Cocaine sensitization increases sub-threshold activity in dopamine neurons from the ventral tegmental area

The progressive escalation of psychomotor responses that results from repeated cocaine administration is termed sensitization. This phenomenon alters the intrinsic properties of dopamine (DA) neurons from the ventral tegmental area (VTA) leading to enhanced dopaminergic transmission in the mesocorticolimbic network. The mechanisms underlying this augmented excitation are nonetheless poorly understood. DA neurons display the hyperpolarization-activated non-selective cation current dubbed Ih. We recently demonstrated that Ih and membrane capacitance are substantially reduced in VTA DA cells from cocaine sensitized rats. The present study shows that 7 days of cocaine withdrawal did not normalize Ih and capacitance. In cells from cocaine sensitized animals the amplitude of excitatory synaptic potentials, at -70mV, was ~39% larger in contrasts to controls. Raise and decay phases of the synaptic signal were faster under cocaine, a result associated with a reduced membrane time constant. Synaptic summation was paradoxically elevated by cocaine exposure as it consisted of a significantly reduced summation indexed but a considerably increased depolarization. These effects are at least a consequence of the reduced capacitance. H-conductance attenuation is unlikely to explain such observations since at -70mV no statistical differences exist in Ih or input resistance. The neuronal shrinkage associated with a diminished capacitance may help to understand two fundamental elements of drug addiction: incentive sensitization and negative emotional states. A reduced cell size may lead to substantial enhancement of cue-triggered bursting which underlies drug-craving and reward anticipation while it could also result in dopamine depletion as smaller neuron might express low levels of tyrosine hydroxylase.

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