Methamphetamine induces long-term alterations in reactivity to environmental stimuli: correlation with dopaminergic and serotonergic toxicity.
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 x 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.
Bortolato
Marco
M
Department of Cardiovascular and Neurological Sciences, University of Cagliari, Cittadella Universitaria, S.S. 554 km 4.500, 09042 Monserrato (CA), Italy. marco_bortolato@yahoo.com
Frau
Roberto
R
Piras
A Paola
AP
Luesu
William
W
Bini
Valentina
V
Diaz
Giacomo
G
Gessa
Gianluigi
G
Ennas
M Grazia
MG
Castelli
M Paola
MP
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013223:Statistics as Topic; D013997:Time Factors
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine