Adaptive Increase in D3Dopamine Receptors in the Brain Reward Circuits of Human Cocaine Fatalities

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Abstract
The mesolimbic dopaminergic system plays a primary role in mediating the euphoric and rewarding effects of most abused drugs. Chronic cocaine use is associated with an increase in dopamine neurotransmission resulting from the blockade of dopamine uptake and is mediated by the activation of dopamine receptors. Recent studies have suggested that the D3receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D3receptor-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) is a reinforcer in rhesus monkeys trained to self-administer cocaine, but not in cocaine-naive monkeys.In vitroautoradiographic localization of [3H]-(+)-7-OH-DPAT binding in the human brain demonstrated that D3receptors were prevalent and highly localized over the ventromedial sectors of the striatum. Pharmacological characterization of [3H]-(+)-7-OH-DPAT binding to the human nucleus accumbens demonstrated a rank order of potency similar to that observed for binding to the cloned D3receptor expressed in transfected cell lines. Region-of-interest analysis of [3H]-(+)-7-OH-DPAT binding to the D3receptor demonstrated a one- to threefold elevation in the number of binding sites over particular sectors of the striatum and substantia nigra in cocaine overdose victims as compared with age-matched and drug-free control subjects. The elevated number of [3H]-(+)-7-OH-DPAT binding sites demonstrates that adaptive changes in the D3receptor in the reward circuitry of the brain are associated with chronic cocaine abuse. These results suggest that the D3receptor may be a useful target for drug development of anti-cocaine medications.