Cocaine and Transcription Factors

Chapter 12

Cocaine and Transcription Factors V. Gonzalez-Nunez and R.E. Rodrı´guez Universidad de Salamanca, Salamanca, Spain

SUMMARY POINTS G

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This chapter focuses on the effects of cocaine in the expression or functionality of transcription factors, mainly in the central nervous system. Cocaine modulates the expression and the functionality of several transcription factors, which control the transcriptional activity of many target genes. Cocaine modulates the functionality of transcription factors by altering their transcriptional level (up- or down-regulation of their expression levels), or it can trigger their translocation to the nucleus, or even promote their binding to the DNA. The effect of cocaine is specific of certain brain areas, and usually depends on the length of the treatment, the route of administration, and the experimental approach. Some of these transcription factors are involved in neural plasticity mechanisms which induce the longterm changes triggered by cocaine. These TF also regulate the rewarding properties of cocaine and its addictive potential. Most of these transcription factors are immediate early genes, which are directly controlled by CREB and/or AP-1, especially by ΔFOSB. The expression of several homeogenes is also altered by chronic cocaine intake. Chronic cocaine administration alters dopaminergic differentiation. Cocaine directly modulates the expression of genes that control the circadian rhythm.

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Some transcription factors are related to neural plasticity, explaining the relationship between cocaine abuse and memory loss. Dopaminergic signaling is the main target of cocaine, as it blocks dopamine reuptake in the synaptic cleft by directly inhibiting the dopamine transporter. Cocaine also impairs the generation of dopamine neurons by modifying the expression of transcription factors that regulate dopaminergic differentiation. Chronic cocaine consumption produces changes in the sleep
wake cycle, which also increase the risk for substance abuse.

LIST OF ABBREVIATIONS CNS CPu CREB DA ΔFOSB D1R D2R DR GR IEG mb MSNs NAc PKa RE TF VTA

central nervous system caudate putamen cAMP response element-binding protein dopamine also deltaFOSB, truncated isoform of FOSB D1 dopamine receptor D2 dopamine receptor dopamine receptor glucocorticoid receptor immediate early gene midbrain medium spiny neurons nucleus accumbens protein kinase A response element transcription factor ventral tegmental area

KEY FACTS G

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It is estimated that 14.1 million people in Europe have used cocaine in their lifetime. Cocaine is one of the drugs of abuse with the highest addictive potential due to its reinforcing properties. Cocaine produces long-term changes in the brain, partly by altering the functionality of transcription factors.

The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00012-9 © 2017 Elsevier Inc. All rights reserved.

12.1 INTRODUCTION As with many other drugs of abuse, cocaine triggers adaptive changes in the reward pathway, where the mesolimbic DA system (NAc
VTA) plays a key role in promoting its reinforcing properties (Nestler, 2001). These 107

108 PART | II Molecular Effects

cellular and molecular adaptations, known as synaptic plasticity, share a common neurobiological basis with learning and memory (Nestler, 2013) and can lead to an “addicted state.” Chronic cocaine consumption triggers a DA overflow, which produces long-lasting changes in gene expression. Transcription factors (TFs) are the main players in the regulation of gene expression, although nowadays the epigenetic modifications are emerging as global (and usually hereditable) mechanisms to control gene expression (McQuown & Wood, 2010). Cocaine modulates the expression and the functionality of several TFs, which control the transcriptional activity of a specific set of genes and induce permanent changes in certain brain regions (Barik et al., 2010).

12.2 STRUCTURE AND FUNCTION OF TRANSCRIPTION FACTORS A TF is a protein which recognizes a specific DNA sequence and is able to promote or repress the transcriptional activity of a target gene. They usually act upstream of the transcriptional start site, and its expression and activation are strictly controlled. Inducible TF are synthesized or activated upon a specific signal, and they are responsible for the differential expression of a specific set of genes (target genes). The prototypical structure of an inducible TF is shown in Fig. 12.1. The dimerization domain and the ligand binding site are usually related to the modulation of TF activity (Table 12.1). The DNA binding domain displays a large amount of structural diversity (Table 12.2), but all of them are able to recognize a specific DNA sequence, called RE.

12.3 COCAINE AND TRANSCRIPTION FACTORS There is a strong body of evidence that cocaine modulates the functionality of TFs. The main findings are summarized in Table 12.3, although the effect of cocaine is specific to certain brain areas, and usually depends on the length of the treatment, the route of administration, and the experimental approach used. Conversely, some TFs may modulate the neuroadaptive responses to cocaine, its rewarding properties, and even its addictive potential. Some of these TFs are involved in neural plasticity mechanisms which induce the long-term changes triggered by cocaine.

12.4 CREB AND AP-1: TFS DIRECTLY REGULATED BY COCAINE Cocaine elicits its actions by directly blocking the presynaptic dopamine transporter (DAT), and as a consequence it increases the synaptic DA concentration. Extracellular DA binds and activates the postsynaptic DA receptors (Kreek, LaForge, & Butelman, 2002): the inhibitory D1R (D1 receptors, DRD1 and DRD5) coupled to Gαi proteins, and the excitatory D2R (D2 receptors, DRD2, DRD3, and DRD4) coupled to Gαs. The activation of adenylyl cyclase by D2R produces an increase in the intracellular levels of cAMP, thus activating PKa. PKa is now able to phosphorylate its target genes, among them CREB. pCREB (phosphoCREB) is the active form of CREB which binds to its recognition sites in the DNA (i.e., the RE) and regulates the transcriptional activity of its target genes, named immediate early genes (IEGs) (Blendy & Maldonado, 1998).

FIGURE 12.1 Structure of a prototypical transcription factor (TF). An inducible TF usually displays four different structural domains: a DNA binding domain (mandatory), a transactivation domain (mandatory), a dimerization domain, and a ligand binding site. The order of these domains does not exhibit a fixed arrangement in the primary structure of the protein.

