Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys

Neuropsychopharmacology. 1999 Jan;20(1):10-28. doi: 10.1016/S0893-133X(98)00050-5.


The dopamine hypothesis of schizophrenia posits that dopamine dysregulation plays a key role in the etiology of schizophrenia. In line with this hypothesis, repeated amphetamine (AMPH) exposure has been shown to alter dopamine systems and induce behaviors reminiscent of positive-like and negative-like symptoms in both human and nonhuman primates. The mechanisms by which AMPH produces disturbances in brain function and behavior are not fully understood. The present study has employed a novel AMPH regimen, 12 weeks of intermittent escalating low doses of AMPH, to produce a nonhuman primate model for the purpose of elucidating the behavioral and neural consequences of excessive dopamine exposure. Behavioral responses to acute AMPH challenge (0.4-0.46 mg/kg) were assessed prior to and following the chronic 12-week treatment regimen, and, at present monkeys have been followed out to 28 months post-treatment. After chronic treatment, enhanced behavioral responses to AMPH challenge were readily apparent at 5 days postwithdrawal, and, were still present at 28 months postwithdrawal. The enhanced behavioral responses to low-dose AMPH challenge that were observed in the present study resemble closely the behavioral profile that has been described for chronic high-dose AMPH treatment in monkeys; i.e., hallucinatory-like behaviors, static posturing, and fine-motor stereotypies were all exacerbated in response to AMPH injection. In some animals, acute challenges after chronic AMPH evoked aberrant behavioral responses that lasted for 4 days. AMPH-treated monkeys also exhibited a significant decrease in the incidence of motor stereotypies in the off-drug periods between challenges. The present results are the first to document persistent long-term behavioral effects of intermittent exposure to repeated low-dose AMPH treatment in nonhuman primates. These findings may lay the groundwork for the development of a primate mode of psychosis with possible positive-like and negative-like symptoms.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamine / administration & dosage
  • Amphetamine / blood
  • Amphetamine / pharmacology*
  • Animals
  • Disease Models, Animal
  • Female
  • Hallucinogens / administration & dosage*
  • Hallucinogens / blood
  • Hallucinogens / pharmacology
  • Hydrocortisone / blood
  • Macaca mulatta
  • Pilot Projects
  • Prolactin / blood
  • Psychotic Disorders
  • Time Factors


  • Hallucinogens
  • Prolactin
  • Amphetamine
  • Hydrocortisone