Long-Lasting Psychotomimetic Consequences of Repeated Low-Dose Amphetamine Exposure in Rhesus Monkeys
Abstract
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.
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Monkeys still display a sensitized response to amphetamine even 2 years post-treatment.
“while monkeys still display a sensitized response to amphetamine even 2 years post-treatment (Castner & Goldman-Rakic, 1999).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Castner & Goldman-Rakic, 1999
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“…of increased locomotor activity, up to 3 months after cocaine exposure (Shuster, Yu, & Bates, 1977) and up to 8 months after morphine exposure (Shuster, Webster, &Yu, 1975), while monkeys still display a sensitized response to amphetamine even 2 years post-treatment (Castner & Goldman-Rakic, 1999).”
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Self-citation
- Authors
- Castner, S.
- Affiliations
- Yale University (US)
- Corresponding author
- Castner, S
- Venue
- Neuropsychopharmacology
- Published
- 1999-01
- Volume
- 20
- Issue
- 1
- Pages
- 10-28
- ISSN
- 0893-133X (ISSN-L)
- OpenAlex
- W2086037111
- Cited by
- 187
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 4 · 2021: 3 · 2020: 44 · 2018: 2 · 2017: 3 · 2015: 7 · 2014: 8 · 2013: 6 · 2012: 4
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH 44866, P50MH044866)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- amphetamine, psychotomimetic effects, dopamine hypothesis of schizophrenia, rhesus monkeys, long-term behavioral effects, amphetamine challenge, motor stereotypies, dopamine dysregulation
- MeSH terms
- Amphetamine, Animals, Disease Models, Animal, Female, Hallucinogens, Hydrocortisone, Macaca mulatta, Pilot Projects, Prolactin, Psychotic Disorders, Time Factors
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