Abstract
Brain-specific neural-zinc-finger transcription factor-2b (NZF2b/7ZFMyt1) is induced in the mesolimbic dopaminergic region after chronic cocaine exposure and lentiviral-mediated expression of NZF2b/7ZFMyt1 in the nucleus accumbens results in decreased locomotor activity (Chandrasekar and Dreyer, 2010). In this study the role of NZF2b/7ZFMyt1 in active cocaine seeking and of its interaction with histone deacetylase on the altered behavior has been observed. Localized expression of NZF2b/7ZFMyt1 in the nucleus accumbens resulted in attenuated cocaine self-administration, whereas silencing this transcription factor with lentiviruses expressing siRNAs increased the animal′s motivation to self-infuse cocaine. Low doses of sodium butyrate, a potent inhibitor of histone deacetylase, were sufficient to reverse the NZF2b/7ZFMyt1-mediated decrease in cocaine self-administration. NZF2b/7ZFMyt1 expression resulted in strong induction of transcription factors REST1 and NAC1 and of the dopamine D2 receptor, with concomitant inhibition of BDNF and its receptor TrkB. We show that NZF2b/7ZFMyt1 colocalizes with histone deacetylase-2 (HDAC2), probably overcoming the suppression of transcriptional activity caused by Lingo1. These findings show that molecular adaptations mediated by NZF2b/7ZFMyt1 expression possibly lead to decreased responsiveness to the reinforcing properties of cocaine and play a prominent role in affecting the behavioral changes induced by the drug.
Highlights
Drugs of abuse induce long-term synaptic changes in the brain’s reward system
In the previous studies we have shown that the brain-specific transcription factor NZF2b/7ZFMyt1 (Neural Zinc Finger Transcription Factor-2b/7-Zinc Finger Myelin Transcription Factor-1) is induced significantly in the brain reward pathway after chronic cocaine administration and may play a key role in regulating the locomotor effects of cocaine (Chandrasekar and Dreyer, 2010)
Stereotaxical www.frontiersin.org injections were performed into the nucleus accumbens (NAc) shell; one group was injected LV-7ZFMyt1, the second group LV-7ZFMyt-short hairpin RNA (shRNA) and the third group the regulatable LV-green fluorescent protein (GFP)
Summary
Drugs of abuse induce long-term synaptic changes in the brain’s reward system. Synaptic plasticity directly underlies addictive behaviors after drug exposure (Nestler, 2000; Conrad et al, 2008; Lüscher and Bellone, 2008), but the mechanisms involved in these processes, and how drug-induced neural plasticity is mediated by transcriptional regulation, are still poorly known. Changes in synaptic transmission and neuronal morphology results from altered gene expression and epigenetic mechanisms, and are the emerging focus for recent investigations on addiction (Nestler, 2000; Tsankova et al, 2004, 2007; Kumar et al, 2005; Renthal et al, 2007). These studies support the key role of cocaine-induced transcription factors and their implication in chromatin remodeling for drug mediated altered gene expression (Berke and Hyman, 2000; Nestler, 2001). In adult neurons this may be associated with learning and memory and in response to psychotropic drugs (Guan et al, 2002; Alarcón et al, 2004; Korzus et al, 2004; Levenson et al, 2004; Li et al, 2004; Renthal et al, 2007)
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