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Stop Animal Exploitation NOW!
S. A. E. N.
"Exposing the truth to wipe out animal experimentation"

Government Grants Promoting Cruelty to Animals

Johns Hopkins University, Baltimore, MD

GEORGE A. RICAURTE - Primate Testing - 2006

Grant Number: 5R01DA013946-05
Project Title: Methamphetamine Neurotoxicity in Nonhuman Primates
PI Information: ASSOCIATE PROFESSOR GEORGE A. RICAURTE, ricaurte@jhmi.edu 

Abstract: DESCRIPTION (provided by applicant):
Abuse of methamphetamine (METH) is a pressing public health concern. In animals, METH has been shown to have neurotoxic potential toward brain dopamine (DA) and serotonin (5- HT) neurons. Despite the strengths of the available METH neurotoxicity data in animals, several important questions remain. First, it is not yet known if the neurotoxic effects of METH in nonhuman primates are reversible and, if so, whether normal DA and 5-HT innervation patterns are re-established. Second, it is not known if temperature, which markedly influences METH neurotoxicity in rodents, similarly influences METH neurotoxicity in primates. Third, the possibility has been raised that slowly escalating dose regimens of METH may be without neurotoxic consequences in primates, a possibility that would have direct implications for human METH abusers. Finally, the functional consequences of METH neurotoxicity have not been well characterized. All four of these questions have both scientific importance and direct clinical relevance. As such, they are the focus of the present proposal. The specific aims of project are: 1) To determine whether or not injured DA and 5-HT neurons in METH-treated monkeys regenerate over time and, if so, whether normal patterns of DA and 5-HT innervation are re-established; 2) To study the effects of ambient temperature on substituted amphetamine neurotoxicity in nonhuman primates; 3) To determine if a regimen of METH administration that begins with a low dose and escalates slowly renders monkeys insensitive to the neurotoxic effects of METH; and 4) To ascertain whether or not monkeys treated with a neurotoxic regimen of METH are at increased risk for developing a Parkinsonian syndrome following administration of the catecholamine synthesis inhibitor, alpha-methyl-para-tyrosine (AMPT). To achieve these aims, a combination of quantitative chemical, anatomic, and behavioral methods will be used. The overall goal of these studies is to better understand the long-term effects of toxic doses of METH on brain DA and 5-HT neurons in nonhuman primates, and to provide a framework for reliably interpreting and anticipating possible deleterious effects of METH abuse in humans.

Thesaurus Terms:
methamphetamine, nervous system regeneration, neuron, neurotoxicology, nonhuman therapy evaluation
Parkinson's disease, dopamine, drug administration rate /duration, neuroprotectant, serotonin, temperature, tyrosine analog
Saimiri, experimental brain lesion, high performance liquid chromatography, immunocytochemistry

Institution: JOHNS HOPKINS UNIVERSITY
W400 Wyman Park Building
BALTIMORE, MD 212182680
Fiscal Year: 2006
Department: NEUROLOGY AND NEUROSURGERY
Project Start: 01-JUN-2002
Project End: 31-JAN-2008
ICD: NATIONAL INSTITUTE ON DRUG ABUSE
IRG: IFCN

JPET 316:1210-1218, 2006

Relationship between Temperature, Dopaminergic Neurotoxicity, and Plasma Drug Concentrations in Methamphetamine-Treated Squirrel Monkeys
 
Jie Yuan, George Hatzidimitriou, Pranav Suthar, Melanie Mueller, Una McCann, and George Ricaurte

Departments of Neurology (J.Y., G.H., P.S., G.R.) and Psychiatry and Behavioral Sciences (U.M.), The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Department of Experimental and Clinical Toxicology (M.M.), Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg (Saar), Germany

Received October 4, 2005; accepted November 14, 2005.

Drug Administration.
d-Methamphetamine (or vehicle) was administered orally. Oral administration was accomplished by orogastric gavage, with the animal gently restrained in a Plexiglas chair during the procedure. Dose selection was based upon pilot studies and published reports indicating that two doses of METH given hours apart have the potential to produce lasting effects on brain DA neurons in nonhuman primates (Melega et al., 1998 ). We ultimately selected a dose of 1.25 mg/kg, given twice at a 4-h interval, because pilot studies showed that this dosage regimen is well tolerated and produced a modest reduction in striatal DA neuronal markers 1 week later, thus leaving room for a possible enhancement by a higher ambient temperature (33C instead of 26C). Drug (or vehicle) administration was performed at 11:00 AM and 3:00 PM, so that assessment of effects on core temperature took place during a relatively stable period of the circadian temperature cycle (see Results).

Overall Design.
Two different groups (n = 45 per group) of drug-naive animals were used to test the effects of increased ambient temperature on METH-induced changes in core temperature and subsequent DA neurotoxicity (i.e., five monkeys received vehicle and METH at 26C and four different monkeys received vehicle and METH at 33C) (Table 1). The rationale for the temperatures selected (26 and 33C) was as follows. An ambient temperature of 26C was selected because it is considered to be in the thermoneutral range for the squirrel monkey (Stitt and Hardy, 1971 ; Robinson and Fuller, 1999 ); an ambient temperature of 33C was used as a "warm" environment because it is toward the high end of the thermoneutral range for the squirrel monkey (Stitt and Hardy, 1971 ; Robinson et al., 1993 ) and because studies in rodents indicate that a 7C increase in ambient temperature increases METH neurotoxicity (Callahan et al., 1998 ).

Please email: GEORGE A. RICAURTE, ricaurte@jhmi.ed to protest the inhumane use of animals in this experiment. We would also love to know about your efforts with this cause: saen@saenonline.org

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Rats, mice, birds, amphibians and other animals have been excluded from coverage by the Animal Welfare Act. Therefore research facility reports do not include these animals. As a result of this situation, a blank report, or one with few animals listed, does not mean that a facility has not performed experiments on non-reportable animals. A blank form does mean that the facility in question has not used covered animals (primates, dogs, cats, rabbits, guinea pigs, hamsters, pigs, sheep, goats, etc.). Rats and mice alone are believed to comprise over 90% of the animals used in experimentation. Therefore the majority of animals used at research facilities are not even counted.

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