Cocaine and Transcription Factors Chapter | 12

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TABLE 12.1 Mechanisms That Regulate the Activity of Transcription Factors (TFs) Mechanism

Example of TF

Covalent modification

Covalent modification produces a conformational change in the 3D structure of the TF, thus activating or inhibiting its ability to bind to the DNA and to regulate transcription G protein phosphorylation G dephosphorylation G glycosylation G acetylation G ubiquitylation G SUMOylation

CREB

Ligand binding

The binding of a ligand produces a conformational change in the 3D structure of the TF, thus activating or inhibiting its ability to bind to the DNA and to regulate transcription G retinoic acid G steroid hormones

Nuclear receptors (e.g., glucocorticoid receptor)

Release of an inhibitor

An inhibitor is bound to the TF, blocking its ability to bind to the DNA or to translocate into the nucleus. A specific signal induces the release of the inhibitor, thus activating the TF

NF-KB

Nuclear translocation

The nuclear localization signal, which is masked in the basal condition, is unmasked by a specific stimuli (e.g. by phosphorylation or release of an inhibitor), thus promoting the translocation of the TF to the nucleus

NFAT NF-KB

De novo synthesis

A specific signal triggers the synthesis of a TF

Homeogenes

Degradation

The TFs is rapidly degraded (by the proteasome) after a specific stimuli G ubiquitinylation can target proteins for proteasomal degradation

FOS

Summary of the main molecular strategies that regulate the activity of a TF. Inducible TFs are activated (or inhibited) by specific biochemical signals, which usually produce a reversible conformational change in the 3D structure of the protein, allowing to switch between an active and an inactive state. This conformational change usually enables the interaction of the TF with its RE in the regulatory promoter, modulating the transcriptional activity of their target genes. TFs can also be synthesized or degraded after specific stimuli.

CREB activation by cocaine treatment is complex and highly variable depending on the brain area (Walters, Kuo, & Blendy, 2003). CREB is an integrator of different signaling pathways, and thus it can be activated by different stimuli, including several drugs of abuse. Besides, CREB regulates the rewarding properties of cocaine (Olson et al., 2005). AP-1 is a FOS/JUN dimer that is formed by one monomer of the FOS family (FOS, FOSB, FOSL1, FOSL2) and one monomer of the JUN family (JUN, JUNB, or JUND) (Hope et al., 1994); AP-1 is the active form of a FOS/JUN dimer, which is able to translocate into the nucleus and activates the expression of IEGs. Interestingly, the expression of FOS/JUN related genes is also under CREB control (Sheng & Greenberg, 1990), so that they are considered IEGs. Cocaine administration induces the expression of members of FOS family (also known as FOS-related antigens or FRAs), although there are certain differences (Hope et al., 1994). FOSL1 and FOSL2 are transiently induced by acute treatment (Piechota et al., 2010). Although there is a major upregulation of FOS expression by acute treatment, this induction decreases after chronic cocaine use (Piechota et al., 2010), reflecting a

desensitization of FOS induction. The truncated isoform of FOSB, ΔFOSB, is highly stable and strongly accumulates after chronic treatment (Hope et al., 1994). Interestingly, the accumulation of ΔFOSB in the NAc is mediated by CREB and SRF (serum response factor), an IEG also activated by cocaine. The concerted binding of these two TFs to the FOSB promoter modulates the rewarding properties of cocaine and locomotor sensitization. To block the induction of ΔFOSB by cocaine, the deletion of both sites (CRE and SRE) in the promoter is required (Vialou et al., 2012). ΔFOSB increases the expression of many lateresponse genes related to locomotor responses, sensitization to cocaine and reward, thus acting as a molecular switch that contributes to relapse after abstinence periods (Nestler, 2001). ΔFOSB upregulates the expression of the 2GluR2 subunit (GRIA2) of the AMPA receptor, decreasing the electric excitability of neurons in the NAc, and downregulates the expression of dynorphin A, enhancing the rewarding properties and the dysphoric effect during withdrawal (Chao & Nestler, 2004). Some of these actions may be mediated by the protein kinase CaMKIIalpha (CAMK2A), which is related to an induction of dendritic spines in MSNs in NAc shell, mediating the

110 PART | II Molecular Effects

TABLE 12.2 Structural Diversity of Transcription Factor (TF) DNA Binding Domains Motif

Description

Zn fingers

The prototypical modular structure (C2H2-type) is formed by 30 residues, 4 of which are 2 invariable Cys and 2 invariable His or Cys; it also displays several conserved hydrophobic residues and a Zn21 ion, which is tetrahedrally coordinated with those Cys and His. Structural diversity of Zn fingers: C2H2-type C4-type C2HC-type C6-type (2 Zn fingers) The Zn fingers fit into the major groove of the DNA and interact with their target sequences

bZIP: Basic Region Leu Zipper

Leu zippers allow TF dimerization: it is an α-helix of 35 residues which displays hydrophobic residues on one face (invariant Leu and Val), allowing the interaction with another α-helix of the same nature, thus forming a coiled coil On its N-terminus, separated by 7 residues, the Leu zipper displays a basic α-helix with comprises the DNA recognition domain

bHLH: Basic helix-loophelix

A basic DNA binding region, followed by a protein dimerization domain, namely two amphipathic α-helices connected by a loop. This motif is usually connected to a Leu zipper, which enhances TF dimerization

HTH: Helix-Turn-Helix

20 residues arranged in 2 α-helices oriented 120 to each other and connected by a short turn: a short first helix, followed by a turn (also named as helix breaker, as it displays a Gly residue), and a second α-helix, which interacts with the DNA

Homeodomain

A special class of HTH which recognizes a target sequence of 180bp. It comprises: a basic N-terminus which fits into the minor groove two antiparallel α-helices a third α-helix, crossed at 90 , that fits into an adjacent major groove

Description of the general structure of the DNA binding domains present in TFs that are regulated by cocaine. These domains can be classified into five main structural motifs that are able to recognize a specific DNA sequence. Most of them contain a basic motif that fits into the major groove of the DNA and establish specific contacts with a consensus DNA sequence.

behavioral responses to cocaine. Both ΔFOSB and CaMKIIalpha are involved in a feedforward loop in the NAc that controls the rewarding properties of chronic cocaine use (Robison et al., 2013).

