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Mechanisms That Regulate the Expression of Dopamine D1 Receptor in Cocaine Addiction
Chapter 15
Mechanisms That Regulate the Expression of Dopamine D1 Receptor in Cocaine Addiction E.V. Kuzhikandathil Rutgers—New Jersey Medical School, Newark, NJ, United States
SUMMARY POINTS
KEY FACTS
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This chapter focuses on mechanisms that regulate expression of the dopamine D1 receptor in the context of cocaine addiction. The dopamine D1 receptor is centrally involved in cocaine-induced locomotor activity, cocaine selfadministration, cocaine-induced behavioral sensitization, cue-elicited cocaine-seeking behavior, and the reinforcing effects of cocaine. Acute and repeated cocaine administration alter the expression of the D1 receptor gene. The D1 receptor gene is regulated at the level of transcription, posttranscription, and posttranslation. The adenosine signaling pathway potentially acts as an autoinhibitor mechanism for downregulating D1 receptor expression. Levamisole, an adulterant in street cocaine, is an inhibitor of the adenosine signaling pathway and could increase D1 receptor expression and accentuate effects of cocaine. Cocaine-induced increase in BDNF levels could mediate the sustained elevation of D1 receptor mRNA and potentially induce the posttranscriptional mechanism observed in cocaine-sensitized animals. The cocaine-sensitive transcription factor, DRRF, competes with positive and negative transcription factors to regulation D1 receptor gene transcription. Posttranscriptional mechanisms involving microRNAmediated translational suppression might underlie the physiological and behavioral responses to cocaine challenge in a sensitized animal. Posttranslational mechanisms affecting D1 receptor trafficking and turnover rates are also likely affected in cocaine-sensitized animals.
The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00015-4 © 2017 Elsevier Inc. All rights reserved.
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In the brain, D1 receptor expression levels are highest in the caudate-putamen (dorsal striatum), nucleus accumbens, substantia nigra, olfactory bulb, amygdala, and medial prefrontal cortex. Lower levels of expression occurs in the hippocampus, cerebellum, thalamic areas, and hypothalamic areas. Synthetic ligands with selectivity for D1 receptors include agonists such as A77636, SK38393, A 68930, CY 208-243, and dihydrexidine and antagonists such as SKF 83566, SCH23390, LE 300, and SCH 39166. Fenoldopam is a clinically used peripheral D1 receptor partial agonist for treating hypertension. The D1 receptors are seven transmembrane G-protein coupled receptors that couple to and stimulate adenylyl cyclase to increase intracellular cAMP levels through the activation of Gαs/olf family of G-proteins. Activation of D1 receptors results in protein phosphorylation, increases in intracellular calcium, and activation of gene expression. Expression of a gene can be regulated at transcriptional, posttranscriptional, or posttranslational levels. Transcriptional regulatory mechanisms involve transcription factors activing via cis regulatory regions in a gene. The transcription factors can activate or inhibit the synthesis of mRNA from the gene. Posttranscriptional regulatory mechanisms can regulate the stability of mRNA and rate of protein synthesis via RNA-binding proteins or regulatory RNAs such as microRNAs. Posttranslational regulatory mechanisms regulate the stability of proteins and trafficking of proteins to various subcellular compartments. 143
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Regulation of gene expression at transcriptional, posttranscriptional, and posttranslational level can be celland tissue-specific, regulated by extrinsic and intrinsic signaling pathways and altered during development, disease, and treatment of disease.
