D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims.
Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry, which affects motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blockade of DA uptake, reciprocal signaling between DA and endogenous opioids has important implications for understanding cocaine dependence. We have used in vitro autoradiography and ligand binding to map D3 DA and kappa opioid receptors in the human brains of cocaine-overdose victims. The number of D3 binding sites was increased one-to threefold over the nucleus accumbens and ventromedial sectors of the caudate and putamen from cocaine-overdose victims, as compared to age-matched and drug-free control subjects. D3 receptor/cyclophilin mRNA ratios in the nucleus accumbens were increased sixfold in cocaine-overdose victims over control values, suggesting that cocaine exposure also affects the expression of D3 receptor mRNA. The number of kappa opioid receptors in the nucleus accumbens and other corticolimbic areas from cocaine fatalities was increased twofold as compared to control values. Cocaine-overdose victims exhibiting preterminal excited delirium had a selective upregulation of kappa receptors measured also in the amygdala. Understanding the complex regulatory profiles of DA and opioid synaptic markers that occur with chronic misuse of cocaine may suggest multitarget strategies for treating cocaine dependence.
Mash
D C
DC
Department of Neurology, University of Miami School of Medicine, Florida 33136, USA. dmash@mednet.med.miami.edu
Staley
J K
JK
D001345:Autoradiography; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002423:Cause of Death; D003042:Cocaine / Q000506:poisoning*; D018491:Dopamine Agonists / Q000493:pharmacokinetics; D062787:Drug Overdose / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007457:Iodine Radioisotopes; D008032:Limbic System / Q000378:metabolism / Q000473:pathology; D009714:Nucleus Accumbens / Q000378:metabolism / Q000473:pathology; D010111:Oxymorphone / Q000493:pharmacokinetics; D019696:Peptidylprolyl Isomerase / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics; D014158:Transcription, Genetic; D014316:Tritium
C493593:DRD3 protein, human; D018491:Dopamine Agonists; D007457:Iodine Radioisotopes; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D017473:Receptors, Opioid, kappa; D013764:Tetrahydronaphthalenes; D014316:Tritium; D010111:Oxymorphone; D019696:Peptidylprolyl Isomerase; D003042:Cocaine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin