Self-vaccination by methamphetamine glycation products chemically links chronic drug abuse and cardiovascular disease.

Methamphetamine abuse is spreading rapidly throughout the United States and is characterized by significant health consequences. The powerfully rewarding effects of methamphetamine are attributed to multiple neuropharmacological actions such as its ability to block plasma membrane transporters of all monoamines, reduce dopamine transporter expression, and inhibit monoamine oxidase activity while increasing tyrosine hydroxylase activity. However, subsequent neuroreceptor changes including monoamine deficits complement this striking increase in monoamine release. Chronic methamphetamine abuse, as studied via self-administration paradigms in rodents, causes progressive dopaminergic neurotoxicity, a neuroanatomical change accompanied by increasing drug tolerance and escalating intake, two behavioral parameters of addiction. We have recently proposed that methamphetamine covalently glycates endogenous proteins. Such an event spurs antibody production against these immunoconjugates, possibly leading to drug sequestration by antibody binding of drug. Here we demonstrate that this drug-dependent glycation mechanism is operative in vivo through the dose-dependent detection of antibodies against methamphetamine-derived advanced glycation end products in rats chronically self-administering methamphetamine. Furthermore, increased levels of proinflammatory cytokines, evidence of potent immunoactivation, were also detected. Given the known role of advanced glycation end products in the alteration of protein function in vivo and the participation of these molecules in various diseases, methamphetamine-derived advanced glycation end products provide an unrecognized molecular mechanism for the development of vasculitis and other cardiovascular maladies reported with high incidence in chronic methamphetamine users.