Abstract
We recently demonstrated that pretreatment with N-(2-chloroethyl)-N- ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.
| Original language | English |
|---|---|
| Pages (from-to) | 777-784 |
| Number of pages | 8 |
| Journal | Journal of Neurochemistry |
| Volume | 72 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1999 |
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Keywords
- Dopamine
- DSP-4
- Locus coeruleus
- Methamphetamine
- Norepinephrine
- Recovery
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience
Cite this
Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2- bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses. / Fornai, Francesco; Giorgi, Filippo S.; Alessandrí, Maria G.; Giusiani, Mario; Corsini, Giovanni U.
In: Journal of Neurochemistry, Vol. 72, No. 2, 1999, p. 777-784.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2- bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses
AU - Fornai, Francesco
AU - Giorgi, Filippo S.
AU - Alessandrí, Maria G.
AU - Giusiani, Mario
AU - Corsini, Giovanni U.
PY - 1999
Y1 - 1999
N2 - We recently demonstrated that pretreatment with N-(2-chloroethyl)-N- ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.
AB - We recently demonstrated that pretreatment with N-(2-chloroethyl)-N- ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.
KW - Dopamine
KW - DSP-4
KW - Locus coeruleus
KW - Methamphetamine
KW - Norepinephrine
KW - Recovery
UR - http://www.scopus.com/inward/record.url?scp=0032922889&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032922889&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.1999.0720777.x
DO - 10.1046/j.1471-4159.1999.0720777.x
M3 - Article
C2 - 9930753
AN - SCOPUS:0032922889
VL - 72
SP - 777
EP - 784
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 2
ER -