LIST OF ABBREVIATIONS ATP BDNF CAD cAMP drd1a DRiP78 DRRF EGFP ER GRK mRNA miRNA PI-3K
adenosine triphosphate brain-derived neurotrophic factor cath A derived cyclic AMP dopamine D1 receptor gene dopamine receptor interacting protein 78 dopamine receptor regulating factor enhanced green fluorescent protein endoplasmic reticulum G-protein receptor kinase messenger RNA microRNA phosphatidylinositol-4,5-bisphosphate 3-kinase
15.1 INTRODUCTION Cocaine’s physiological effects are primarily due to its ability to block monoamine uptake transporters. The blockade results in elevated levels of synaptic dopamine, serotonin, and norepinephrine (Mu¨ller & Homberg, 2015; Schmidt & Weinshenker, 2014; Zhang, Schlussman, Ho, & Kreek, 2003). Acute and repetitive elevation of these monoamine neurotransmitters, due to cocaine administration, results in both immediate and long-term changes in function and expression of the monoamine receptors. Among monoamines, the effect of cocaine on dopamine and its receptors has been thoroughly studied (Anderson & Pierce, 2005). Most drugs of abuse, including cocaine, increase extracellular dopamine affecting the mesocorticolimbic reward and reinforcement pathway, which ultimately causes the physiological and behavioral phenotypes associated with drug addiction. Results from pharmacological and genetic knockout studies strongly suggest that the dopamine D1 receptor is a key mediator of the effects of cocaine and various drugs of abuse (Hummel & Unterwald, 2002). Studies using behavioral and electrophysiological approaches with D1 receptor agonist SKF38393 and antagonist SCH23390 have shown that the D1 receptor is essential for mediating the effects of cocaine (Henry, Greene, & White, 1989; Hummel & Unterwald, 2002). Molecular-level studies have shown that the cocaine-induced changes in signaling and gene expression are also mediated by the D1 receptor (Hummel & Unterwald, 2002). Studies using D1 receptor knock-out mice have established the role of the D1 receptor in mediating the cocaine-induced locomotor activity,
cocaine-self administration, behavioral sensitization, cueelicited cocaine-seeking behavior, and the reinforcing effects of cocaine (Caine et al., 2007; Chen & Xu, 2010; Karlsson, Hefner, Sibley, & Holmes, 2008). Acute and chronic cocaine administration of cocaine alter expression of various genes, including the D1 receptor. The effects of cocaine on expression of D1 receptor mRNA and protein expression are brain region specific (Hummel & Unterwald, 2002). The studies to date have often reported contradictory results because of differences in cocaine administration protocols, species/strains of rodents, time of assessment, brain regions investigated, and assays for measuring D1 receptor mRNA and protein levels (Table 15.1). The general consensus is that intermittent cocaine treatment increases D1 receptor mRNA expression, but does not change D1 receptor protein (Table 15.1). Overall, these disparate descriptive studies have clearly established that cocaine alters the expression of D1 receptors; however, the extracellular factors, signaling pathways, and molecular mechanisms that regulate cocaine-induced changes in D1 receptor expression remain to be determined. This knowledge deficit needs to be addressed as, despite being a therapeutic target for treating addictive disorders, clinically viable ligands that directly modulate D1 function have been difficult to develop. Given the well-documented cocaine-induced changes in D1 receptor expression, indirect manipulation of D1 receptor expression provides an alternate approach to treating cocaine addiction. In this chapter, the various mechanisms that have been reported to regulate expression of D1 receptor and their potential relevance to cocaine addiction are discussed.
