Abstract
Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.
Highlights
By natural and fostered mothers were compared in the The number of Tyrosine hydroxylase (TH)-positive fibers in both the core and Conditioned place preference (CPP) (Figure 1a; t = 6.877, P < 0.0001) or ethanol shell divisions of the nucleus accumbens (NAcc) were significantly consumption (Figure 1b; t = 12.58, P < 0.0001) tests. reduced in in utero GCs (iuGC) animals (Figure 2a, shell: t = 2.827, the hypolocomotor profile observed in non- P = 0.022; Figure; core: t = 10.48, P < 0.0001; Supplefostered iuGC animals in the open field test was not mentary Figure S3), in parallel with markedly seen in cross-fostered iuGC rats (Figure 1c), morphine reduced NAcc levels of DA (t = 2.567, P = 0.0247)
Current views subjects most likely reflects receptor hypersensitivity suggest that repetitive exposure to drugs of abuse due to the hypodopaminergic state previously inevolve from goal-directed behaviors into habit-based duced by iuGC
We previously demonstrated that stress, The regulation of Drd[2], implicated in different associated with increased GC secretion, alters the phases of addiction, is seemingly complex;[44] structure of the corticostriatal loops and steers the the short DRD2 isoform interacts with DA transporters development of instrumental behavior into habitual and functions as a presynaptic autoreceptor to behavior.[39]
Summary
We previously demonstrated that fetal exposure to GC leads to hyper-emotionality in adulthood.[11]. A multimodal analysis was used to further define the molecular neurobiological mechanisms that underlie the initiation and reversibility of drug-seeking behavior by prenatal exposure to GC
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