Modulation of HCN channels in lateral septum by nicotine

Abstract

The effects of addictive drugs most commonly occur via interactions with target receptors. The same is true of nicotine and its multiple receptors in a variety of cell types. However, there are also side effects for given substances that can dramatically change cellular, tissue, organ, and organism functions. In this study, we present evidence that nicotine possesses such properties, and modulates neuronal excitability. We recorded whole-cell voltages and currents in neurons situated in the dorsal portion of the lateral septum in acute coronal brain slices of adult rats. Our experiments in the lateral septum revealed that nicotine directly affects HCN – hyperpolarization-activated cyclic nucleotide gated non-selective cation channels. We demonstrate that nicotine effects persist despite the concurrent application of nicotinic acetylcholine receptors’ antagonists – mecamylamine, methyllycaconitine, and dihydro-β-erythroidine. These results are novel in regard to HCN channels in the septum, in general, and in their sensitivity to nicotine, in particular.

Addictive neurons

“…In rats sensitized to cocaine the peak tail currents are also blocked, but the magnitude of final decay remained unaffected and is similar to that of saline treated animals. HCN currents waveform is comparable to LS neurons including that of tails [19] despite the differences in HP of −60 vs. −70 mV. The major distinction between the LS and VTA DA neurons is the activation threshold of −100 vs. −80 mV, respectively [92] .…”

“…Since these are similar DA neurons holding the MP at identical −60 mV would be comprehensive as it is shown during recording of sag and its abolishment in the same 2 nd cell. Consistently, the rebound action potential − RAP − is obliterated by ZD7288 [18,19] . Note that as highlighted the ZD7288 exerts heterogeneous effects on neurons [19] .…”

“…Consistently, the rebound action potential − RAP − is obliterated by ZD7288 [18,19] . Note that as highlighted the ZD7288 exerts heterogeneous effects on neurons [19] .…”

“…DA neurons in these two nuclei can be distinguished only by delays in RAPs (~300 vs. 800 ms, Figure 4), since all other active and passive parameters are comparable. RAPs are sensitive to the magnitude of sag and not every neuron exhibits them, sometimes there is only a rebound tail potential − RTP [19] . Selective blockade of HCN channels by 60 µM ZD 7288 reduces inward currents, but perhaps not completely or some subunits are still activated, since at −125 and −115 mV steps there are gradually increasing currents with a latency of ~1 s [30] .…”

“…Selective blockade of HCN channels by 60 µM ZD 7288 reduces inward currents, but perhaps not completely or some subunits are still activated, since at −125 and −115 mV steps there are gradually increasing currents with a latency of ~1 s [30] . The ZD 7288 effects on both sag currents and potentials are heterogeneous and also in terms of required concentrations [19] . The magnitudes of tails are a better indicative of the potency of ZD or any other drugs on HCN channels ( Figure 5).…”