Elsevier

Neuropharmacology

Volume 58, Issue 2, February 2010, Pages 436-443
Neuropharmacology

Cocaine exposure modulates dopamine and adenosine signaling in the fetal brain

https://doi.org/10.1016/j.neuropharm.2009.09.007Get rights and content

Abstract

Exposure to cocaine during the fetal period can produce significant lasting changes in the structure and function of the brain. Cocaine exerts its effects on the developing brain by blocking monoamine transporters and impairing monoamine receptor signaling. Dopamine is a major central target of cocaine. In a mouse model, we show that cocaine exposure from embryonic day 8 (E8) to E14 produces significant reduction in dopamine transporter activity, attenuation of dopamine D1-receptor function and upregulation of dopamine D2-receptor function. Cocaine's effects on the D1-receptor are at the level of protein expression as well as activity. The cocaine exposure also produces significant increases in basal cAMP levels in the striatum and cerebral cortex. The increase in the basal cAMP levels was independent of dopamine receptor activity. In contrast, blocking the adenosine A2a receptor downregulated the basal cAMP levels in the cocaine-exposed brain to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine's effects on the embryonic brain. In support of this suggestion, we found that the cocaine exposure downregulated adenosine transporter function. We also found that dopamine D2- and adenosine A2a-receptors antagonize each other's function in the embryonic brain in a manner consistent with their interactions in the mature brain. Thus, our data show that prenatal cocaine exposure produces direct effects on both the dopamine and adenosine systems. Furthermore, the dopamine D2 and adenosine A2a receptor interactions in the embryonic brain discovered in this study unveil a novel substrate for cocaine's effects on the developing brain.

Introduction

Cocaine exposure during the fetal period can lead to lasting impairment of neurological function (Chasnoff et al., 1989a, Chasnoff et al., 1989b, Chiriboga et al., 1993, Chiriboga et al., 2009, Delaney-Black et al., 1996, Eyler et al., 2009, Kosofsky and Wilkins, 1998). Cocaine exerts its effects by blocking the activity of monoamine transporters. Central actions of cocaine are believed to be mainly due to blockade of the dopamine transporter, the resulting decrease in dopamine re-uptake at the synapse and increase in extracellular dopamine levels (Bhide, 2009, Meyer et al., 1993, Ritz et al., 1990, Ritz et al., 1987). Persistent increases in extracellular dopamine levels can impair pre- and pos-synaptic receptor activity by impairing receptor – G-protein coupling mechanisms (Zhen et al., 2001). Since cocaine in the maternal circulation can penetrate the placental and fetal blood–brain barriers, and since dopamine, dopamine transporter and dopamine receptors are present in the fetal brain, cocaine from the maternal circulation can disrupt dopaminergic signaling mechanisms in the fetal brain (Akbari et al., 1992, Jones et al., 2000, Kosofsky et al., 1994, Levitt et al., 1997, Mayes, 1999, Meyer et al., 1993, Wang et al., 1995b).

Cocaine can interfere with dopaminergic signaling in the mature brain via direct actions on the dopaminergic system as well as indirectly via its effects on the adenosine receptor (Shen et al., 2008, Soria et al., 2006). Dopamine and adenosine receptors engage in antagonistic interactions that play significant roles in the regulation of motor and cognitive functions (Fuxe et al., 2007, Schwarzschild et al., 2006). Whether dopamine–adenosine interactions occur in the embryonic brain or whether cocaine can affect the adenosine system of the embryonic brain has remained unclear.

We report that administration of cocaine to pregnant mice from 8th to 14th day of pregnancy [embryonic day 8 (E8) to E14; equivalent to first trimester of human gestation] not only impairs dopamine receptor signaling but also adenosine receptor signaling in the brain. Cocaine's effects on the dopaminergic system involve attenuation of D1-receptor signaling and enhancement of D2-receptor signaling. Cocaine's effects on the adenosine system of the embryonic brain involve reduction in extracellular adenosine uptake and increase in extracellular adenosine levels. We also show that antagonistic interactions between dopamine D2- and adenosine A2a-receptors occur in the embryonic brain. Therefore, cocaine likely produces its effects on brain development by directly affecting the dopamine and adenosine signaling mechanisms and also by impairing dopamine–adenosine interactions.

Section snippets

Animals

Timed-pregnant Swiss-Webster mice were obtained from Charles River Laboratories (Wilmington, MA). A transplacental cocaine exposure paradigm described previously (Kosofsky et al., 1994, Wilkins et al., 1998) was used to expose mouse embryos to cocaine twice daily from the morning of embryonic day 8 (E8; day of conception = E0) to the evening of E14, inclusive. At the beginning of the experiment, pregnant dams of comparable weight were assigned to cocaine (40 mg/kg/day) or saline control groups.

Results

We used 3H-dopamine uptake to assay dopamine transporter function in the striatum and cerebral cortex from saline- or cocaine-exposed E15 mice. We found a significant decrease in 3H-dopamine uptake in the striatum (∼50%; p < 0.001) of the cocaine-exposed embryos compared to saline-exposed embryos (Fig. 1A) indicating attenuation of dopamine transporter function and increased extracellular dopamine. The cocaine exposure did not produce statistically significant changes in 3H-dopamine uptake in

Discussion

Our data show that prenatal cocaine exposure influences dopamine and adenosine signaling in the striatum and cerebral cortex. Moreover, the data show that dopamine D2 and adenosine A2a-receptors antagonize each other's actions in the embryonic brain. Therefore, cocaine likely exerts its effects on the developing brain by directly interfering with dopamine and adenosine receptor signaling as well as via impairment of dopamine D2 and adenosine A2a receptor interactions.

A number of earlier studies

Acknowledgements

Supported by USPHS grants RO1DA020796 and P30NS045776 to PGB and a fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil to RCCK. We gratefully acknowledge advice and assistance from our colleagues Deirdre McCarthy, Jia-Qian Ren and John Sims in the course of this work.

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