12.5 IMMEDIATE EARLY GENES IEGs are TFs which display binding sites for CREB and/or AP-1 on their promoter, so that the expression of IEGs is controlled by: (1) CREB; (2) AP-1 (mainly by ΔFOSB); and (3) a group of TFs requires a concerted regulation by both CREB and ΔFOSB (Fig. 12.2). A combinatorial effect of CREB and AP-1 REs in the promoters allows a differential regulation of their target IEGs. Most IEGs are TFs which control the expression levels of their downstream targets, called effector proteins or lateresponse genes. Tyrosine hydroxylase, which is the ratelimiting enzyme of DA biosynthesis (Chao & Nestler, 2004), cytoskeletal proteins related to dendritic spine formation and spine density (Russo et al., 2010), HOM, ARC, and Synaptotagmin IV (Yuferov et al., 2003) are prototypical examples of effector proteins. Late-response

genes mediate the cellular responses to cocaine, the synaptic plasticity, and the long-term changes related to an addictive phenotype (Nestler, Hope, & Widnell, 1993). EGRs, NF-κB (NFKB1), and the glucocorticoid receptor (GR or NR3C1) are the most relevant IEGs. It is important to note that many IEGs, as well as CREB and AP-1, are transcriptional integrators of different signaling pathways, thus allowing the crosstalk between cocaine signaling and other signal transduction pathways, hence explaining the wide spectra of pharmacological actions elicited by cocaine abuse. Conversely, the activation of these signaling pathways by e.g. stress or environmental factors is able to modulate the reinforcing properties of cocaine and relapse after a withdrawal period.

12.5.1 EGRs Early growth response genes (EGR1-4) are the prototypical examples of IEGs, as their expression is increased by acute and ascending doses of cocaine (Piechota et al., 2010). Induction of EGR1 expression by acute cocaine is mediated by D1Rs (Drago, Gerfen, Westphal, & Steiner, 1996), while

TABLE 12.3 List of Transcription Factors (TFs) Affected by Cocaine Administration Gene

Name (Description)

Aliases

GeneCards ID

ENSEMBL ID

UniProt KB

DNA Binding Domain

Transcription Factor Binding Site in DNA Consensus Sequence*

Effect of Cocaine#

ARNTL

Aryl Hydrocarbon Receptor Nuclear TranslocatorLike

BMAL1

GC11P013299

ENSG00000133794

O00327

Basic helix-loophelix (bHLH)

E-box 50 - GHCACGTG-30

G

CLOCK

G

Clock Circadian Regulator

GC04M056294

ENSG00000134852

O15516

Basic helix-loophelix (bHLH)

E-box 50 - GHCACGTG-30

G

Downregulated in caudateputamen after chronic cocaine exposure Upregulated in striatum after cocaine self-administration

23776671 15994025 18452895

Regulates sensitization to cocaine in Drosophila

10446052 23776671 18452895

It might regulate Tyr decarboxylase expression

ENSG00000118260

P16220

Basic-leucine zipper (bZIP)

G

Upregulated in rats after selfadministration

cAMP responsive element 50 CGGTGACGTCAC-30

G

Complex interaction Increase of pCREB levels after chronic cocaine Regulates the rewarding properties of cocaine

9856954 15944383

CAMP Responsive Element-Binding Protein 1

CREB

CREM

CAMP Responsive Element Modulator

ICER

GC10P035415

ENSG00000095794

Q03060

Basic-leucine zipper (bZIP)

cAMP responsive element 50 CGGTGACGTCAC-30

G

Upregulated by acute cocaine treatment

20459597

CSRNP1

Cysteine-SerineRich Nuclear Protein 1

AXUD1

GC03M039159

ENSG00000144655

Q96S65

Putative domain A cysteine-rich or a basic domain

5-AGAGTG-3

G

Upregulated by acute cocaine treatment

20459597

EGR1

Early Growth Response 1

Zif268 KROX24 NGFI-A

GC05P137801

ENSG00000120738

P18146

Zn finger C2H2-type

50 -TGCGTGGGYG-30

G

Upregulated by cocaine treatment

1613551 1356432 8229780 7905595 7825122 7854036 7609608 8905721 8884777 12687634 20459597 18452895

CREB1

GC02P208394

PMID

G

G

(different experimental approaches used)

(Continued )

TABLE 12.3 (Continued) Gene

Name (Description)

Aliases

GeneCards ID

ENSEMBL ID

UniProt KB

DNA Binding Domain

Transcription Factor Binding Site in DNA Consensus Sequence*

Effect of Cocaine#

EGR2

Early Growth Response 2

KROX20

GC10M064571

ENSG00000122877

P11161

Zn finger C2H2-type

50 NGCGTGGGCGGR30

G

Upregulated by acute and by ascending doses of cocaine

12687634 20459597

EGR3

Early Growth Response 3

GC08M022545

ENSG00000179388

Q06889

Zn finger C2H2-type

GSG site 5-GCGGGGGCG-3

G

Induction of EGR3 ribosomeassociated mRNA in D1 neurons in NAc after repeated cocaine administration Triggers upregulation of Camk2alpha, CREB, FOSB, NR4A2, and SIRT1 in D1 neurons Reduction of EGR3 ribosomeassociated mRNA in D2 neurons in NAc It can be related to circadian rhythm

25995477 9488654

G

G

G

EGR4

Early Growth Response 4

EN1

Engrailed Homeobox 1

FOS

FBJ Murine Osteosarcoma Viral Oncogene Homolog

NGFI-C

C-FOS

GC02M073518

ENSG00000135625

Q05215

Zn finger C2H2-type

GSG site 5-GCGGGGGCG-3

G

Upregulated ascending doses of cocaine

20459597

GC02M119694

ENSG00000163064

Q05925

Homeodomain Engrailed class Helix-turn-helix (HTH) 1 20 conserved amino acids

50 -TAATTA-30

G

Upregulated by chronic cocaine treatment

17070804

GC14P075745

ENSG00000170345

P01100

Basic-leucine zipper (bZIP) Forms dimers with proteins of the JUN family

50 -ATGACTCATC-30

G

Upregulated by cocaine treatment

7969045 7946359 21359726 8755486 8884777 12687634 20459597 20633205 24642598

(different experimental approaches used) G

G

FOSB (αFOSB)

FBJ murine Osteosarcoma Viral Oncogene Homolog B

AP-1

PMID

GC19P045971

ENSG00000125740

P53539

Basic-leucine zipper (bZIP)

50 -TGA[C/G]TCA-30

G

Major upregulation by acute cocaine treatment Decrease in mRNA levels following chronic cocaine, reflecting a desensitization of FOS induction Upregulated by cocaine treatment

(different experimental approaches used)

7969045 7946359 8531143 8609891

Forms dimers with proteins of the JUN family

G

G

G

Upregulation of ΔFOSB, a truncated splice variant which accumulates after chronic cocaine treatment ΔFOSB regulates sensitization to cocaine and reward ΔFOSB is a critical factor in the positive feedforward loop which regulates the reward circuitry of the brain

8609891 8755486 10499584 14566342 16957076 18552739 20459597 20633205 23467346

FOSL1

FOS-Like Antigen 1

FRA1

GC11M065659

ENSG00000175592

P15407

Basic-leucine zipper (bZIP) Forms dimers with proteins of the JUN family

50 -TGA[C/G]TCA-30

G

Upregulated by acute cocaine treatment

20459597

FOSL2

FOS-Like Antigen 2

FRA-2

GC02P028615

ENSG00000075426

P15408

Basic-leucine zipper (bZIP) Forms dimers with proteins of the JUN family

50 -TGA[C/G]TCA-30

G

Upregulated by acute cocaine treatment

15879001 20459597

FOXO3

Forkhead Box O3

FOXO3a

GC06P108881

ENSG00000118689

O43524

Homeodomain Forkhead class 5 ‘winged helix’ 100aa Two wings of small betasheets (W1, W2), three alpha helices (H1, H2, H3), and three beta-sheets (S1, S2, S3) H1-S1-H2-H3S2-W1-S3-W2

50 -TGTAAACA-30

G

Activation by chronic cocaine treatment

25698746

Deacetylation of FOXO3 by SIRT1 enhances its transcriptional activity

HIF3A

Hypoxia Inducible Factor 3, Alpha Subunit

IPAS

GC19P046800

ENSG00000124440

Q9Y2N7

Basic helixloop-helix (bHLH) 1 PAS domain

Hypoxia response element (HRE) 50 -T[A/G]CGT-30

G

Downregulated by cocaine

20459597

JUN

Jun ProtoOncogene

AP-1

GC01M059246

ENSG00000177606

P05412

Basic-leucine zipper (bZIP) 1 HTH Forms dimers with proteins of the FOS family

50 -GATGACTCATCN30

G

Upregulated by cocaine treatment

7969045 24642598

(different experimental approaches used)

(Continued )

TABLE 12.3 (Continued) Gene

Name (Description)

Aliases

GeneCards ID

ENSEMBL ID

UniProt KB

DNA Binding Domain

Transcription Factor Binding Site in DNA Consensus Sequence*

Effect of Cocaine#

JUNB

Jun B ProtoOncogene

AP-1

GC19P012902

ENSG00000171223

P17275

Basic-leucine zipper (bZIP) 1 HTH Forms dimers with proteins of the FOS family

50 -TGA[C/G]TCA-30

G

Basic-leucine zipper (bZIP) 1 HTH Forms dimers with proteins of the FOS family

50 -ATGACGTCATCN30

Zn finger C2H2-type

GC box 50 -GGGGCGGGG-30 GT box 50 -GGTGTGGGG-30

G

Homeodomain LIM class Helix-turn-helix (HTH)

FLAT sequence 50 -TAATTA-30

G

MADS box An amphipathic alpha-helix 1 a basic Nterminus Forms an antiparallel coiled coil domain by dimerization

CArG-box 50 -CCAAAAATAG-30

MADS box An amphipathic alpha-helix 1 a basic Nterminus Forms an antiparallel coiled coil domain by dimerization

50 - DCYAAAAATAG [A/C]-30

JUND

KLF16

LMX1B

MEF2A

MEF2C

Jun D ProtoOncogene

Kruppel-Like Factor 16

AP-1

DRRF

LIM Homeobox Transcription Factor 1, Beta

LMX-1.2

Myocyte Enhancer Factor 2A

MEF2

Myocyte Enhancer Factor 2C

GC19M018391

GC19M001852

GC09P129376

GC15P100107

GC05M088013

ENSG00000130522

ENSG00000129911

ENSG00000136944

ENSG00000068305

ENSG00000081189

P17535

Q9BXK1

O60663

Q02078

Q06413

Upregulated by cocaine treatment

PMID

7969045 8755486

(different experimental approaches used)

