mechanisms. Thus, although bath application of nifedipine (10–30 μM) or low Ca2+, high Mg2+ Ringer blocked the ADP without affecting the ramp potential, equimolar substitution of Co2+ for Ca2+ blocked both components of the voltage response. Nominal Ca2+ Ringer containing Co2+ also blocked the HAP evoked between −55 and −68 mV. We conclude that the ADP elicited in DA neurons after blockade of apamin-sensitive Ca2+-activated K+ channels is mediated by a voltage-dependent, L-type Ca2+ channel and represents a transient form of the regenerative plateau oscillation in membrane potential previously shown to underlie apamin-induced bursting activity. These data provide further support for the notion that modulation of apamin-sensitive Ca2+-activated K+ channels in DA neurons exerts a permissive effect on the conductances that are involved in the expression of phasic activity.

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