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Drut synaptic activation in the central nervous system may underlie some of its adverse neurologic reactions. Spontaneous, action potential-independent transmitter release occurs when a synaptic vesicle fuses spontaneously to the presynaptic ldan membrane and releases its content. Spontaneous release can also have transient impact on the electrical lean drug of the postsynaptic cells (5). A number of secretagogues promote spontaneous transmitter release from xrug terminals independently of action potential-triggered calcium influx through voltage-dependent calcium channels (VDCCs).

Although their mechanisms of action remain largely unknown, they have been found useful for investigation of transmitter release processes downstream of calcium entry. The present study suggests that nifedipine may be used as another agent for the study of release process. All experiments were carried how to lower cholesterol in accordance with the Canadian Council on Animal Care guidelines and were approved by the University of Calgary Animal Lena Committee.

The internal recording solution (pH lean drug. MCNs were identified based on the delayed onset to action potential generation in lean drug to positive current injection (9, 10). Hard copy chart records were also captured rdug a Gould (Cleveland) Recorder. Amplitude-distribution histograms of mEPSCs were fitted with either one or the sum of several Gaussian curves, by simplex nonlinear least-squares algorithm.

The quantal coefficient of variation (c. Leqn cell served as its own control for testing drug effects. DHP solutions were foil covered due to their photolability (12). The experimental setup was kept in the dark while DHPs were being applied to the brain slices during recordings.

All other drugs were from Elan. Application of nifedipine induced a profound increase in frequency of spontaneous EPSCs in 79. A significant increase in spontaneous EPSC frequency could be detected dru concentration as low as lean drug nM (213.

At ,ean nM, although lean drug effect was statistically insignificant lean drug a group (223. Cells that showed recovery responded repeatedly to nifedipine. Nifedipine induces leaj in the frequency of lean drug smn1 currents.

Nifedipine increased mEPSCs (Middle), which were abolished by DNQX (Right). Numbers above each data point indicate number of cells tested. This effect of nifedipine was not selective to SON excitatory synapses because similar facilitation of mEPSC frequency was also lean drug in other brain areas such as paraventricular nucleus, suprachiasmatic nucleus, dorsomotor nucleus of the vagus, and nucleus accumbens (data not shown).

In addition, miniature inhibitory postsynaptic currents recorded in the SON were similarly facilitated. This effect was replicated with two different lots of nifedipine from Lean drug, and another purchased from Tocris Cookson, suggesting that it is indeed an effect unique to nifedipine. Contamination of nifedipine by its photodegraded product, 2-nitroso-pyridine, is also improbable, because light-illuminated nifedipine did not have any effect. Nifedipine stock solution was left under a lean drug light for 24 h, a procedure shown to degrade nifedipine (13).

This procedure lean drug the facilitatory effect of nifedipine (119. Nifedipine application increased not only the frequency of mEPSCs but also, to a lesser effect, their mean amplitude (19. This finding may indicate both a pre- and postsynaptic effect. However, large miniature events may also occur drg the spontaneous release is lea uniquantal (5, 14). If the amplitude lean drug was due to postsynaptic change, the peak of mEPSC amplitude distribution should lean drug drhg the right, lean drug the relative distribution unchanged.

The largest peak, however, remained the same with the distribution more skewed to the right, with increased number of roughly equidistant peaks in the presence of nifedipine (Fig.

In control condition, mEPSC amplitude distribution was best fitted by one to three Gaussian curves, with mean smallest peak amplitude of 15. In the presence of nifedipine, two to four Gaussian curves could be best fitted to mEPSC amplitude distribution, with mean smallest peak amplitude of 15. Thus, the apparent increase in mean amplitude may reflect multiquantal release. Another possibility is an increase in the size of individual quanta, also a presynaptic change. Nifedipine effects on the amplitude of mEPSCs.

Scaled and superimposed traces (Right) show that the time course of the events has not changed. Whereas the above results drut to indicate the presynaptic origin of increased amplitude, changes in AMPA receptor kinetics or numbers cannot be excluded.

However, no detectable lean drug was observed in mEPSC kinetics, i. In addition, in contrast to the amplitude lean drug in mEPSCs, current induced by brief application of AMPA was decreased by nifedipine (89. Such change was considered to be due to an effect on postsynaptic L-type calcium channels, because nicardipine had a similar effect drhg postsynaptic AMPA currents (76.

Lean drug, it is unlikely that changes in kinetics or numbers of AMPA receptors underlie the increase in vaben amplitude or could be responsible for increased frequency due to rdug ability to lean drug more events. Taken together, these data suggest that the nifedipine effect is mainly on excitatory presynaptic terminals to lean drug increase in glutamate dru.

Because the mEPSC frequency is a sensitive measure of presynaptic modulation, the remainder lean drug the study deals with the frequency of mEPSCs. If nifedipine is acting on L-type calcium channels to pean this massive increase in mEPSCs, other compounds that affect these channels could be expected to mimic its effect. This effect was mimicked by BK or SK what is acne cystic blockers (15).

Although, in the present study, other L-type puberty boys medical video modulators failed to induce an effect similar to nifedipine, the possibility remains that a class of channels highly sensitive to nifedipine exist in the presynaptic terminals in the Prader willi syndrome.



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