Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.
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.
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Kevin D
KD
Lominac
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Courtney L
CL
McKenna
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Lisa M
LM
Schwartz
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Paige N
PN
Ruiz
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Melissa G
MG
Wroten
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Bailey W
BW
Miller
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
John J
JJ
Holloway
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Katherine O
KO
Travis
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Ganesh
G
Rajasekar
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Dan
D
Maliniak
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Andrew B
AB
Thompson
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Lawrence E
LE
Urman
Behavioral Neuroscience, Methamphetamine Abuse Research Center, Veterans Affairs Medical Center, Oregon Health and Science University Portland, OR, USA.
Tamara J
TJ
Phillips
Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara Santa Barbara, CA, USA.
Karen K
KK
Szumlinski
addiction vulnerability; dopamine; methamphetamine; nucleus accumbens; prefrontal cortex; sensitization; serotonin