Neurotoxicity Research

, Volume 26, Issue 2, pp 152–167

Methamphetamine-Induced Neurotoxicity Disrupts Pharmacologically Evoked Dopamine Transients in the Dorsomedial and Dorsolateral Striatum

  • John D. Robinson
  • Christopher D. Howard
  • Elissa D. Pastuzyn
  • Diane L. Byers
  • Kristen A. Keefe
  • Paul A. Garris
Original Article

DOI: 10.1007/s12640-014-9459-y

Cite this article as:
Robinson, J.D., Howard, C.D., Pastuzyn, E.D. et al. Neurotox Res (2014) 26: 152. doi:10.1007/s12640-014-9459-y

Abstract

Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.

Keywords

Methamphetamine Dopamine Transient Release Uptake Voltammetry 

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • John D. Robinson
    • 1
  • Christopher D. Howard
    • 1
  • Elissa D. Pastuzyn
    • 2
  • Diane L. Byers
    • 1
  • Kristen A. Keefe
    • 2
    • 3
  • Paul A. Garris
    • 1
  1. 1.School of Biological SciencesIllinois State UniversityNormalUSA
  2. 2.Interdepartmental Program in NeuroscienceUniversity of UtahSalt Lake CityUSA
  3. 3.Department of Pharmacology and ToxicologyUniversity of UtahSalt Lake CityUSA

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