Lead-induced changes in dopamine D1 sensitivity: modulation by drug discrimination training

Area of Science:

• Neuroscience
• Toxicology
• Pharmacology

Background:

• Lead (Pb) exposure is known to alter dopamine system functions, leading to enhanced sensitivity to dopamine agonists.
• Previous studies indicate Pb exposure shifts dose-effect functions for D1 and D2 agonists, suggesting altered dopamine receptor sensitivity.

Purpose of the Study:

• To investigate the mechanisms underlying Pb-induced D1 supersensitivity.
• To determine the contribution of synergistic D1-D2 receptor interactions to Pb-induced D1 supersensitivity.
• To evaluate the impact of chronic D1 agonist administration in drug discrimination procedures on Pb-induced changes in dopamine system function.

Main Methods:

• Rats were exposed to lead acetate (50 or 150 ppm) from weaning.
• Operant drug discrimination procedures were used to train rats to discriminate the D1 agonist SKF38393 from saline.
• Dose-effect curves for SKF38393 were assessed in the presence and absence of the D2 antagonist haloperidol.
• The effect of discontinuing drug discrimination training on SKF38393 sensitivity was evaluated.

Main Results:

• Pb-exposed rats showed greater sensitivity to the D1 agonist SKF38393 compared to control rats, consistent with previous findings.
• Pb-induced D1 supersensitivity was maintained in the presence of the D2 antagonist haloperidol, suggesting D1/D2 interactions do not contribute.
• Discontinuation of training led to sensitization in control rats but not in Pb-treated rats, indicating Pb-induced D1 subsensitivity.

Conclusions:

• D1/D2 receptor interactions do not appear to mediate Pb-induced D1 supersensitivity.
• Pb-induced D1 supersensitivity may result from altered responses to chronic D1 agonist administration in Pb-modified dopamine systems.
• These findings question dopamine availability depletion as a primary mechanism for Pb-induced alterations in dopamine system function.