Intermittent Cocaine Self‐Administration Reduces H‐current In Putative Dopaminergic Neurons of The Ventral Tegmental Area

Abstract

Cocaine use produces different effects in the Mesocorticolimbic System (MCL) depending on the temporal pattern in which they are consumed. The Intermittent Access (IntA) cocaine self-administration is a protocol that better simulates human behavior due to the intermittent pattern of drug administration. Unlike Long Access (LgA) cocaine self-administration, which generates tolerance, IntA, produces psychomotor, incentive, and neural sensitization of the MCL. Dopamine (DA) neurons display a prominent mixed cation current conductance known as the hyperpolarization-activated cyclic nucleotide current, or Ih, that contributes to neural processes such as resting membrane potential, firing frequency modulation, and synaptic transmission. Since experimenter administered drug sensitization alters the intrinsic properties of DA neurons from the ventral tegmental area (VTA), we asked if neural sensitization of this system after exposure to IntA includes these intrinsic alterations in DA neurons. Using the whole-cell patch-clamp technique in brain slices, we investigated the effects of IntA on Ih and neuronal excitability. Hyperpolarizing current injections followed by sudden depolarizing steps were used to analyze rebound excitation. Increasing depolarizing current injections were used to evaluate how neurons respond to the depolarizing stimulus. Our preliminary results demonstrate that IntA protocol produces a significant Ih amplitude reduction (P<0.05) and an increase in number of rebound action potentials. Additionally, the depolarizing current step protocol showed a significant increase in the number of action potentials (APs)(P<0.05). These results suggest that the Ih modulation is present in both models that sensitize the MCL. Such reduction of Ih amplitude and the increase in APs may be considered one of the neuronal plasticity changes that contributes to the development of drug addiction. In addition, the incentive-sensitization view of addiction which states that drug-seeking and taking is produced by a hyper-responsive DA system could also involve these modifications. Therefore, we conclude that this reduction may be part of an homeostatic mechanism in response to the hyper-responsive DA system.