G

Upregulated by cocaine treatment

7969045

(different experimental approaches used)

Downregulated by acute cocaine treatment in NAc

11390978

It regulates DA receptor expression

G

G

Upregulated by cocaine treatment in zebrafish embryos Not affected in mammals

17070804 23219907

Induction of MEF2 phosphorylation at an inhibitory site by chronic cocaine treatment

18760698

pMEF2 inhibits the transcription of target genesIt may regulate the dendritic spine density, and thus mediating synaptic plasticity

G

G

Upregulated by acute cocaine treatment: SIK1 kinase phosphorylates HDAC5 and promotes its cytoplasmic export, thus activating MEF2C. MEF2C induces its own transcriptional activation Lower induction by chronic cocaine

21954104

MYT1

NFATC4

NFKB1

Myelin Transcription Factor 1

NZF2

GC14P024834

Nuclear Factor Of Activated TCells, Cytoplasmic, CalcineurinDependent 4

Nuclear Factor of Kappa Light Polypeptide Gene Enhancer in B-Cells 1

NKX2-1

NK2 Homeobox 1

NPAS2

Neuronal PAS Domain Protein 2

GC20P062796

NF-Kappa-B NK-κB

MOP4

GC04P103422

ENSG00000196132

ENSG00000100968

ENSG00000109320

Q01538

Q14934

P19838

Zn finger CysCysHisCys (C2HC)-type Two clusters of 7 zinc fingers in total

50 -AAA[G/C]TTT N5 AAA[G/C]TTT-30

p53 like domain RHR-N (Relhomology region) Beta-sandwich structure: 9 β-strands grouped in 2 sheets with a Greek-key topology

50 -GGAAAA-30

p53 like domain RHR-N (Relhomology region) Beta-sandwich structure: 9 β-strands grouped in 2 sheets with a Greek-key topology

50 GGGGGAATCCCC-30

G

Upregulation of NZF-2b isoform in the mesolimbic DA pathway by chronic cocaine treatment

19786102 20407577

It triggers the induction of REST1 and NAc1 and the inhibition of BDNF

G

Traslocation to the nucleus in striatal neurons by repeated cocaine exposure

18184313

It upregulates ITPR1 and GLUR2It may be partly responsible for striatal plasticity

G

G

G

Upregulated by chronic cocaine treatment (via ΔFOSB) It may mediate the long-term adaptations in NAc to cocaine exposure (e.g., the abundance of dendritic spines) It modulates the rewarding properties of cocaine

11595774 19295158 24642598

Higher IHC labelling in the developing forebrain by prenatal exposure to cocaine

21940433

GC14M036985

ENSG00000136352

P43699

Homeodomain Helix-turn-helix (HTH)

50 -R[G/C] CACTYRAG-30

G

GC02P101436

ENSG00000170485

Q99743

Basic helix-loophelix (bHLH)

50 -[G/T] CCACGTGAC-30

Contradictory evidence G

G

Downregulated by chronic cocaine treatment (15994025) Upregulation by chronic cocaine treatment (23776671)

23776671 15994025 25444159

It is responsible for PER upregulation by chronic cocaine G

G

G

Regulates sensitivity to cocaine reward in the NAc Directly controls DRD3 expression Changes in its rhythmic expression by chronic cocaine (Continued )

TABLE 12.3 (Continued) Gene

Name (Description)

Aliases

GeneCards ID

ENSEMBL ID

UniProt KB

DNA Binding Domain

Transcription Factor Binding Site in DNA Consensus Sequence*

Effect of Cocaine#

NR3C1

Nuclear Receptor Subfamily 3, Group C, Member 1 Gluco Corticoid Receptor

GR

GC05M142639

ENSG00000113580

P04150

Nuclear receptor and transcription factor Zn finger C4-type

50 NAGAACAGNCTGT TCT-30

G

G

G

G

G

PMID

It is necessary for cocaine sensitization (strain specific) It may regulate the vulnerability to develop cocaine abuse (modulating the addictive properties of cocaine) Downregulated in a chronic model in a astrocytoma cell line It might regulate the motivational properties of cocaine (but it depends on the neuronal population) It selectively modulates responses to cocaine rather than to morphine (in dopaminoceptive neurons)

7675174 12805318 16188404 19234455 20554270

NR4A1

Nuclear Receptor Subfamily 4, Group A, Member 1

NUR77 NGFI-B

GC12P052416

ENSG00000123358

P22736

Nuclear receptor and transcription factor Zn finger C4-type

50 -AAAGGTCA-30 50 -TGACCTTTNCNT30

G

Upregulated by acute and chronic cocaine (strain specific)

10719211 12687634 18452895

NR4A2

Nuclear Receptor Subfamily 4, Group A, Member 2

NURR1

GC02M157180

ENSG00000153234

P43354

Nuclear receptor and transcription factor Zn finger C4-type

50 -AAAGGTCA-30 50 -AAAT[G/A][C/T] CA-30

G

Downregulated by chronic cocaine Also downregulated in cocaine abusers and in zebrafish embryos (48hpf)

11959923 15094491 17070804 23219907

NR4A3

Nuclear Receptor Subfamily 4, Group A, Member 1

NOR1

OTP

Orthopedia Homeobox

G

GC09P102584

ENSG00000119508

Q92570

Nuclear receptor and transcription factor Zn finger C4-type

50 -AAAGGTCA-30 50 -TGACCTTTNCNT30

G

Upregulated by acute and chronic cocaine (strain specific)

