The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats

Rationale: Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. Objectives: The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. Methods: Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. Results: Developmental lead exposure produced subsensitivity to SKF-82958 (D-1-like dopamine receptor agonist), quinpirole (D-2-like dopamine receptor agonist), and apomorphine (mixed D-1-like/D-2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the K-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 <mu>g/dl). Conclusions: These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.