15.2 COCAINE-INDUCED CHANGES IN D1 RECEPTOR EXPRESSION Acute and repeated chronic cocaine administration have been reported to change D1 receptor expression in rodent models. While a majority of the studies with rodents have used rats, the recent availability of genetically modified mice that express the enhanced green fluorescent protein (EGFP) in cells that endogenously express D1 receptors has facilitated novel studies (Lawhorn, Edusei, Zhou, Ho, & Kreek, 2013; Tobo´n & Kuzhikandathil, 2014). The drd1a-EGFP mouse carries transgenes in which the D1 receptor promoter is fused to the EGFP reporter gene. Fig. 15.1 shows a representative image of a brain slice from the drd1a-EGFP demonstrating robust expression of the D1 receptor mRNA in the striatum and cortex. Numerous studies have shown that administration of cocaine rapidly increases the expression of D1 receptor mRNA (reviewed in Hummel & Unterwald, 2002). A recent study has shown that acute binge administration of
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TABLE 15.1 A List of Representative Studies That Report Cocaine-Induced Changes in D1 Receptor mRNA and Protein Expression Species
Sex/ Age
Cocaine Dose and Administration Protocol
Time of Measurement (After Last Dose)
D1 Receptor mRNA Expression Changes
D1 Receptor Protein Expression Changes
Citations
Fischer rats
Male/ 60 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 2, 7, 14 days
30 min
ND
Increased binding (SCH23390) in NAc, OT, SN & VP
Unterwald et al. (1994). J. Pharmacol. Exp. Therap. 270, 13871397
Fischer rats
Male/ 60 days
15 mg/kg each injection; daily 2 injections, 14 h apart; 14 days
180 min
ND
Increased binding (SCH23390) in NAc and OT
Unterwald et al. (2001). Brain Research, 900, 103109
Long Evans rats
Male, 300 g
4-Week selfadministration; 1 h/day, daily
120 min or 7 days
Increase in striatum, NAc, OT, cortex, hippocampus, thalamus
Decreased binding (SCH23390) in striatum, NAc, OT, cortex, thalamus, hippocampus
Laurier et al. (1994). Brain Research 634, 3140
SpragueDawley rats
Male, 280 g
15 mg/kg each injection; daily 3 injections, 1 h apart; 2, 7, 14 days
60 min
ND
Decreased in vivo binding (PETSCH23390) in striatum
Tskuada et al. (1996) J. Neurosci., 76707677
Wistar rats
Male, 280 g
20 mg/kg daily injection; 10 days
14 h
Increase in striatum, frontal cortex
ND
Scmidt-Mutter, et al. (1999) Neuropsychopharmacol, 21(5), 662669
C57BL/6J mice
Male/ 70 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 14 days
45 min
ND
Increased binding (SCH23390) in caudate but not NAc or OT
Sclussman et al. (2003). Pharmacol. Biochem. Behav. 75, 123131
C57BL/6J & drd1a-EGFP (FVB) mice
Male/ 23 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 7 days
30, 60 min
Increase in caudate but not in NAc
No change in protein expression in caudate or NAc
Tobon et al. (2015) Eur. J. Neurosci. 42(2), 18491857
ND, not determined; NAc, nucleus accumbens; OT, olfactory tubercle; SN, substantia nigra; VP, ventral pallidum; SCH23390, D1 receptor selective antagonist; PET, positron emission tomography.
cocaine rapidly and significantly increases the number of EGFP-expressing cells specifically in the dorsolateral striatum of the drd1a-EGFP mice (Lawhorn et al., 2013); this suggests an increase in transcriptional activity of the dopamine D1 receptor gene. Several studies have consistently shown that repeated cocaine administration alters the expression of D1 receptors in various brain regions (reviewed in Hummel & Unterwald, 2002). Overall, the results suggest that repeated cocaine administration over 714 days
increases the expression of D1 receptor mRNA in the striatum. Using the drd1a-EGFP mouse model, we have recently shown that binge administration of cocaine results in an increase in D1 receptor mRNA, but not D1 receptor protein, expression in the caudate putamen. This change is not observed in the nucleus accumbens (Tobo´n, Catuzzi, Cote, Sonaike, & Kuzhikandathil, 2015). Interestingly, when sensitized mice are administered a single challenge dose of cocaine, there is a rapid increase in D1 receptor protein expression within
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FIGURE 15.1 Representative coronal striatal brain slice from the drd1a-EGFP mice. Brain was isolated from a male drd1a-EGFP mouse on postnatal day 7. Two hundred micrometer coronal section was mounted on glass slide and viewed with an inverted fluorescence microscope. Several overlapping images of one hemisphere were obtained using a 20 3 objective and integrated using Image J.
30 minutes in the caudate putamen. Taken together, from these results, we can infer that the D1 receptor expression is regulated at the transcriptional and posttranscriptional level by cocaine.
