Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment

• Published in: European journal of pharmacology Vol. 607; no. 1; pp. 68 - 73
• Main Authors: Hanson, Jarom E., Birdsall, Elisabeth, Seferian, Kristi S., Crosby, Marcus A., Keefe, Kristen A., Gibb, James W., Hanson, Glen R., Fleckenstein, Annette E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.04.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - drug effects; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - pharmacology; Drug Resistance; Male; Medical sciences; Methamphetamine; Methamphetamine - administration & dosage; Methamphetamine - toxicity; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Resistance; Time Factors; Tolerance; Vesicular Monoamine Transport Proteins - drug effects; Vesicular Monoamine Transport Proteins - metabolism; Resistance; Tolerance; Neurotoxicity; Dopamine; Methamphetamine; Amphetamine derivatives; CNS stimulant; Psychotropic; Toxicity; Metamfetamine; Sympathomimetic; Catecholamine; Treatment; Neurotransmitter
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2009.01.037

Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently “challenged” with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity.