ADAPTIVE INCREASE IN D-3 DOPAMINE-RECEPTORS IN THE BRAIN REWARD CIRCUITS OF HUMAN COCAINE FATALITIES

The mesolimbic dopaminergic system plays a primary role in mediating t he euphoric acid rewarding effects of most abused drugs. Chronic cocai ne use is associated with an increase in dopamine neurotransmission re sulting from the blockade of dopamine uptake and is mediated by the ac tivation of dopamine receptors. Recent studies have suggested that the D-3 receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D-3 receptor-preferring agonist 7-hydroxy-N,N-d-n-prop yl-2-aminotetralin (7-OH-DPAT) is a reinforcer in rhesus monkeys train ed to self-administer cocaine, but not in cocaine-naive monkeys. In vi tro autoradiographic localization of [H-3]-(+)-7-OH-DPAT binding in th e human brain demonstrated that D-3 receptors were prevalent and highl y localized over the ventromedial sectors of the striatum. Pharmacolog ical characterization of [H-3]-(+)-7-OH-DPAT binding to the human nucl eus accumbens demonstrated a rank order of potency similar to that obs erved for binding to the cloned D-3 receptor expressed in transfected cell lines. Region-of-interest analysis of[H-3]-(+)-7-OH-DPAT binding to the D-3 receptor demonstrated a one- to threefold elevation in the number of binding sites over particular sectors of the striatum and su bstantia nigra in cocaine overdose victims as compared with age-matche d and drug-free control subjects. The elevated number of [H-3]-(+)-7-O H-DPAT binding sites demonstrates that adaptive changes in the D-3 rec eptor in the reward circuitry of the brain are associated with chronic cocaine abuse. These results suggest that the D-3 receptor may be a u seful target for drug development of anti-cocaine medications.