Excessive cocaine use results from decreased phasic dopamine signaling in the striatum.
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.
1] Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, Washington, USA. [2] Department of Pharmacology, University of Washington, Seattle, Washington, USA. [3].
Ingo
I
Willuhn
1] Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, Washington, USA. [2] Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Lauren M
LM
Burgeno
Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Peter A
PA
Groblewski
1] Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, Washington, USA. [2] Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Paul E M
0000000287497026
PE
Phillips
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D055664:Electrochemical Techniques; D016014:Linear Models; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D004298:Dopamine