Serotonin transporters upregulate with chronic cocaine use.
Cocaine potently inhibits serotonin (5-HT) reuptake in cell bodies and at nerve terminals and 5-HT has been implicated as a modulator of dopaminergic neurotransmission. Chronic use of cocaine may lead to a "serotonin-deficit" form of 5-HT dysregulation. We have examined the status of the 5-HT transporter (SERT) using ligand binding and autoradiographic methods in subgroups of cocaine overdose deaths. Quantitative autoradiography of [125I]RTI-55 was used to map and measure the effect of chronic cocaine use on SERT densities in the striatum, substantia nigra, amygdala, and adjacent paralimbic cortical areas of cocaine overdose (CO) victims with and without preterminal evidence of excited delirium (ED). SERT densities were elevated in the nucleus accumbens and throughout the anterior and posterior sectors of striatum in CO victims compared with age-matched and drug-free control subjects. In contrast, SERT densities were increased significantly in the anterior striatum, but not the posterior sectors in ED victims. Significant elevations in SERT were measured in the orbitofrontal gyrus (Brodmann area 11), the anterior portion of the insular cortex and the cingulate gyrus (Brodmann area 24) in CO and ED victims. Saturation binding site analysis demonstrated an increase in the density of RTI-55 binding sites with no change in the affinity of the radioligand for the SERT. Chronic cocaine exposure upregulated SERT densities in the substantia nigra of the CO, but not ED victims. The lack of SERT upregulation in the substania nigra and posterior striatum suggests the possibility of a distinct phenotype for fatal ED victims that exhibited an acute onset of bizarre and violent behavior prior to death. Adaptive changes in the SERT densities may contribute to depressed mood and drug craving associated with acute cocaine abstinence.
Mash
D C
DC
Department of Neurology, School of Medicine, University of Miami, Miami, FL 33136, USA. dmash@newssun.med.miami.edu
Staley
J K
JK
Izenwasser
S
S
Basile
M
M
Ruttenber
A J
AJ
D000328:Adult; D001345:Autoradiography; D002352:Carrier Proteins / Q000378:metabolism*; D002908:Chronic Disease; D003042:Cocaine / Q000031:analogs & derivatives / Q000506:poisoning; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000473:pathology; D018765:Dopamine Uptake Inhibitors / Q000506:poisoning; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011869:Radioligand Assay; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; D015854:Up-Regulation / Q000187:drug effects
D002352:Carrier Proteins; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine