Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine.

Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18, 48 and 72 h after injection of amphetamine. The effects of inactivation of the basolateral amygdala (BLA) and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal, there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. The data support a model in which the negative affective state following acute amphetamine withdrawal is associated with a decrease in DA neuron population activity, driven by hyperactivity of the BLA. Although ketamine reversed the hypodopaminergic state following withdrawal, the failure to reduce immobility in the modified FST indicates that different processes underlying negative emotional state may exist between depression and drug withdrawal.