Chronic early-life lead exposure sensitizes adolescent rats to cocaine: Role of the dopaminergic system

Abstract

Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb²⁺) intoxication and schizophrenia (SZ). In animal models, Pb²⁺ exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb²⁺ exposure affects addiction circuits, we hypothesized that early life Pb²⁺ exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb²⁺ exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg^-1) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [³H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb²⁺ exposure increases the acute locomotor response to the higher dose of cocaine in Pb²⁺-exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb²⁺-exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb²⁺-induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb²⁺ exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb²⁺ exposure. Our data provides further support to the notion that Pb²⁺ exposure is an environmental risk factor for psychiatric disorders and substance abuse.

Keywords: D1 dopamine receptor; cocaine; dopaminergic system; lead; mental disorder (disease); substance abuse.