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

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 6to examine the effect of cocaine exposure on the distribution and density of 2 receptors in autopsy studies of human cocaine fatalities. The selective labeling of the 2 receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY Ն (ϩ)-bremazocine Ͼ Ͼ U50,488 Ն U69,593) distinct from either the 1 or 3 receptor subtypes. Visualization of [ 125 I]IOXY labeling revealed that 2 receptors localize to mesocortical and subcortical limbic areas, including the cingulate, entorhinal, insular, and orbitofrontal cortices and the nucleus accumbens and amygdala. The number of 2 receptors in the nucleus accumbens and other limbic brain regions from cocaine fatalities was increased twofold as compared with age-matched and drugfree control subjects. Cocaine overdose victims, who experienced paranoia and marked agitation before death, also had elevated densities of 2 receptors in the amygdala. These findings demonstrate for the first time that 2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of 2 receptor 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.

Suppressed Prolactin Response to Dynorphin A1–13 in Methadone-Maintained Versus Control Subjects

“…The large presence of mRNA for these two proteins in the limbic region implicates the -opioid system in the modulation of affective states and the addictive diseases. -Receptor expression is increased in the nucleus accumbens and the caudate putamen of rats after chronic binge-pattern cocaine and, in human cocaine overdose victims, -receptor expression is increased in the nucleus accumbens and the amygdala (Unterwald et al, 1994;Staley et al, 1997). Similar druginduced changes have also been reported for -opioid receptor expression (Unterwald et al, 1994;Zubieta et al, 1996).…”

Absence of Δ-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice

“…Indeed, stimulation of -opioid receptors through endogenous dynorphins in response to other dysphoric-aversive stimuli has been reported (Staley et al, 1997;Hutchinson et al, 2000). Additional studies will be performed to determine whether the motivational responses of other aversive stimulus are also modified in prodynorphin knockout mice.…”

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

“…Chronic cocaine administration has also been shown to increase kappa-opioid receptor expression in rats, a finding also seen in human cocaine overdose deaths (Unterwald et al, 1994;Staley et al, 1997). Natural and synthetic kappaopioid receptor agonists directly infused into the striatum or administered systemically to rodents will both attenuate cocaine-induced dopamine surges in the nucleus accumbens and block cocaine-induced conditioned place preference (Maisonneuve et al, 1994;Zhang et al, 2004a, b).…”