Serotonin transporters upregulate with chronic cocaine use

Cocaine potently inhibits serotonin (5-HT) reuptake in cell bodies and at n erve 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 transp orter (SERT) using ligand binding and autoradiographic methods in subgroups of cocaine overdose deaths. Quantitative autoradiography of [I-125]RTI-55 was used to map and measure the effect of chronic cocaine use on SERT densi ties in the striatum, substantia nigra, amygdala, and adjacent paralimbic c ortical areas of cocaine overdose (CO) victims with and without preterminal evidence of excited delirium (ED). SERT densities were elevated in the nuc leus accumbens and throughout the anterior and posterior sectors of striatu m in CO victims compared with age-matched and drug-free control subjects. I n contrast, SERT densities were increased significantly in the anterior str iatum, but not the posterior sectors in ED victims. Significant elevations in SERT were measured in the orbitofrontal gyrus (Brodmann area 11), the an terior 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 affi nity of the radioligand for the SERT. Chronic cocaine exposure upregulated SERT densities in the substantia nigra of the CO, but not ED victims. The l ack of SERT upregulation in the substania nigra and posterior striatum sugg ests the possibility of a distinct phenotype for fatal ED victims that exhi bited an acute onset of bizarre and violent behavior prior to death. Adapti ve changes in the SERT densities may contribute to depressed mood and drug craving associated with acute cocaine abstinence. (C) 2000 Elsevier Science B.V. All rights reserved.