The neurotoxicity of methamphetamine to monoaminergic neurons was examined. Neurotoxicity was assessed by quantitative autoradiography using radioligands specific for binding to norepinephrine, dopamine, and serotonin uptake sites. High-dose administration of methamphetamine led to decreases in binding to uptake sites for the three monoamines. Norepinephrine binding sites were decreased in certain amygdaloid nuclei and in the dorsomedial hypothalamic nucleus. Serotonin binding sites were reduced in widespread brain areas, while dopamine binding sites were reduced in the caudate putamen, olfactory tubercle, and nucleus accumbens. The decreases in binding site density for the three monoamines are limited to terminal field areas; cell body areas are not affected. Our results indicate that methamphetamine is neurotoxic to serotonin, dopamine, and norepinephrine neurons. The neurotoxicity to norepinephrine neurons is in selected brain areas.

The uptake of L-proline by synaptosomes isolated from different regions of the brain was investigated. The highest rates of transport and the largest accumulation ratios were found in synaptosomes from the midbrain, striatum, hippocampus and hypothalamus, with lower activity in the cortex and medulla (+ pons) and lowest in the cerebellum. The high affinity, Na+-dependent proline uptake had a Km of 12/tM, a V,, of 0.6 nmol.min-'.mg protein-' and the maximum accumulation ratio ([proline]i/[proline],,) at 2 CM added radioactive amino acid was 40-50. Our results suggest that: (1) only 5-10% of the synaptosomal population accumulates proline through the high-affinity uptake; (2) the characteristics of the proline uptake system into the prolinergic nerve endings are remarkably similar to those of other amino acid neurotransmitters (GABA, aspartate and glutamate); (3) the behavior of proline is consistent with this amino acid being a neurotransmitter in the central nervous system.

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There have been a number of claims that high-dose administration of cocaine to rats leads to neurotoxic effects on dopamine neurons. In this study possible neurotoxic effects on monoamine neurons were examined by measuring the effects of cocaine (35 mg/kg daily for 10 days) on the binding of radioligands to uptake sites for dopamine, serotonin and norepinephrine using qualitative autoradiography. No effects of cocaine on any of the binding sites were observed and therefore, it is concluded that cocaine, unlike amphetamine derivatives which have similar pharmacologic properties, does not produce neurotoxic effects on monoamine neurons.