TY - JOUR
T1 - Methamphetamine-induced dopaminergic neurotoxicity in mice
T2 - Long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine
AU - Itzhak, Yossef
AU - Martin, Julio L.
AU - Ali, Syed F.
N1 - Funding Information:
This work was supported by USPHS awards DA08584 and DA12867 from the National Institute on Drug Abuse, National Institutes of Health. The authors appreciate the excellent technical assistance of Cindy Achat.
PY - 2002/10
Y1 - 2002/10
N2 - High doses of methamphetamine (METH) cause the depletion of striatal dopaminergic markers; however, little is known about the behavioral consequences of METH-induced neurotoxicity. In the present study, the authors investigated the effect of a neurotoxic dose of METH (5 mg/kg; every 3 h x 3) on the subsequent response of Swiss Webster mice to (a) the psychomotor-stimulating effect of METH and (b) the acquisition and maintenance of conditioned place preference (CPP) by METH. The latter is a paradigm for the assessment of the rewarding properties of abused substances. The administration of the high dose of METH resulted in significant depletion of dopamine (DA) and its metabolites and dopamine transporter (DAT) binding sites in the striatum. The dopaminergic markers were below control levels until the 95th day after METH administration. METH-pretreated mice were sensitized to the psychomotor-stimulating effect of METH (1 mg/kg) as determined on Days 3 and 74 after the initial exposure to the neurotoxic dose of METH. However, the acquisition of CPP by METH (0.5 mg/kg) was markedly reduced in the mice pretreated with the neurotoxic dose of METH compared with the control group. The CPP was maintained for 8 weeks in the control group but not in the METH group. A priming injection of METH (0.5 mg/kg) caused marked reinstatement of place preference in the control group; this response was maintained for three additional weeks. However, the priming injection of METH resulted in diminished place preference in the METH group and the conditioned response dissipated within 3 weeks. These findings suggest that METH-induced striatal dopaminergic neurotoxicity is associated with two opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse.
AB - High doses of methamphetamine (METH) cause the depletion of striatal dopaminergic markers; however, little is known about the behavioral consequences of METH-induced neurotoxicity. In the present study, the authors investigated the effect of a neurotoxic dose of METH (5 mg/kg; every 3 h x 3) on the subsequent response of Swiss Webster mice to (a) the psychomotor-stimulating effect of METH and (b) the acquisition and maintenance of conditioned place preference (CPP) by METH. The latter is a paradigm for the assessment of the rewarding properties of abused substances. The administration of the high dose of METH resulted in significant depletion of dopamine (DA) and its metabolites and dopamine transporter (DAT) binding sites in the striatum. The dopaminergic markers were below control levels until the 95th day after METH administration. METH-pretreated mice were sensitized to the psychomotor-stimulating effect of METH (1 mg/kg) as determined on Days 3 and 74 after the initial exposure to the neurotoxic dose of METH. However, the acquisition of CPP by METH (0.5 mg/kg) was markedly reduced in the mice pretreated with the neurotoxic dose of METH compared with the control group. The CPP was maintained for 8 weeks in the control group but not in the METH group. A priming injection of METH (0.5 mg/kg) caused marked reinstatement of place preference in the control group; this response was maintained for three additional weeks. However, the priming injection of METH resulted in diminished place preference in the METH group and the conditioned response dissipated within 3 weeks. These findings suggest that METH-induced striatal dopaminergic neurotoxicity is associated with two opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse.
KW - Conditioned place preference (CPP)
KW - Dopaminergic neurotoxicity
KW - Psychomotor stimulation
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U2 - 10.1016/S0278-5846(02)00257-9
DO - 10.1016/S0278-5846(02)00257-9
M3 - Article
C2 - 12452543
AN - SCOPUS:0036776173
VL - 26
SP - 1177
EP - 1183
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
SN - 0278-5846
IS - 6
ER -