15.3 EXTRACELLULAR FACTORS THAT REGULATE D1 RECEPTOR EXPRESSION How cocaine regulates the expression of D1 receptors is not known. Studies distinguishing acute and long-term effects of cocaine suggest that the underlying extracellular factors and signaling mechanism for the acute and longterm effect might be very different. Acutely administered cocaine blocks dopamine, serotonin, and norepinephrine uptake transporters and elevates the levels of these monoamine neurotransmitters (Mu¨ller & Homberg, 2015; Schmidt & Weinshenker, 2014; Zhang et al., 2003). The acute effects of cocaine might be mediated by dopamine, serotonin, and/or norepinephrine acting on their cognate receptors and altering levels of second messengers such as cAMP and calcium.
15.3.1 Adenosine and cAMP Studies in SK-N-MC human neuroblastoma cells, which express endogenous D1 receptors, have shown a bimodal
regulation of D1 receptor expression by dopamine and D1 receptor agonist, SKF38393, wherein an initial upregulation is followed by a downregulation of endogenous D1 receptor mRNA (Sidhu, Olde, Humblot, Kimura, & Gardner, 1999). We have reported that extracellular cAMP via adenosine A2A receptor decreases expression of endogenous D1 receptors in the CAD mouse catecholaminergic cell line (Do, Sun, Beuve, & Kuzhikandathil, 2007b) and in the kidney of type I diabetic rats (Kuzhikandathil, Clark, & Li, 2011). We observed that elevating intracellular cAMP also downregulates the expression of D1 receptors in the CAD cell line (Do et al., 2007b). These studies suggest that D1 receptor-induced elevation of intra- and extracellular cAMP might have an autoinhibitory effect on D1 receptor expression wherein a persistent increase in steady-state cAMP levels might lead to D1 receptor downregulation via the extracellular cAMP-adenosine signaling pathway (Do et al., 2007b). A key component of the extracellular cAMPadenosine signaling pathway is the ecto-protein, tissue nonspecific alkaline phosphatase (TNAP), which generates adenosine from ATP or AMP (metabolite of cAMP or ATP). We have shown that inhibitors of the adenosine signaling pathway can prevent extracellular cAMP from downregulating D1 receptor expression in CAD cell line and in diabetic rat kidneys (Do et al., 2007b; Kuzhikandathil et al., 2011). One of these inhibitors is levamisole, an adulterant, commonly found in street cocaine that causes severe side effects in cocaine addicts (Larocque & Hoffman, 2012). We have shown that levamisole prevents the downregulation of D1 receptor expression in CAD cells and diabetic rat kidneys (Do et al., 2007b; Kuzhikandathil, et al., 2011). Fig. 15.2 shows a working model of how levamisole, by blocking TNAP and preventing the downregulation of D1 receptors, could enhance the behavioral and physiological effects of cocaine.
15.3.2 Dopamine Among dopamine receptors, the dopamine D3 receptor is a potential candidate for regulation of D1 receptor expression as it couples to Gαi/o G-proteins, which inhibits adenylate cyclase and decreases cAMP levels. Cocaine administration could drive increased D3 receptor signaling resulting in decreased steady-state cAMP levels and increased D1 receptor expression. D3 receptor is coexpressed with D1 receptors in the direct pathway (Beaulieu & Gainetdinov, 2011). Pharmacological and knock-out animal studies have suggested a role for D3 receptors in cocaine addiction (Karasinska, George, Cheng, & O’Dowd, 2005; Song et al., 2012). The levels of D3 receptors are elevated in rodent models of sensitization; in particular, levels of D3 receptors in the dorsal striatum are elevated in rodents addicted to cocaine (Guillin et al., 2001).
