Methamphetamine-, d-Amphetamine-, and p-Chloroamphetamine-Induced Neurotoxicity Differentially Effect Impulsive Responding on the Stop-Signal Task in Rats

Neurotox Res. 2016 May;29(4):569-82. doi: 10.1007/s12640-016-9605-9. Epub 2016 Feb 4.


Abused amphetamines, such as d-amphetamine (AMPH) and methamphetamine (METH), are highly addictive and destructive to health and productive lifestyles. The abuse of these drugs is associated with impulsive behavior, which is likely to contribute to addiction. The amphetamines also differentially damage dopamine (DA) and serotonin (5-HT) systems, which regulate impulsive behavior; therefore, exposure to these drugs may differentially alter impulsive behavior to effect the progression of addiction. We examined the impact of neurotoxicity induced by three amphetamines on impulsive action using a stop-signal task in rats. Animals were rewarded with a food pellet after lever pressing (i.e., a go trial), unless an auditory cue was presented and withholding lever press gained reward (i.e., a stop trial). Animals were trained on the task and then exposed to a neurotoxic regimen of either AMPH, p-chloroamphetamine (PCA), or METH. These regimens preferentially reduced DA transporter levels in striatum, 5-HT transporter levels in prefrontal cortex, or both, respectively. Assessment of performance on the stop-signal task beginning 1 week after the treatment revealed that AMPH produced a deficit in go-trial performance, whereas PCA did not alter performance on either trial type. In contrast, METH produced a deficit in stop-trial performance (i.e., impulsive action) but not go-trial performance. These findings suggest that the different neurotoxic consequences of substituted amphetamines are associated with different effects on inhibitory control over behavior. Thus, the course of addiction and maladaptive behavior resulting from exposure to these substances is likely to differ.

Keywords: Amphetamine; Behavioral inhibition; Dopamine; Impulsive action; Serotonin; Stop-signal task.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Central Nervous System Stimulants / toxicity*
  • Dextroamphetamine
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Impulsive Behavior / drug effects*
  • Male
  • Methamphetamine
  • Motor Activity / drug effects
  • Neuropsychological Tests
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / physiopathology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Time Factors
  • p-Chloroamphetamine


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Methamphetamine
  • p-Chloroamphetamine
  • Dextroamphetamine
  • Dopamine