Excessive cocaine use results from decreased phasic dopamine signaling in the striatum

The authors measured striatal dopamine (DA) release in vivo using fast-scan cyclic voltammetry in a model involving escalating self-administration of cocaine in rats. Phasic DA release in ventromedial striatum was negatively correlated with escalation of cocaine intake. The DA precursor L-DOPA restored phasic DA release and reversed escalation of cocaine intake. Drug addiction is a neuropsychiatric disorder marked by escalating drug use. Dopamine neurotransmission in the ventromedial striatum (VMS) mediates acute reinforcing effects of abused drugs, but with protracted use the dorsolateral striatum is thought to assume control over drug seeking. We measured striatal dopamine release during a cocaine self-administration regimen that produced escalation of drug taking in rats. Surprisingly, we found that phasic dopamine decreased in both regions as the rate of cocaine intake increased, with the decrement in dopamine in the VMS significantly correlated with the rate of escalation. Administration of the dopamine precursor L-DOPA at a dose that replenished dopamine signaling in the VMS reversed escalation, thereby demonstrating a causal relationship between diminished dopamine transmission and excessive drug use. Together these data provide mechanistic and therapeutic insight into the excessive drug intake that emerges following protracted use.