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

Abstract

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 selfadministration 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.addiction ͉ advanced glycation end product ͉ vasculitis

Behavioral regulation in methamphetamine abusers: An fMRI study

“…This worldwide epidemic brings with it collateral health issues, including MA-induced cardiovascular disease (Treweek et al, 2007; Wijetunga et al, 2004), increased rates of HIV infection (Colfax and Shoptaw, 2005; Huff, 2006; Jones, 2005), and prominent psychiatric symptoms (Chen et al, 2005; Chen et al, 2003; Iyo et al, 2004; McKetin et al, 2006; Sato et al, 1992; Srisurapanont et al, 2003). The highly addictive nature of MA, and its profound negative impact on society makes this drug a major public health concern in the 21 st century (United, 2009).…”

Effects of cannabinoid CB1 receptor antagonist rimonabant in consolidation and reconsolidation of methamphetamine reward memory in mice

“…The prevalence of METH abuse has increased dramatically in many countries in recent years, which has resulted in serious health and social problems (Degenhardt et al 2008;Griffiths et al 2008;Maxwell and Rutkowski 2008;Michels et al 2007;Pluddemann et al 2008). The powerful rewarding effects of METH are thought to be attributed to multiple pharmacological actions, including the blockade of plasma membrane transporters of all monoamines, the suppression of dopamine transporter expression, and the inhibition of monoamine oxidase activity while increasing tyrosine hydroxylase activity (Kalivas 2007;Pulvirenti and Koob 1994;Treweek et al 2007;Vezina 2004). Worth noting is that the majorities of studies have directed their focus on the effect of monoamine system on the neurochemical mechanism of METH.…”

Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

“…In humans it is reported that METH abusers have severe dilated cardiomyopathy [ 17 ]. In an animal model, Treweek et al (2007) indicated glycation of endogenous proteins and production of pro-inflammatory cytokines as possible unrecognized molecular mechanisms of cardiovascular disease in chronic METH abusers [ 18 ]. In an in vitro study, METH accelerates the beating rate and intracellular Ca 2+ oscillation pattern in rat cardiomyocytes in culture [ 19 ].…”