Cocaine sensitization increases subthreshold 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, nonselective cation current, dubbed IhWe recently demonstrated that Ihand 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 Ihand capacitance. In cells from cocaine-sensitized animals, the amplitude of excitatory synaptic potentials, at -70 mV, was ∼39% larger in contrast 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. Ihattenuation is unlikely to explain such observations, since at -70 mV, no statistical differences exist in Ihor 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, whereas it could also result in DA depletion, as smaller neurons might express low levels of tyrosine hydroxylase.



This work uses a new approach that directly extracts important biophysical parameters from alpha function-evoked synaptic potentials. Two of these parameters are the cell membrane capacitance (Cm) and rate at any time point of the synaptic waveform. The use of such methodology shows that cocaine sensitization reduces Cmand increases the speed of synaptic signaling. Paradoxically, although synaptic potentials show a faster decay under cocaine their temporal summation is substantially elevated.
Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico; and.|Departamento de Ciencias Naturales, Universidad del Sagrado Corazón, San Juan, Puerto Rico.
Francisco
F
Arencibia-Albite
Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico; and.
Rafael
R
Vázquez-Torres
Department of Physiology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico; and carlos.jimenez8@upr.edu.
Carlos A
CA
Jiménez-Rivera
D000818:Animals; D001703:Biophysics; D059333:Central Nervous System Sensitization / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors; D059290:Dopaminergic Neurons / Q000187:drug effects*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology*
D018765:Dopamine Uptake Inhibitors; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine
EPSP; capacitance; cocaine; h-current; temporal summation