Abstract
Previous work from our group and others utilizing animal models have demonstrated long-lasting structural and functional alterations in the meso-cortico-striatal dopamine pathway following prenatal cocaine (PCOC) treatment. We have shown that PCOC treatment results in augmented D1-induced cyclic AMP (cAMP) and cocaine-induced immediate-early gene expression in the striatum of adult mice. In this study we further examined basal as well as cocaine or D1-induced activation of a set of molecules known to be mediators of neuronal plasticity following psychostimulant treatment, with emphasis in the dorsal striatum (Str) and nucleus accumbens (NAc) of adult mice exposed to cocaine in utero. Basally, in the Str of PCOC treated mice there were significantly higher levels of (1) CREB and Ser133 P-CREB (2) Thr34 P-DARPP-32 and (3) GluA1 and Ser 845 P-GluA1 when compared to prenatal saline (PSAL) treated mice. In the NAc there were significantly higher basal levels of (1) CREB and Ser133 P-CREB, (2) Thr202/Tyr204 P-ERK2, and (3) Ser845 P-GluA1. Following acute administration of cocaine (15 mg/kg, i.p.) or D1 agonist (SKF 82958; 1 mg/kg, i.p.) there were significantly higher levels of Ser133 P-CREB, Thr34 P-DARPP-32, and Thr202/Tyr204 P-ERK2 in the Str that were evident in all animals tested. However, these cocaine-induced increases in phosphorylation were significantly augmented in PCOC mice compared to PSAL mice. In sharp contrast to the observations in the Str, in the NAc, acute administration of cocaine or D1 agonist significantly increased P-CREB and P-ERK2 in PSAL mice, a response that was not evident in PCOC mice. Examination of Ser 845 P-GluA1 revealed that cocaine or D1 agonist significantly increased levels in PSAL mice, but significantly decreased levels in the PCOC mice in both the Str and NAc. We also examined changes in brain-derived neurotrophic factor (BDNF). Our studies revealed significantly higher levels of the BDNF precursor, pro-BDNF, and one of its receptors, TrkB in the Str of PCOC mice compared to PSAL mice. These results suggest a persistent up-regulation of molecules critical to D1 and BDNF signaling in the Str of adult mice exposed to cocaine in utero. These molecular adaptations may underlie components of the behavioral deficits evident in exposed animals and a subset of exposed humans, and may represent a therapeutic target for ameliorating aspects of the PCOC-induced phenotype.
Highlights
Over the past 25 years since crack cocaine became a drug commonly abused by pregnant women, multiple clinical, and preclinical studies have identified alterations in fetal brain development with lasting consequences on brain structure and function resulting from prenatal cocaine (PCOC) exposure (Kosofsky et al, 1994; reviewed in Trask and Kosofsky, 2000; Kosofsky and Hyman, 2001)
We found that following acute administration of cocaine (15 mg/kg, i.p.) or D1 agonist (SKF 82958; 1 mg/kg, i.p.) there were significantly higher levels of Ser133 P-CREB, Thr34 P-DARPP-32, and Thr202/Tyr204 P-ERK2 evident in the Str in both prenatal treatment groups
In parallel we have identified that the growth factor pro-brain-derived neurotrophic factor (BDNF), and TrkB, a BDNF receptor, are upregulated in the Str but not nucleus accumbens (NAc) of adult PCOC mice
Summary
Over the past 25 years since crack cocaine became a drug commonly abused by pregnant women, multiple clinical, and preclinical studies have identified alterations in fetal brain development with lasting consequences on brain structure and function resulting from prenatal cocaine (PCOC) exposure (Kosofsky et al, 1994; reviewed in Trask and Kosofsky, 2000; Kosofsky and Hyman, 2001). PCOC exposure has been shown to result in subtle reductions in IQ and cognitive development (Alessandri et al, 1998; Lester et al, 1998), delayed language development (Beeghly et al, 2006), and impairments in tasks requiring sustained attention (Accornero et al, 2007). Such studies support the idea that intrauterine exposure to cocaine most profoundly alters attention, arousal, and reactivity, functions that may negatively impact learning and memory in exposed offspring (Mayes et al, 1998).
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