Abstract
The hyperpolarization-activated cation current (I(h)) is a determinant of intrinsic excitability in various cells, including dopaminergic neurons (DA) of the ventral tegmental area (VTA). In contrast to other cellular conductances, I(h) is activated by hyperpolarization negative to -55 mV and activating I(h) produces a time-dependent depolarizing current. Our laboratory demonstrated that cocaine sensitization, a chronic cocaine behavioral model, significantly reduces I(h) amplitude in VTA DA neurons. Despite this reduction in I(h), the spontaneous firing of VTA DA cells after cocaine sensitization remained similar to control groups. Although the role of I(h) in controlling VTA DA excitability is still poorly understood, our hypothesis is that I(h) reduction could play a role of a homeostatic controller compensating for cocaine-induced change in excitability. Using in vivo single-unit extracellular electrophysiology in isoflurane anesthetized rats, we explored the contribution of I(h) on spontaneous firing patterns of VTA DA neurons. A key feature of spontaneous excitability is bursting activity; bursting is defined as trains of two or more spikes occurring within a short interval and followed by a prolonged period of inactivity. Burst activity increases the reliability of information transfer. To elucidate the contribution of I(h) to spontaneous firing patterns of VTA DA neurons, we locally infused an I(h) blocker (ZD 7288, 8.3 μM) and evaluated its effect. I(h) blockade significantly reduced firing rate, bursting frequency, and percent of spikes within a burst. In addition, I(h) blockade significantly reduced acute cocaine-induced spontaneous firing rate, bursting frequency, and percent of spikes within a burst. Using whole-cell patch-clamp, we determine the progressive reduction of I(h) after acute and chronic cocaine administration (15 mg/k.g intraperitoneally). Our data show a significant reduction (~25%) in I(h) amplitude after 24 but not 2 h of acute cocaine administration. These results suggest that a progressive reduction of I(h) could serve as a homeostatic regulator of cocaine-induced spontaneous firing patterns related to VTA DA excitability.