Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge.

Full Abstract

A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.1-4.0 mg/kg over 14 days) attenuated the toxicity of a subsequently administered high-dose METH binge (4 x 6 mg/kg at 2 h interval) that itself produced behavioral stereotypy, increases in core temperature, and decreases in DA system phenotypic markers in caudate-putamen (CP). Using those ED-METH and binge protocols in the present studies, pharmacokinetic and pharmacodynamic parameters that may have contributed to the apparent neuroprotection afforded by ED-METH were assessed. The ED-METH regimen itself reduced [(3)H]WIN35,428 (WIN) binding to the dopamine transporter (DAT) by 15% in CP, but did not affect DA content. During the METH binge, ED-METH pretreated animals showed attenuated increases in core temperature while concurrent microdialysis studies in CP showed a reduced DA response despite unaltered extracellular levels of METH. At 1 h after the binge, concentrations of METH and its metabolite amphetamine in brain and plasma were unaffected by the ED-METH. The results show that ED-METH pretreatment produces reductions in DAT binding and the DA response during a subsequent METH binge by altering pharmacodynamic and not pharmacokinetic parameters.

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Author information

Author/s: O'Neil, Meghan L (ML); Kuczenski, Ronald (R); Segal, David S (DS); Cho, Arthur K (AK); Lacan, Goran (G); Melega, William P (WP);

Affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, 90095-1735, USA.

Grants: DA-01,568 (Agency:NIDA NIH HHS) ; DA-02,854 (Agency:NIDA NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Synapse (New York, N.Y.) (Synapse), published in United States. (Language: eng)

Reference: 2006-Nov; vol 60 (issue 6) : pp 465-73

Dates: Created 2006/08/30; Completed 2006/10/19; Revised 2007/11/14;

PMID: 16897726, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

3,4-Dihydroxyphenylacetic Acid - metabolism
Amphetamine - metabolism
Amphetamine-Related Disorders - metabolism; pathology; psychology
Animals
Body Temperature - drug effects
Central Nervous System Stimulants - administration & dosage; pharmacokinetics; pharmacology
Chromatography, High Pressure Liquid
Cocaine - analogs & derivatives; metabolism
Dopamine Uptake Inhibitors - metabolism

Dopamine Uptake Inhibitors - metabolism
Gas Chromatography-Mass Spectrometry
Homovanillic Acid - metabolism
Male
Methamphetamine - administration & dosage; pharmacokinetics; pharmacology
Microdialysis
Neostriatum - metabolism; pathology
Rats
Rats, Sprague-Dawley

Associated Chemicals: Central Nervous System Stimulants (0) ; Dopamine Uptake Inhibitors (0) ; 3,4-Dihydroxyphenylacetic Acid (102-32-9) ; Amphetamine (300-62-9) ; Homovanillic Acid (306-08-1) ; Cocaine (50-36-2) ; (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester (50370-56-4) ; Methamphetamine (537-46-2)

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