Abstract
Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5–10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.
Highlights
Methamphetamine (MA) is a potent, highly addictive, amphetamine derivative with intense psychomotor-activating properties
To relate MA’s effects upon indices of DAEC in Biochemical studies of C57BL/6J (B6) and MAH/LDR mice, we examined for the total protein expression of DAT and D2 dopamine receptors (D2Rs), the latter of which serves as an autoreceptor regulating DAEC
When obtained by conventional microdialysis, the average basal DAEC levels within both the nucleus accumbens (NAC) and mPFC were moderately lower in MA-treated mice at 21 days withdrawal (Table 1)
Summary
Methamphetamine (MA) is a potent, highly addictive, amphetamine derivative with intense psychomotor-activating properties. MA is a substrate for plasma membrane monoamine transporters, including the dopamine (DA) transporter (DAT), as well as for the vesicular monoamine transporter, and is reported to inhibit monoamine oxidase (e.g., Fleckenstein et al, 2007; Chen et al, 2009). Through these mechanisms, MA profoundly increases DA within forebrain terminals, notably nucleus accumbens (NAC), dorsal striatum and prefrontal cortex (PFC) (e.g., Sulzer et al, 2005). Whereas it is generally held that repeated MA exposure elicits a sensitization of forebrain dopamine release that contributes to the development of behavioral sensitization and/or underpins this drug’s positivereinforcing or rewarding properties
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