Effects of methamphetamine, iprindole and phencyclidine on the serotonergic system of the rat brain.

The effects of administering methamphetamine to iprindole-treated rats on serotonergic metabolism in the cerebral cortex, neostriatum and hypothalamus and on dopamine metabolism in the neostriatum have been investigated. Methamphetamine (17.5 mg/kg, i.p.) was administered two hours after iprindole (10 mg/kg, i.p.)- Three and 7 days after injection significant decreases (p <0.05) were seen in tryptophan hydroxylase (TPH) activity, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in all brain regions examined. A significant decrease in TPH activity was observed after 1 day; however, 5-HT and 5-HIAA concentrations were not significantly different from saline controls. After 14 days, all parameters were decreased with the exception of hypothalamic TPH activity, which was not significantly different from saline control. Neostriatal tyrosine hydroxylase (TH) activity and dopamine (DA) concentrations were significantly depressed at all time points examined. Methamphetamine (17.5 mg/kg i.p.) administered to iprindole-treated rats, was required to produce a significant decrease in these parameters of the serotonergic and dopaminergic systems. Significant decreases were observed using doses of iprindole of 5 mg/kg and methamphetamine of 17.5 mg/kg. Iprindole alone produced a significant increase in TPH activity (to 138% of control) in the cerebral cortex after 1 day. After 3 days, cortical TPH activity had fallen to 82% of control, whereas 5-HT and 5-HIAA were significantly increased over control. No effects were seen in the hippocampus, hypothalamus or neostriatum. Clomipramine, amitriptyline and chlorpromazine also produced significant increases in cortical TPH activity 1 day after an injection of 10 mg/kg. This evidence suggests that, in the presence of a metabolic inhibitor, methamphetamine has neurotoxic effects similar to the halogenated amphetamines on the serotonergic system. These drugs produce a long-lasting decrease in TPH activity and 5-HT concentrations. Secondly, administration of iprindole alone, and possibly other antidepressant drugs, produces changes in TPH activity that reflect an ability to alter 5-HT biosynthesis independent of brain tryptophan concentrations. Phencyclidine (PCP) was found to have little effect on the neo-striatal serotonergic system; the only significant changes being an increase in 5-HIAA concentrations after 15 and 30 minutes. Cerebellar GAD activity was decreased 6 and 12 hours after 4 injections of PCP (10 mg/kg, i.p.) over 12 hours. This decrease was observed at a dose of 5 mg/kg. No changes were seen after either acute or chronic administration of the drug. These changes in cerebellar GAD activity may account for the convulsant activity of this abused drug.