I blockade reduces cocaine-induced firing patterns of putative dopaminergic neurons of the ventral tegmental area in the anesthetized rat.

The hyperpolarization-activated cation current (I) 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 is activated by hyperpolarization negative to -55 mV and activating I produces a time-dependent depolarizing current. Our laboratory demonstrated that cocaine sensitization, a chronic cocaine behavioral model, significantly reduces I amplitude in VTA DA neurons. Despite this reduction in I, the spontaneous firing of VTA DA cells after cocaine sensitization remained similar to control groups. Although the role of I in controlling VTA DA excitability is still poorly understood, our hypothesis is that I 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 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 to spontaneous firing patterns of VTA DA neurons, we locally infused an I blocker (ZD 7288, 8.3 μM) and evaluated its effect. I blockade significantly reduced firing rate, bursting frequency, and percent of spikes within a burst. In addition, I 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 after acute and chronic cocaine administration (15 mg/k.g intraperitoneally). Our data show a significant reduction (~25%) in I amplitude after 24 but not 2 h of acute cocaine administration. These results suggest that a progressive reduction of I could serve as a homeostatic regulator of cocaine-induced spontaneous firing patterns related to VTA DA excitability.