ABSTRACT
Methamphetamine is a highly addictive and potent stimulant, the use of which has increased significantly in recent years. In addition to the severe behavioral and societal consequences associated with methamphetamine abuse, methamphetamine can cause persistent damage to monoaminergic nerve terminals in rats, as measured by either monoamine concentrations or activity of the rate limiting synthetic enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Repeated, sub-neurotoxic doses of methamphetamine, however, can cause rats to become resistant to the neurotoxic effects of multiple high-dose administrations of methamphetamine; a phenomenon known as tolerance. This study investigates the persistence of tolerance evoked by pretreatment with escalating-dose administrations of methamphetamine. Rats were pretreated over several days with low, escalating doses of methamphetamine, followed by high-dose methamphetamine challenge after variable recovery periods. Results revealed that tolerance to monoaminergic deficits persisted for at least one week, but was completely eliminated by 31 days. There were no differences in the distribution of methamphetamine or its major metabolite, amphetamine, between methamphetamine-pretreated animals and saline-pretreated animals 2 h after the final methamphetamine challenge injection, and there were no regional differences in methamphetamine concentrations between the frontal cortex, hippocampus or striatum. We also observed that while methamphetamine pretreatment attenuated the hyperthermia caused by the high-dose methamphetamine challenge, significant reductions in methamphetamine-induced hyperthermia were not required for the development of tolerance with this regimen.
Subject(s)
Biogenic Monoamines/metabolism , Brain Chemistry/drug effects , Central Nervous System Stimulants/pharmacology , Methamphetamine/pharmacology , Amphetamines/metabolism , Animals , Body Temperature/drug effects , Central Nervous System Stimulants/pharmacokinetics , Chromatography, Liquid , Dose-Response Relationship, Drug , Drug Tolerance , Male , Mass Spectrometry , Methamphetamine/pharmacokinetics , Nerve Tissue Proteins/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
The objective of this preliminary study was to determine whether hair can be used as an adjunct specimen for the monitoring of opiate use in a drug-treatment program. Subjects (n = 10) initiating clinical therapy for opiate addiction were monitored for up to 17 weeks with hair and urinalysis. Questionnaires were administered weekly to document hair cuts and chemical treatments. Hair specimens were collected weekly by cutting at the scalp and segmented into 1-cm lengths prior to analysis. Codeine (COD), morphine (MOR), and 6-monoacetylmorphine (6-MAM) concentrations in hair were measured by liquid chromatography-mass spectrometry (LC-MS) [limit of detection (LOD): 20 pg/mg for COD and 6-MAM; 50 pg/mg MOR]. Urine specimens were analyzed by semiquantitative radioimmunoassay (25-ng/mL cutoff) and LC-MS for codeine (COD), morphine (MOR), morphine-3beta-glucuronide (M3G), morphine-6 beta-glucuronide (M6G), and 6-monoacetylmorphine (6-MAM). The LOD and limit of quantitation (LOQ) in urine for COD, M3G, M6G, and 6-MAM were 10 ng/mL and 25 ng/mL for MOR. Interpretation of the segmental hair data in this study was complex and generally was not in agreement with urine data in most cases. Evaluation of hair data suggested that 6 of 10 subjects discontinued opiate use by the end of the study, whereas 3 of 10 appeared to have reduced their use. One subject appeared not to have used opiates throughout the entire study. In contrast, evaluation of urine data suggested that only 4 of 10 subjects significantly reduced use, and 6 of 10 continued drug use on at least an intermittent basis. Urine appeared to be a more sensitive indicator of changes in the pattern(s) of drug use during the course of clinical drug treatment.
