Frontiers in Systems Neuroscience (May 2014)

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation

  • Kevin D Lominac,
  • Courtney L McKenna,
  • Lisa M Schwartz,
  • Paige N Ruiz,
  • Melissa G Wroten,
  • Bailey W Miller,
  • John J Holloway,
  • Katherine O Travis,
  • Ganesh eRajasekar,
  • Dan eMaliniak,
  • Andrew B Thompson,
  • Lawrence E Urman,
  • Tamara ePhillips,
  • Karen K Szumlinski

DOI
https://doi.org/10.3389/fnsys.2014.00070
Journal volume & issue
Vol. 8

Abstract

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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 versus 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.

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