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

Abstract

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.

Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression

“…4b. Indeed, ketamine was also found to restore DA neuron firing in rats 24 hours after amphetamine withdrawal 55 . Therefore, although acute stressors tend to activate the dopamine system via the hippocampus-accumbens circuit, with prolonged stress and withdrawal there is a compensatory and long-term decrease in VTA DA neuron firing driven by an ilPFC-amygdala pathway.…”

“…However, when examined at longer time points following stress or amphetamine withdrawal there is a 50% reduction in tonic DA activity. 54, 55 This compensatory down-regulation following DA system activation is referred to as an opponent process 56, 57 ; that is, when the DA system is acutely activated, there is a subsequent, prolonged compensatory decrease in the responsivity of the DA system. This subsequent DA down-regulation is dependent on the BLA 54, 55 .…”

“…The duration of the stressor impacts the magnitude and duration of the negative affective state associated with its withdrawal 56, 57 . Thus, acute activation of the DA system by amphetamine or stress-induced DA neuron activation is followed by a depression of DA neuron firing 54, 55 . However, if the stressor is presented over a much longer period of time, the consequent depressive-like state is also maintained for an extended period following withdrawal.…”

NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice

“…497 Activation of TRPV1 channels is known to induce depolar-498 ization in the neurons through enhancing the calcium 499 influx (Madasu et al, 2015). In this regard, a study by rodents (Koltunowska et al, 2013;Belujon et al, 2015;527 Fuller et al, 2015). Nevertheless, evidence indicates that 528 administration of NMDA receptor antagonists potently 529 enhances dopaminergic system activity in mesocorticol-530 imbic circuits (Li et al, 2015;Cui et al, 2015).…”

La ketamina come antidepressivo ad azione rapida: controversia e implicazioni [translation of “Ketamine as a rapid antidepressant: the debate and implications” by Dr. Giacomo Galli and Dr. Serena Saraceni]

“…Queste scoperte ribadiscono come la ketamina abbia un effetto stimolante (Belujon 2016). Non c'è un'evidenza scientifica che possa provare che il rapido effetto antidepressivo associato all'uso di ketamina è diverso dal "rush" provocato dagli stimolanti.…”