RADIOLIGAND BINDING AND IMMUNOAUTORADIOGRAPHIC EVIDENCE FOR A LACK OFTOXICITY TO DOPAMINERGIC NERVE-TERMINALS IN HUMAN COCAINE OVERDOSE VICTIMS

Radioligand binding to and immunolabeling of transport sites associate d with monoamine-containing synaptic vesicles affords a novel approach for mapping the integrity of dopaminergic (DAergic) nerve terminals, The present study used [(125)]iodovinyltetrabenazine ([I-125]TBZ) and a fusion protein antibody directed at the large intraluminal loop of t he neuronal vesicular monoamine transporter (hVMAT2-loop) as probes to assess the effects of chronic cocaine use on the integrity of DAergic nerve terminals in the striatum of cocaine fatalities. Visualization of [I-125]TBZ binding in human brain revealed a distinct pattern of la beling throughout the rostral-caudal extent of the striatum. Saturatio n binding of [I-125]TBZ in striatal membranes demonstrated a single hi gh affinity site (K-d = 2.3 +/- 0.9 nM and B-max = 55.5 +/- 8.1 pmol/g tissue) with a pharmacological profile (tetrabenazine greater than or equal to iodovinyltetrabenazine > ketanserin greater than or equal to reserpine > haloperidol > GBR 12909) consistent with the specific lab eling of hVMAT2. Quantitative in vitro autoradiography demonstrated no significant alteration in the density of [I-125]TBZ binding sites in the anterior and posterior sectors of the striatum in cocaine fataliti es with and without preterminal excited delirium as compared to drug-f ree and age-matched control subjects. Similarly, the levels of hVMAT2- loop immunoreactivity were not significantly different across control and cocaine fatality groups. The results demonstrate the lack of an al teration in [I-125]TBZ binding sites and hVMAT2 protein in the striatu m from a young cohort of cocaine fatalities. Since striatal VMAT2 is p rimarily associated with DAergic nerve terminals, these results sugges t that chronic cocaine use failed to affect the integrity of striatal DAergic nerve terminals.