Long-lasting psychotomimetic consequences of repeated low-dose amphetamine exposure in rhesus monkeys.
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.
Castner
S A
SA
Yale University School of Medicine, Section of Neurobiology, New Haven, CT 06510, USA.
Goldman-Rakic
P S
PS
D000661:Amphetamine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006213:Hallucinogens / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood; D008253:Macaca mulatta; D010865:Pilot Projects; D011388:Prolactin / Q000097:blood; D011618:Psychotic Disorders; D013997:Time Factors
D006213:Hallucinogens; D011388:Prolactin; D000661:Amphetamine; D006854:Hydrocortisone