Locus coeruleus activation during environmental novelty gates cocaine-induced long-term hyperactivity of dopamine neurons.

A key feature of the brain is the ability to handle novelty. Anything that is new will stimulate curiosity and trigger exploration. Novelty preference has been proposed to predict increased sensitivity to cocaine. Different brain circuits are activated by novelty, but three specific brain regions are critical for exploring a novel environment: the noradrenergic neurons originating from the locus coeruleus (LC), the dopaminergic neurons from the ventral tegmental area (VTA), and the hippocampus. However, how exploring a novel environment can interfere with the reward system and control cocaine impact on VTA dopamine neuron plasticity is unclear. Here, we first investigated the effects of exposure to a novel environment on the tonic electrophysiological properties of VTA dopamine neurons. Then, we explored how exposure to a novel environment controls cocaine-evoked plasticity in dopamine neurons. Our findings indicate that LC controls VTA dopamine neurons under physiological conditions but also after cocaine.

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

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