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Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neur

Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neur

  1. Wanderer
    Yossef Itzhak, Cindy N. Achat-Mendes, Syed F. Ali, Karen L. Anderson

    Department of Psychiatry and Behavioral Sciences (R-629)
    University of Miami School of Medicine
    Gautier Building Room no. 503
    1011 NW 15th Street
    Miami, FL 33136

    Division of Neurotoxicology
    National Center for Toxicological Research, FDA Jefferson, AR 72079

    Received 11 April 2003
    Received in revised form 29 June 2003
    Accepted 30 July 2003

    Amphetamine analogs such as p-chloroamphetamine (PCA) cause serotonergic and dopaminergic neurotoxicity. The behavioral consequences and the responsiveness to psychostimulants following the neurotoxic insult are unclear. The present study was undertaken to investigate the outcome of neurotoxic and non-neurotoxic PCA pre-treatments on the sensitivity of Swiss Webster mice to the psychomotor stimulating effects of PCA, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. PCA (15 mg/kg × 2; i.p.) caused 37–70% depletion of dopaminergic and serotonergic markers in mouse brain. Saline and PCA (15 mg/kg × 2) mice were challenged on days 5, 12, 40 and 74 with one of the following drugs: PCA (5 mg/kg), MDMA (10 mg/kg) and cocaine (20mg/kg). The PCA pre-exposed mice showed marked locomotor sensitization from days 5–74 to all three drugs tested. The time course of the sensitized response coincided with the time course of the neurotoxic insult as determined by reduced densities of striatal dopamine transporter and frontal cortex serotonin transporter binding sites. A single injection of PCA (5 mg/kg) caused neither neurotoxicity nor sensitization to the locomotor stimulating effects of PCA, MDMA and cocaine. Repeated administration of a low non-neurotoxic dose of PCA (5 mg/kg/day; 6 days) caused a transient locomotor sensitization to PCA that dissipated after one month. Results of the present study suggest that PCA-induced serotonergic and dopaminergic neurotoxicity coincides with long-lasting locomotor sensitization to psychostimulants. These findings may be relevant to the psychopathology of amphetamines induced neurotoxicity.