Abstract
The dysregulation of the dopaminergic system is implicated in multiple neurological and neuropsychiatric disorders such as Parkinson disease and drug addiction. The primary target of psychostimulants such as amphetamine and methamphetamine is the dopamine transporter (DAT), the major regulator of extracellular dopamine levels in the brain. However, the behavioral and neurophysiological correlates of methamphetamine and amphetamine administration are unique from one another, thereby suggesting these two compounds impact dopaminergic neurotransmission differentially. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. In dopaminergic neurons the spontaneous firing rate was enhanced by extracellular application of amphetamine > dopamine > methamphetamine and was DAT-dependent. Amphetamine > methamphetamine similarly enhanced DAT-mediated inward current, which was sensitive to isosmotic substitution of Na(+) or Cl(-) ion. Although isosmotic substitution of extracellular Na(+) ions blocked amphetamine and methamphetamine-induced DAT-mediated inward current similarly, the removal of extracellular Cl(-) ions preferentially blocked amphetamine-induced inward current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. The results reveal a new mechanism for methamphetamine-induced dysregulation of dopaminergic neurons.
Highlights
Behavioral and neurophysiological correlates of methamphetamine and amphetamine differ via unknown mechanisms
Extracellular Amphetamine and Methamphetamine Differentially Alter the dopamine transporter (DAT)-mediated Firing Rate of Dopaminergic Neurons—The DAT substrates, dopamine, amphetamine, and methamphetamine interact with the transporter, are transported into the neuron, and elicit an excitatory current that is blocked by DAT antagonist [13, 29, 42]
Consistent with previous reports, the results suggest that dopamine modulation of the firing rate of dopaminergic neurons depends on the activity of the transporter
Summary
Behavioral and neurophysiological correlates of methamphetamine and amphetamine differ via unknown mechanisms. We further examined the unique mechanisms by which amphetamine and methamphetamine regulate DAT function and dopamine neurotransmission; in the present study we examined the impact of extracellular and intracellular amphetamine and methamphetamine on the spontaneous firing of cultured midbrain dopaminergic neurons and isolated DAT-mediated current. The intracellular application of methamphetamine, but not amphetamine, prevented the dopamine-induced increase in the spontaneous firing of dopaminergic neurons and the corresponding DAT-mediated inward current. Relative to dopamine and methamphetamine, amphetamine induces a greater increase in the frequency of the DAT-dependent spontaneous firing rate of midbrain dopamine neurons and elicits a larger DAT-dependent inward current that is uniquely more sensitive to isosmotic substitution of the external ClϪ ions. Because the nature of drug-induced dysregulation of DAT is important in the etiology of drug addiction, these data provide new information for the exploring treatment of methamphetamine addiction
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