Prolonged-access to Cocaine Induces Distinct Homer2 DNA Methylation, Hydroxymethylation, and Transcriptional Profiles in the Dorsomedial Prefrontal Cortex of Male Sprague-Dawley Rats

Overview

Journal Neuropharmacology

Specialties Neurology
Pharmacology

Date 2018 Oct 1

PMID 30268522

Citations 5

Authors

Kyle L Ploense

Xiang Li

Danay Baker-Andresen

Amanda E Carr

Nick Woodward

Jared Bagley

Karen K Szumlinski

Timothy W Bredy

Tod E Kippin

Affiliations

Soon will be listed here.

Abstract

Repeated cocaine administration induces many long-term structural and molecular changes in the dorsal medial prefrontal cortex (dmPFC) and are known to underlie aspects of cocaine-seeking behavior. DNA methylation is a key long-lasting epigenetic determinant of gene expression and is implicated in neuroplasticity, however, the extent to which this epigenetic modification is involved in the neuroplasticity associated with drug addiction has received limited attention. Here, we examine the relation between DNA methylation and gene expression within the dorsal medial prefrontal cortex (dmPFC) following limited cocaine self-administration (1 h/day), prolonged cocaine self-administration (6 h/day), and saline self-administration (1 h/day). Rats were fitted with intravenous catheters and allowed to lever press for saline or cocaine (0.25 mg/kg/0.1 mL infusion) in the different access conditions for 20 days. Prolonged-access rats exhibited escalation in cocaine intake over the course of training, while limited-access rats did not escalate cocaine intake. Additionally, limited-access and prolonged-access rats exhibited unique Homer2 epigenetic profiles and mRNA expression. In prolonged-access rats, Homer2 mRNA levels in the dmPFC were increased, which was accompanied by decreased DNA methylation and p300 binding within the Homer2 promoter. Limited-access animals exhibited decreased DNA methylation, decreased DNA hydroxymethylation, and increased p300 binding within the Homer2 promoter. These data indicate that distinct epigenetic profiles are induced by limited-versus prolonged-access self-administration conditions that contribute to transcriptional profiles and lend support to the notion that covalent modification of DNA is implicated in addiction-like changes in cocaine-seeking behavior.

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References

Dackis C, OBrien C . Cocaine dependence: a disease of the brain's reward centers. J Subst Abuse Treat. 2001; 21(3):111-7. DOI: 10.1016/s0740-5472(01)00192-1. View

Ahmed S, Kenny P, Koob G, Markou A . Neurobiological evidence for hedonic allostasis associated with escalating cocaine use. Nat Neurosci. 2002; 5(7):625-6. DOI: 10.1038/nn872. View

Goldstein R, Volkow N . Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002; 159(10):1642-52. PMC: 1201373. DOI: 10.1176/appi.ajp.159.10.1642. View

Paterson N, Markou A . Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport. 2003; 14(17):2229-32. DOI: 10.1097/00001756-200312020-00019. View

Ben-Shahar O, Ahmed S, Koob G, Ettenberg A . The transition from controlled to compulsive drug use is associated with a loss of sensitization. Brain Res. 2003; 995(1):46-54. DOI: 10.1016/j.brainres.2003.09.053. View

Kalivas P, McFarland K, Bowers S, Szumlinski K, Xi Z, Baker D . Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci. 2003; 1003:169-75. DOI: 10.1196/annals.1300.009. View

Szumlinski K, Dehoff M, Kang S, Frys K, Lominac K, Klugmann M . Homer proteins regulate sensitivity to cocaine. Neuron. 2004; 43(3):401-13. DOI: 10.1016/j.neuron.2004.07.019. View

Numachi Y, Yoshida S, Yamashita M, Fujiyama K, Naka M, Matsuoka H . Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain. Ann N Y Acad Sci. 2004; 1025:102-9. DOI: 10.1196/annals.1316.013. View

Kalivas P, Szumlinski K, Worley P . Homer2 gene deletion in mice produces a phenotype similar to chronic cocaine treated rats. Neurotox Res. 2004; 6(5):385-7. DOI: 10.1007/BF03033313. View

10.

Kippin T, Fuchs R, See R . Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl). 2006; 187(1):60-7. DOI: 10.1007/s00213-006-0386-3. View

11.

Wee S, Specio S, Koob G . Effects of dose and session duration on cocaine self-administration in rats. J Pharmacol Exp Ther. 2007; 320(3):1134-43. DOI: 10.1124/jpet.106.113340. View

12.

Hellemans J, Mortier G, De Paepe A, Speleman F, Vandesompele J . qBase relative quantification framework and software for management and automated analysis of real-time quantitative PCR data. Genome Biol. 2007; 8(2):R19. PMC: 1852402. DOI: 10.1186/gb-2007-8-2-r19. View

13.

Szumlinski K, Ary A, Lominac K . Homers regulate drug-induced neuroplasticity: implications for addiction. Biochem Pharmacol. 2007; 75(1):112-33. PMC: 2204062. DOI: 10.1016/j.bcp.2007.07.031. View

14.

Smith M, Ward S, Roberts D . Lesions of the dorsomedial frontal cortex block sensitization to the positive-reinforcing effects of cocaine. Pharmacol Biochem Behav. 2007; 88(3):238-46. DOI: 10.1016/j.pbb.2007.08.007. View

15.

Kalivas P . Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res. 2008; 14(2-3):185-9. DOI: 10.1007/BF03033809. View

16.

Ben-Shahar O, Obara I, Ary A, Ma N, Mangiardi M, Medina R . Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex. Synapse. 2009; 63(7):598-609. PMC: 2749486. DOI: 10.1002/syn.20640. View

17.

Yoshimochi K, Daitoku H, Fukamizu A . PCAF represses transactivation function of FOXO1 in an acetyltransferase-independent manner. J Recept Signal Transduct Res. 2010; 30(1):43-9. DOI: 10.3109/10799890903517947. View

18.

Freeman W, Lull M, Patel K, Brucklacher R, Morgan D, Roberts D . Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration. BMC Neurosci. 2010; 11:29. PMC: 2837051. DOI: 10.1186/1471-2202-11-29. View

19.

George O, Koob G . Individual differences in prefrontal cortex function and the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2010; 35(2):232-47. PMC: 2955797. DOI: 10.1016/j.neubiorev.2010.05.002. View

20.

Ito S, DAlessio A, Taranova O, Hong K, Sowers L, Zhang Y . Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010; 466(7310):1129-33. PMC: 3491567. DOI: 10.1038/nature09303. View