10719211

GC05M076924

ENSG00000171540

Q5XKR4

Homeodomain Paired-like class Helix-turn-helix (HTH) 1 14 amino acid motif

50 -TAATTA-30 50 -TAATGG-30

G

Downregulated by cocaine treatment in zebrafish embryos Upregulated in rats

23219907 18452895

G

PITX3

GC10M103979

Paired-Like Homeodomain 3

ENSG00000107859

O75364

Homeodomain Bicoid class Helix-turn-helix (HTH)

50 -TAATCC-30

G

G

Downregulated by chronic cocaine treatment and in cocaine abusers It might be regulating the locomotor activating effects of cocaine (e.g., locomotor sensitization)

SOX2

SRY (Sex Determining Region Y)-Box 2

GC03P181429

ENSG00000181449

P48431

High mobility group (HMG) box Three α-helices in an irregular array

50 -CCCATTGTTC-30

Down-regulation of SOX2 expression on NPCs, inducing cell differentiation to a neuronal cell type Might be responsible for impairment in memory formation

SRF

Serum Response Factor (C-Fos Serum Response ElementBinding Transcription Factor)

GC06P043138

ENSG00000112658

P11831

MADS box An amphipathic alpha-helix 1 a basic Nterminus Forms an antiparallel coiled coil domain by dimerization

50 -CCATATATGGNA30

G

Signal Transducer and Activator of Transcription 1, 91kDa

GC02M191829

Ig-like fold 9 strands grouped in 2 sheets, forming a beta-sandwich with a Greekkey topology Activated by phosphorylation via JAK kinases

50 NATTTCCNGGAAAT30

G

Ig-like fold 9 strands grouped in 2 sheets, forming a beta-sandwich with a Greekkey topology Activated by phosphorylation via JAK kinases

50 -CTTCCGGGAA-30

G

STAT1

STAT3

Signal Transducer and Activator of Transcription 3 (Acute-Phase Response Factor)

APRF

GC17M040465

ENSG00000115415

ENSG00000168610

P42224

P40763

G

15094491 17070804 18704092

16766721

Activated by cocaine It allows ΔFOSB accumulation (in joint action with CREB)

22649236

Increased DNA binding by chronic cocaine treatment

8987828

(JAK activation pathway)

Increased DNA binding by chronic cocaine treatment

8987828 24642598

(JAK activation pathway) G

STAT3 binding sites are enriched in cocaine-responsive genes

(Continued )

TABLE 12.3 (Continued) Gene

Name (Description)

TBR1

T-Box, Brain, 1

Aliases

GeneCards ID

ENSEMBL ID

UniProt KB

DNA Binding Domain

Transcription Factor Binding Site in DNA Consensus Sequence*

Effect of Cocaine#

GC02P162272

ENSG00000136535

Q16650

T-box (large protein domain) Ig-like Two perpendicular α-helices form the DNA interacting domain

50 -TCACACCT-30

G

Transient downregulation in the developing forebrain by prenatal exposure to cocaine

PMID

21940433

Delayed expression in postmitotic cells

Comprehensive list of TFs affected by cocaine treatment and displayed in alphabetical order by official gene symbol. It includes the following information for each TF: the official gene symbol, name of gene, alias (alternative gene name), GeneCards ID, ENSEMBL ID, UniProt KB ID, the type of protein domain that binds to DNA, the target DNA sequence (the consensus sequence of the RE is given), a description of the main effect of cocaine administration and the PMID (PubMed identifier) of selected publications which refer to the interaction between cocaine and the TF. In most cases, cocaine (either acute or chronic administration) modulates the functionality of TFs by altering their transcriptional level, promoting their activation or enabling DNA binding. In some cases the rewarding properties of cocaine are also modulated by the activation of these TFs. * D, not C; H, not G; N, any base; R, purine (A or G); Y, pyrimidine (C or T); [N/N], any of the two bases inside the brackets. # D1, D1-type MSNs; D2, D2-type MSNs; TH, Tyrosine hydroxylase.

Cocaine and Transcription Factors Chapter | 12

119

FIGURE 12.2 Interaction of transcription factors (TFs) directly regulated by cocaine and immediate early genes (IEGs). The intracellular actions of cocaine in the postsynaptic neuron are mediated by three signaling pathways (in red (bigger font in print version)): CREB (the most studied pathway), SIK pathway, and STAT1/STAT3 JNK pathway. An increase in the cAMP levels activates the cAMP/PKa pathway, which induces the phosphorylation of CREB. pCREB controls the transcriptional activity of many IEGs, among them FOS/JUN (AP-1) family, ERGs and NFKB1, which are TFs that control the expression of other genes, either TFs or not. The expression of some TFs is exclusively under the control of pCREB, other TFs are regulated by AP-1, while other TFs need the concerted action of pCREB and ΔFOSB. There is less published evidence for the relationship between cocaine and the SIK and JNK pathways. In blue (medium font in print version) and green (underlined in print version), TFs modulated by cocaine which regulate the expression of other TFs and in black (smaller font in print version), the TFs which regulate the expression of other genes that are not TFs. The solid lines indicate that the expression of the complete set of genes is regulated by the TF upstream, and the thin lines represent that only the marked gene is under the control of a given TF. The following TFs are not included in the scheme due to lack of solid evidence: SRF (although there is weak evidence to be under the control of EGR1 and NFKB1, and it regulates FOS expression), PITX3 (its regulatory promoter may contain a RE for NFKB1), SOX2 (there is weak evidence to be downstream of CREB, EGR1-4, FOXO3, GR, and even the STAT pathway), OTP (Barreto-Valer et al., 2013) reported that, in zebrafish, OTP expression is regulated by NODAL, which displays a RE for NFKB1 in its regulatory promoter) and MEF2A.

chronic cocaine treatment reduces EGR1 expression in CPu, NAc shell, and prelimbic cortex (Ennulat, Babb, & Cohen, 1994), and recovers again during withdrawal (Hammer & Cooke, 1996). These changes could serve as a biochemical basis to induce drug craving. EGR3 is part of a feedforward loop that enhances the rewarding properties of cocaine, as it triggers the upregulation of CREB and FOSB, and also induces the expression of CAMK2A, NR4A2, and SIRT1 in D1 MSNs in the NAc. In contrast, the association of EGR3 mRNA with ribosomes is reduced in D2 neurons (Chandra et al., 2015). EGR3 also interacts with the histone methylation enzyme G9a (EHMT2) and the DNA methylation enzyme DNMT3A (Chandra et al., 2015).

