Features of the Dopaminergic Neurotoxicity of Methamphetamine: A Comparison with MPTP
The amphetamines and cocaine are powerful CNS stimulants and common drugs of abuse. It is widely accepted that both the amphetamines and cocaine owe their stimulant properties to an interaction with brain dopaminergic systems. As an example, the administration to mice of d-amphetamine or of cocaine results in a large increase in locomotor activity of a relatively short duration which can be blocked by a number of dopamine receptor antagonists. Moreover, both cocaine and d-amphetamine cause an ipsilateral rotation in rats with a unilateral lesion of the nigrostriatal pathway. This rotational behavior also can be blocked by pretreatment of the rats with dopamine receptor antagonists. These data might suggest that these behavioral responses to d-amphetamine and cocaine are due to a common pharmacological mechanism. However this is not the case. It is generally accepted that d-amphetamine and several of its structural analogs are CNS stimulants because they facilitate the release of dopamine. In contrast, cocaine and several structural analogs are thought to be stimulants because they block the reuptake (uptake) of synaptically released dopamine. The differences in their mode of action can be demonstrated by the observations that treatment of mice with the tyrosine hydroxylase inhibitor α-methylpara-tyrosine prevents the increased locomotor activity caused by the amphetamines but has no effect on that caused by cocaine. In contrast, treatment of mice with reserpine prevents the increased activity caused by cocaine and other dopamine uptake inhibitors but has no effect on that caused by the amphetamines (Ross, 1978). These data suggest that the behavioral effects of d-amphetamine and related compounds are due to their release of newly synthesized dopamine while the behavioral effects of cocaine and other dopamine uptake inhibitors are due to their blockade of uptake of dopamine which is derived mainly from the reserpine-sensitive storage pool.
KeywordsNMDA Receptor Nigrostriatal Pathway Dopamine Receptor Antagonist Tyrosine Hydroxylase Activity Dopaminergic Neurotoxicity
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