κ2Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims

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Abstract
Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry that affect motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blocking DA reuptake into the presynaptic nerve terminal, reciprocal signaling between DA and endogenous opioids has important implications for cocaine dependence. The present study used the opioid antagonist 6 β-[125iodo]-3,14-dihydroxy-17-cyclopropylmethyl-4,5 α-epoxymorphinan ([125I]IOXY) after pretreatment with the site-directed acylating agents 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidiazole-HCl (μ-selective) andN-phenyl-N-[1-(2-(4-isothiocyanato)-phenethyl)-4-piperidinyl]-propanamide-HCl (δ-selective) to examine the effect of cocaine exposure on the distribution and density of κ2receptors in autopsy studies of human cocaine fatalities. The selective labeling of the κ2receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY ≥ (+)-bremazocine ≫ U50,488 ≥ U69,593) distinct from either the κ1or κ3receptor subtypes. Visualization of [125I]IOXY labeling revealed that κ2receptors localize to mesocortical and subcortical limbic areas, including the cingulate, entorhinal, insular, and orbitofrontal cortices and the nucleus accumbens and amygdala. The number of κ2receptors in the nucleus accumbens and other limbic brain regions from cocaine fatalities was increased twofold as compared with age-matched and drug-free control subjects. Cocaine overdose victims, who experienced paranoia and marked agitation before death, also had elevated densities of κ2receptors in the amygdala. These findings demonstrate for the first time that κ2receptor numbers are upregulated by cocaine exposure. The molecular adaptation of κ2receptor numbers may play a role in the motivational incentive associated with episodes of binge cocaine use and in the dysphoria that follows abrupt cocaine withdrawal.