Sensitization of locus ceruleus neurons during withdrawal from chronic stimulants and antidepressants

The effects of chronic exposure to cocaine, amphetamine and desipramine on noradrenergic neurons in the locus ceruleus were examined using intracellular recordings in rat brain slices. Animals were treated for 2 weeks with either cocaine, amphetamine or desipramine, and all recordings were made after a 1- week withdrawal period. Cells from all three drug-treated groups showed a significant increase in sensitivity to the acute effects of cocaine and amphetamine in prolonging the time course of the noradrenaline-mediated inhibitory postsynaptic potential. At the highest cocaine and amphetamine doses tested (10 and 3 μM, respectively), the inhibitory postsynaptic potential duration was increased approximately 233% in the drug-treated groups relative to saline controls. In addition, locus ceruleus neurons from the cocaine-, amphetamine- and desipramine-treated groups showed a significant 10, 12 and 17% increase, respectively, in the maximum outward current produced by clonidine. There was also a significant increase in the behavioral sensitivity of the drug-treated animals to the sedative effects of clonidine. The mechanisms responsible for the increased sensitivity to the acute effects of cocaine, amphetamine and alpha-2 agonists may play a role in the withdrawal response to psychostimulants.