12.5.2 NFKB1 The expression of this TF in the NAc is greatly induced by chronic cocaine exposure and is mediated by ΔFOSB

(Ang et al., 2001). NFKB1 has been related to the control of structural and behavioral plasticity to cocaine in the NAc. It mediates the long-term adaptations to cocaine exposure, as it increases the abundance of dendritic spines on MSNs, and it also modulates the rewarding properties of cocaine (Russo et al., 2009).

12.5.2.1 The Glucocorticoid Receptor (NR3C1) The glucocoticoid receptor (GR) differentially regulates the behavioral responses to cocaine and morphine, as inactivation of GR in dopaminoceptive neurons reduces the conditioned place preference and locomotor sensitization triggered by cocaine (Barik et al., 2010). GR also regulates the reinforcing properties of cocaine and the motivation to self-administration, thus modulating cocaine abuse (Ambroggi et al., 2009). However, the modulation of the HPA axis by cocaine is strain specific (Fisher vs Lewis rats), which indicates that it can be genetically

120 PART | II Molecular Effects

determined (Ortiz, DeCaprio, Kosten, & Nestler, 1995). Interestingly, the GR provides a link between cocaine and the circadian rhythm, as dexamethasone is able to activate PER1 transcription by binding to a functional GR (Balsalobre et al., 2000). Conversely, the circadian coregulators CRY1 and CRY2 bind to glucocorticoid REs located in the promoter of target genes and repress the GR-induced transcription (Lamia et al., 2011).

12.6 HOMEOBOX-CONTAINING GENES AND OTHER TFS RELATED TO CNS DEVELOPMENT Exposure to cocaine during the embryonic period causes a delay in the expression of TBR1 (which is a marker of newly generated projection neurons) in postmitotic neurons in the medial prefrontal cortex of mouse embryos, as it is transiently downregulated at E15 (McCarthy et al., 2011). Cocaine treatment also inhibits proliferation and migration of neural precursor cells and promotes early cell differentiation, which is related to SOX2 inhibition. These changes may be related to impairment in memory formation that has been related to in utero exposure to cocaine (Hu et al., 2006).

It has been shown that cocaine administration alters the expression pattern of some homeogenes through a stillunknown mechanism, and that these genes may be related to the regulation of synaptic plasticity. Prenatal exposure to cocaine increases NKX2-1 immunoreactivity in the basal forebrain at E15, thus reducing the postmitotic neuron migration from the basal to the dorsal forebrain (McCarthy et al., 2011). FOXO3 induces the expression of cell death-related genes, triggering apoptosis in the absence of surviving signals or by oxidative stress. Chronic cocaine induces the deacetylation of FOXO3, increasing its transcriptional activity and upregulating its target genes, such as GADD45α and the kinase inhibitor P27KIP1. Besides, overexpression of a functional FOXO3 in the NAc increases conditioned place preference, showing that FOXO3 promotes the rewarding responses to cocaine (Ferguson et al., 2015).

12.7 TFS RELATED TO DOPAMINERGIC (DA) DIFFERENTIATION Cocaine administration displays differential effects in the expression of TFs related to mbDA differentiation (some of these TF are homeogenes), thus modifying the development and survival of its own target neurons (Fig. 12.3A). FIGURE 12.3 Transcription factors (TFs) regulated by cocaine that control (A) dopaminergic differentiation and (B) circadian rhythm. There are two biological processes that are particularly affected by cocaine: (A) Dopaminergic differentiation and (B) Circadian rhythm. (A) The acquisition of a dopaminergic phenotype involves the concerted action of a set of genes (TFs in blue (dark gray in print versions)), and the expression of most of them is modified by cocaine. The dopamine transporter (DAT), which is the target of cocaine, is highlighted in red (light gray in print versions). (B) The expression of the main elements of the central circadian pacemaker is under the control of several TFs known to be altered by cocaine administration, thus elucidating the link between cocaine abuse and disrupted sleep
wake cycles.

Cocaine and Transcription Factors Chapter | 12

Chronic cocaine exposure increases EN1 expression, and downregulates NURR1 and PITX3, while EN2 was reported to remain unaffected (Leo et al., 2007). Also, PITX3 and NURR1 are downregulated in mbDA neurons in cocaine abusers (Bannon, Pruetz, Barfield, & Schmidt, 2004; Bannon et al., 2002) and their expression is also altered in cocaine-treated zebrafish embryos (BarretoValer, Lopez-Bellido, & Rodriguez, 2013). Contradictory results have been reported for LMX1B: while Leo et al. (2007) did not observe any changes in its expression after chronic cocaine administration in adult male SpragueDawley rats, the zebrafish orthologues Lmx1ba and Lmx1bb were upregulated in embryos exposed to cocaine (Barreto-Valer et al., 2013). Besides, KLF16, which regulates DRD1 and DRD2 expression, is downregulated in the NAc by acute cocaine treatment (Hwang et al., 2001), so that it can be responsible for the short-term actions of cocaine. Also, there is contradictory evidence for OTP: its expression is increased in adult male Sprague-Dawley rats exposed to cocaine (Lynch, Girgenti, Breslin, Newton, & Taylor, 2008), while it is reduced in zebrafish embryos (BarretoValer et al., 2013).

