Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neurotoxicity in mice.
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 x 2; i.p.) caused 37-70% depletion of dopaminergic and serotonergic markers in mouse brain. Saline and PCA (15 mg/kg x 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 (20 mg/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.
Itzhak
Yossef
Y
Department of Psychiatry and Behavioral Sciences (R-629), University of Miami School of Medicine, Miami, FL 33136, USA.yitzhak@med.miami.edu
Achat-Mendes
Cindy N
CN
Ali
Syed F
SF
Anderson
Karen L
KL
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D020258:Neurotoxicity Syndromes / Q000209:etiology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity*; D050486:Serotonin Plasma Membrane Transport Proteins; D013997:Time Factors; D010133:p-Chloroamphetamine / Q000633:toxicity*
D000779:Anesthetics, Local; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D006213:Hallucinogens; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D010133:p-Chloroamphetamine; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine