D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex

Neuroscience. 2002;109(3):499-516. doi: 10.1016/s0306-4522(01)00508-5.


The behavioral sensitization produced by the repeated administration of D-amphetamine is known to involve dopaminergic neurons in the mesoaccumbens pathway. Induction of this process is dependent on action of the drug in the ventral tegmental area while its expression involves action in the nucleus accumbens. We studied here the putative involvement of dopaminergic projections other than the mesoaccumbens in this phenomenon. We examined the influence of dopaminergic lesion of the medial prefrontal cortex, the amygdala and the entorhinal cortex in the behavioral sensitization produced by repeated injections of amphetamine either peripherally or directly into the ventral tegmental area of the brain. The repeated administration of amphetamine induced a behavioral sensitization, with the ventral tegmental area a critical site for induction of the process. This sensitization to amphetamine cross-reacted with morphine and was still observed 2 weeks after cessation of the treatment. Bilateral 6-hydroxydopamine lesion of dopaminergic terminals in either the medial prefrontal cortex or the amygdala, but not in the entorhinal cortex, prevented the development of behavioral sensitization to amphetamine and the cross-sensitization with morphine, whether the amphetamine pretreatment was administered peripherally or directly into the ventral tegmental area. In conclusion, these results indicated that behavioral sensitization to amphetamine, which involves dopaminergic neurons of the ventral tegmental area, is also dependent on dopaminergic neurotransmission of the medial prefrontal cortex and amygdala but not of the entorhinal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects*
  • Amygdala / injuries
  • Amygdala / physiopathology
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Dextroamphetamine / pharmacology*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Interactions / physiology
  • Drug Tolerance / physiology*
  • Entorhinal Cortex / drug effects*
  • Entorhinal Cortex / injuries
  • Entorhinal Cortex / physiopathology
  • Male
  • Morphine / pharmacology
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Oxidopamine / pharmacology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / injuries
  • Prefrontal Cortex / physiopathology
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / pathology
  • Rats
  • Rats, Wistar
  • Sympatholytics / pharmacology


  • Sympatholytics
  • Morphine
  • Oxidopamine
  • Dextroamphetamine
  • Dopamine