12.8 TFS AND CIRCADIAN RHYTHM Many drugs of abuse disrupt the sleep
wake cycle, and conversely individuals with disrupted circadian rhythm are more prone to substance abuse and addiction. The connections between the master clock and the reward circuitry mediate the effects of cocaine in the circadian rhythms, and the regulation of cocaine intake, sensitization, and rewarding properties by the circadian clock (Logan, Williams, & McClung, 2014). In Drosophila, CLOCK, BMAL, and PER orthologues regulate sensitization to cocaine (Andretic, Chaney, & Hirsh, 1999). Studies with mutant mice have revealed that NPAS2 regulates sensitivity to cocaine reward in the NAc and directly controls DRD3 expression; besides, chronic cocaine treatment disrupts NPAS2 and DRD3 oscillating expression in the NAc, providing a link between circadian genes and drug reward (Ozburn et al., 2015). Cocaine can entrain circadian rhythms by altering the transcriptional rate of master clock genes under the control of cocaine-responsive TFs (Fig. 12.3B). However, evidence is controversial. Uz et al. (2005) reported an upregulation of CLOCK in CPu and a downregulation of ARNTL after repeated cocaine injections, while they did not observe any changes for the CLOCK analogue NPAS2. In contrast, Lynch et al. (2008) found an increase in the expression of CLOCK, ARNTL, PER2, and CRY1 in the dorsal striatum after cocaine self-administration. Falcon, Ozburn, Mukherjee, Roybal, & McClung (2013) did not observe any changes for CLOCK and

121

BMAL, while NPAS2 was greatly affected by chronic cocaine treatment.

12.9 ALTERNATIVE SIGNALING PATHWAYS THAT MEDIATE THE EFFECTS OF COCAINE IN THE EXPRESSION AND ACTIVITY OF TFS 12.9.1 JAK/STAT Pathway Cytokine regulation can also influence intracellular responses to chronic cocaine via JAK/STAT signaling. There is evidence that chronic cocaine use induces an increase in Janus kinase (JAK2) immunoreactivity in DA and non-DA cells from the VTA (Berhow, Hiroi, Kobierski, Hyman, & Nestler, 1996). As a consequence of JAK2 activation, an enhanced binding of STAT(1/3) dimer to the DNA and an FOS upregulation were detected when CNTF was present (Berhow et al., 1996). Besides, STAT3 binding sites are overrepresented by sixfold in those genes that are differentially expressed in cocaine abusers, although STAT3 levels remain unchanged (Bannon et al., 2014). Interestingly, there is potential crosstalk between TFs, as STAT3 directly interacts with NFKB1: they can synergistically bind to the DNA promoters and cooperate to activate the expression of target genes, or they can mutually inhibit their activity (Grivennikov & Karin, 2010).

12.9.2 MEF2C MEF2C is induced by acute rather than by chronic cocaine treatment, possibly indicating the existence of a regulatory feedback loop. SIK1 (salt induced kinase) may be activated by intracellular Na1 or by D2 receptor-AktGSK3β pathway and as a result, it phosphorylates HDAC5 (histone deacetylase 5), which is exported from the nucleus. This cytoplasmic translocation allows MEF2C activation and the expression of its downstream target genes, among them NR4A1 (Dietrich, Takemori, Grosch-Dirrig, Bertorello, & Zwiller, 2012).

12.9.3 MEF2A The Ca21/calmodulin pathway stimulates calcineurin (a protein phosphatase) to dephosphorylate and thus activate MEF2A proteins. MEF2A dimerize with either coactivators (such as p300) or with corepressors (HDACs), and regulate the expression of target genes. As a consequence of MEF2A activation, there is a reduction in the number of excitatory synapses, regulating dendritic spine density. Chronic cocaine use, acting via the D1 receptor, promotes the phosphorylation of MEF2A at the inhibitory sites P-Ser408/444, blocking the expression of their target genes (Pulipparacharuvil et al., 2008).

122 PART | II Molecular Effects

12.10 CONCLUSION Chronic cocaine exposure (rather than acute administration) promotes the activation of a large number of TFs, most of them IEGs under the control of CREB and/or ΔFOSB. IEGs regulate the expression of different target genes involved in synaptic plasticity, behavioral and rewarding properties of cocaine, DA differentiation, and maintenance of DA phenotype. These processes are responsible for the long-term changes triggered by cocaine abuse. Cocaine-regulated TFs also interact among themselves, either synergistically or with opposing functions, as well as with other signaling pathways, thus reflecting the complexity of cocaine-elicited responses.

MINI-DICTIONARY OF TERMS G

G

G

G

G

G

G

Transcription factor: A protein which recognizes and binds to a response element, thus promoting or repressing the transcriptional activity of a target gene. Response element: A DNA sequence, usually located in the regulatory promoter, which is specifically recognized by a transcription factor. Immediate early genes (IEGs): A set of genes which are rapidly expressed after a certain stimulus. IEGs are usually transcription factors which control the expression of late-response genes that are responsible for changes in cell function or morphology. Dopamine: A neurotransmitter derived from amino acid tyrosine which elicits its actions by activating two types of receptors, D1R and D2R. ΔFOSB: Also known as deltaFOSB, is a splice variant of the FOSB gene which lacks 101 residues on its Cterminus and is highly stable. Its expression is induced after chronic drug exposure and it gradually accumulates in the brain in a region-specific manner. Homeogenes: These genes code for transcription factors that control the general body plan of an embryo along the antero-posterior axis. Homeogenes are highly conserved throughout the evolutionary scale. Circadian rhythm: A biological process which oscillates with approximately 24-h period. It controls the sleep
wake cycle, hormonal secretion, body temperature, and feeding, among others.

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