Neurotoxicity Research

, Volume 15, Issue 3, pp 232–245 | Cite as

Methamphetamine Induces Long-Term Alterations in Reactivity to Environmental Stimuli: Correlation with Dopaminergic and Serotonergic Toxicity

  • Marco Bortolato
  • Roberto Frau
  • A. Paola Piras
  • William Luesu
  • Valentina Bini
  • Giacomo Diaz
  • Gianluigi Gessa
  • M. Grazia Ennas
  • M. Paola Castelli


Methamphetamine (METH) abuse is known to induce persistent cognitive and behavioral abnormalities, in association with alterations in serotonin (5-HT) and dopamine (DA) systems, yet the neurobiological mechanisms underpinning this link are elusive. Thus, in the present study we analyzed the long-term impact of an acute toxic regimen of METH (4 mg/kg, subcutaneous × 4 injections, 2 h apart) on the reactivity of adult male rats to environmental stimuli, and correlated it to toxicity on 5-HT and DA innervations. Two separate groups of METH-injected rats were compared to their saline-treated controls on object exploration and startle paradigms, at either 1 or 3 weeks after METH administration, respectively. Twenty-four hours after behavioral testing, animals were sacrificed, and the neurotoxic effects of the METH schedule on DA and 5-HT terminals were measured through immunochemical quantification of their transporters (DAT and 5-HTT). At both 1 and 3 weeks after treatment, METH-injected rats exhibited a significant decline in the number of exploratory approaches to unfamiliar objects, which was significantly correlated with a parallel reduction in DAT immunoreactivity (IR) in the nucleus accumbens (NAc) core. Furthermore, METH-treated rats displayed a significant enhancement in startle magnitude after 3 (but not 1) weeks, which was inversely correlated with a decrement in 5-HTT IR in the Cg3 infralimbic area of prefrontal cortex. Our results suggest that METH induces long-term changes in object exploration and startle responsiveness, which may be respectively underpinned by reductions in DAergic and 5-HTergic brain terminals.


Methamphetamine Object exploration Startle reflex DAT 5-HTT 



This work was partially supported by grants from Fondazione Banco di Sardegna to M.P.C.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Marco Bortolato
    • 1
    • 2
    • 3
  • Roberto Frau
    • 2
    • 3
  • A. Paola Piras
    • 2
  • William Luesu
    • 4
  • Valentina Bini
    • 2
  • Giacomo Diaz
    • 5
  • Gianluigi Gessa
    • 2
    • 6
  • M. Grazia Ennas
    • 3
    • 4
  • M. Paola Castelli
    • 2
    • 3
    • 6
  1. 1.Department of Cardiovascular and Neurological SciencesUniversity of Cagliari, Cittadella UniversitariaMonserrato (CA)Italy
  2. 2.Department of Neuroscience “Bernard B.Brodie”University of Cagliari, Cittadella UniversitariaMonserrato (CA)Italy
  3. 3.Tourette Syndrome CenterMonserrato (CA)Italy
  4. 4.Department of CytomorphologyUniversity of CagliariMonserrato (CA)Italy
  5. 5.Department of Biomedical Sciences and BiotechnologyUniversity of CagliariMonserrato (CA)Italy
  6. 6.Center of Excellence for the Neurobiology of AddictionsUniversity of CagliariMonserrato (CA)Italy

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