Methamphetamine (METH) is abused by humans; tolerance develops, and users increase their consumption. METH is taken in binge patterns in which the user takes the drug constantly for several days, then stops taking the drug for a period of time. METH causes dose-dependent damage to the dopamine (DA) and serotonin (5-HT) systems of the brain. Evidence suggests that DA and 5-HT systems change with age; therefore, information about the effects of taking METH early in life, on behavior and neurochemistry late in life, is of great interest. The specific hypotheses we intend to test are: 1.) METH treatment in the young adult rat impairs neurochemical and behavioral function; 2.) METH treatment in the young adult rat interacts with the aging process to produce more profound impairments as the rat matures.
Specific Aim A is to model human drug-taking behavior in rats, and to study the long-term effects of METH on learning and performance. Questions addressed by specific Aim A are a.) does a binge pattern of drug administration in young rats cause deficits in young animals and b.) does this pattern of drug administration interact with the aging process. Behavior will be evaluated on two complex tasks. The first task is a reaction time task which has been shown to detect deficits 3 months after a single METH regimen. The second is the differential reinforcement of low rate schedule which has been shown to detect METH-induced acquisition deficits. Rats will be treated with METH at discreet intervals throughout early adulthood, and tested as they age. Rats will be administered METH regimens 4 times, at 6 wk intervals, beginning at age 20 wks. Rats will be trained on the two behavioral tasks before the beginning of METH treatment. The performance of the rats will then be evaluated during drug free periods until they are 72 wks old. Acquisition of the two tasks will be evaluated in separate groups of mature rats who will have received the same binge pattern of METH treatment. We will also study the effects of METH treatment on exploratory locomotor behavior.
Specific Aim B is to make neurochemical measures of 5-HT and DA after the four METH regimens. Questions addressed by specific Aim B are a.) does a binge pattern of drug administration decrease the ability of METH to release 5-HT and DA in vivo, and b.) does this pattern of drug administration cause larger transmitter depletions compared to a single METH regimen. In vivo measures of extracellular DA and 5-HT will be made in response to drug challenge (low doses of METH) using in vivo dialysis; post-mortem monoamine tissue concentrations will also be measured. The proposed post-mortem experiments of Aim B will provide time-based measurements of DA and 5-HT levels which can be correlated with behavioral results from specific Aim A.
| Sabol, K E; Richards, J B; Broom, S L et al. (2003) Effects of stimulus salience and methamphetamine on choice reaction time in the rat: central tendency versus distribution skew. Behav Pharmacol 14:489-500 |
| Sabol, K E; Roach, J T; Broom, S L et al. (2001) Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine release in vivo. Brain Res 892:122-9 |
| Sabol, K E; Richards, J B; Yung, K (2000) The effects of high-dose methamphetamine in the aging rat: differential reinforcement of low-rate 72-s schedule behavior and neurochemistry. J Pharmacol Exp Ther 294:850-63 |
| Richards, J B; Sabol, K E; de Wit, H (1999) Effects of methamphetamine on the adjusting amount procedure, a model of impulsive behavior in rats. Psychopharmacology (Berl) 146:432-9 |
