Increased Sensitivity to Cocaine Self-Administration in HIV-1 Transgenic Rats is Associated with Changes in Striatal Dopamine Transporter Binding

• Published in: Journal of neuroimmune pharmacology 2015-09, Vol.10 (3), p.493-505
• Main Authors: McIntosh, Scot, Sexton, Tammy, Pattison, Lindsey P., Childers, Steven R., Hemby, Scott E.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Binding sites; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cocaine; Cocaine - administration & dosage; Cocaine - analogs & derivatives; Cocaine - pharmacology; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins - drug effects; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - pharmacology; Dose-Response Relationship, Drug; Heroin - administration & dosage; Heroin - pharmacology; HIV Infections - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Immunology; Male; Narcotics - administration & dosage; Narcotics - pharmacology; Neostriatum - drug effects; Neostriatum - metabolism; Neurosciences; Original Article; Pharmacology/Toxicology; Protein Binding - drug effects; Rats; Rats, Inbred F344; Rats, Transgenic; Rodents; Self Administration; Virology
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-015-9594-0

Cocaine abuse in HIV patients accelerates the progression and severity of neuropathology, motor impairment and cognitive dysfunction compared to non-drug using HIV patients. Cocaine and HIV interact with the dopamine transporter (DAT); however, the effect of their interaction on DAT binding remains understudied. The present study compared the dose–response functions for intravenous self-administration of cocaine and heroin between male HIV-1 transgenic (HIV-1 Tg) and Fischer 344 rats. The cocaine and heroin dose–response functions exhibit an inverted U-shape for both HIV-1 Tg and F344 rats. For cocaine, the number of infusions for each dose on the ascending limb was greater for HIV-1 Tg versus F344 rats. No significant changes in the heroin dose–response function were observed in HIV-1 Tg animals. Following the conclusion of self-administration experiments, DAT binding was assessed in striatal membranes. Saturation binding of the cocaine analog [ 125 I] 3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester ([ 125 I]RTI-55) in rat striatal membranes resulted in binding curves that were best fit to a two-site binding model, allowing for calculation of dissociation constant (K d ) and binding density (B max ) values that correspond to high- and low-affinity DAT binding sites. Control HIV-1 Tg rats exhibited a significantly greater affinity (i.e., decrease in K d value) in the low-affinity DAT binding site compared to control F344 rats. Furthermore, cocaine self-administration in HIV-1 Tg rats increased low-affinity K d (i.e., decreased affinity) compared to levels observed in control F344 rats. Cocaine also increased low-affinity B max in HIV-1 Tg rats as compared to controls, indicating an increase in the number of low-affinity DAT binding sites. F344 rats did not exhibit any change in high- or low-affinity K d or B max values following cocaine or heroin self-administration. The increase in DAT affinity in cocaine HIV-1 Tg rats is consistent with the leftward shift of the ascending limb of the cocaine dose–response curve observed in HIV-1 Tg vs. F344 rats, and has major implications for the function of cocaine binding to DAT in HIV patients. The absence of HIV-related changes in heroin intake are likely due to less dopaminergic involvement in the mediation of heroin reward, further emphasizing the preferential influence of HIV on dopamine-related behaviors.