Abstract

High-dose methamphetamine (METH) causes damage to the dopamine and serotonin neurons in the brains of laboratory animals. The purpose of this report was to determine the long-term consequences of high-dose METH treatment on behavior and neurochemistry. Rats were trained on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule of reinforcement. Twelve weeks after training began (age 23 weeks), they received one or three high-dose METH regimens. Each regimen consisted of four injections of 15 mg/kg, at 2-h intervals. Each regimen was separated by 7 weeks. A second group received METH treatment at age 23 weeks, but behavioral training was not initiated until the rats reached age 60 weeks. A third group received METH treatment without behavioral training. DRL behavior showed mild impairments 3 to 18 weeks after the onset of treatment; the impairments did not persist into middle age. At age 70 weeks, serotonin concentrations were decreased in somatosensory cortex, occipital cortex, and hippocampus but not in other subcortical structures. Serotonin tissue concentrations were enhanced in septum and striatum but only in rats receiving three regimens and behavioral training. Dopamine was not depleted at age 70 weeks. In three additional groups, one, two, or three METH regimens were administered, and tissue concentrations were measured 6 weeks after the last treatment (corresponding to the times of the behavioral test blocks in the DRL experiments). Serotonin depletions were noted in cortex, hippocampus, amygdala, and striatum but not in septum, hypothalamus, nucleus accumbens/olfactory tubercle, or ventral midbrain. Dopamine was decreased in striatum and septum but not in nucleus accumbens/olfactory tubercle, amygdala, hypothalamus, or ventral midbrain. DRL 72-s schedule impairments are attributed to serotonin depletions. Three METH regimens did not result in greater behavioral or neurochemical deficits than one regimen.