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FIGURE 15.2 Working model for effect of adenosine and levamisole on cocaine-induced D1 receptor expression. (A) In animals administered cocaine, elevated dopamine (red (gray in print versions) ellipses) binds D1 receptors (D1R), increases adenylate cyclase (AC) activity, elevates cAMP levels and elicits cocaine-induced behavioral effects. Sustained elevation of intracellular cAMP leads to paracrine export of cAMP and, metabolite, AMP from cells which together with ATP, AMP, and cAMP from exocrine sources is converted to adenosine (green (black in print versions) ellipse) by tissue nonspecific alkaline phosphatase (TNAP). Adenosine binds receptors (AdoR) such as A2A receptors which downregulates the expression of D1 dopamine receptors. This autoinhibitory feedback mechanism for downregulation of D1 receptor is blocked when production of adenosine by TNAP is inhibited by levamisole (B). This results in increased D1 receptor expression and enhanced behavioral and physiological effects of cocaine.
15.3.3 Norepinephrine Among adrenergic receptors, the alpha 1 and alpha 2 receptors couple to Gαq and Gαi/o signaling pathways. The reported rapid increase in calcium levels following an acute dose of cocaine supports a role for a Gαq-mediated signaling process (Luo, Volkow, Heintz, Pan, & Du, 2011). Studies have shown that alpha 1 antagonism decreases and alpha 2 antagonism increases cocaine-induced locomotor response, suggesting that alpha 1 receptors like D1 receptors are important for the cocaine-induced enhanced locomotor response. The alpha 1b receptor subtype couples to Gαq G-proteins and facilitates cocaine-induced sensitization. Specifically, mice lacking the alpha 1b adrenergic receptor have decreased acute and sensitized response to cocaine (reviewed in Schmidt & Weinshenker, 2014).
15.3.4 Serotonin Acute cocaine administration has been reported to increase extracellular serotonin levels in several brain regions (reviewed in Mu¨ller & Homberg, 2015). This coupled with low nanomolar affinity of serotonin for 5-HT receptors suggest a potential role for serotonin in mediating changes in D1 receptor expression. Among serotonin receptors, the 5-HT1 and 5-HT2 receptors are of interest; in particular 5-HT1A and 5-HT2A receptors which have high affinity for serotonin and are coupled to Gαi/o and Gαq G-protein signaling, respectively. Most studies suggest that activation of the 5-HT1A and 5-HT2A receptors facilitates the induction and expression of cocaineinduced sensitization while other subtypes either have an inhibitory effect on cocaine-induced behaviors or have no
effect (reviewed in Mu¨ller & Homberg, 2015). Interestingly, it has been reported that 5-HT2A and alpha1b-adrenergic receptors mediate locomotor response and behavioral sensitization to cocaine and amphetamines (Auclair, Drouin, Cotecchia, Glowinski, & Tassin, 2004).
15.3.5 Brain-Derived Neurotrophic Factor Numerous studies have shown that cocaine administration increases brain-derived neurotrophic factor (BDNF) levels in the striatum (reviewed in McGinty, Whitfield, & Berglind, 2010). Manipulation of BDNF-TrkB signaling in the dorsal striatum by deleting the expression of TrkB in D1- and D2-expressing cells (using drd1a-cre and drd2-cre mice) affects cocaine-induced behaviors (Lobo et al., 2010). However, to date the role of BDNF-TrkB signaling in regulating D1 receptor expression following cocaine administration is not known. We have shown that BDNF-TrkB signaling increases D1 receptor expression in studies using the CAD cell line and TrkB null mice (Do, Kerr, & Kuzhikandathil, 2007a). We have also shown that BDNF-induced upregulation of D1 receptor expression exhibits posttranscriptional regulation. In CAD cells transfected with TrkB receptor, BDNF induces expression of D1 receptor mRNA within 3 hours, while protein levels do not increase until 12 hours later (Do et al., 2007a). The BDNF-TrkB induction of D1 receptor expression is mediated by the PI-3 kinase signaling pathway (Do et al., 2007a). Our working model, shown in Fig. 15.3, postulates that the persistent upregulation of D1 receptor mRNA in cocaine-sensitized animals is mediated by BDNF which might also impart posttranscriptional regulation on D1 receptor expression (Tobon et al., 2015).
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15.4 TRANSCRIPTIONAL REGULATION OF D1 RECEPTOR EXPRESSION The D1 receptor gene has a cell type-specific promoter of B6400 bp with two promoters, a single intron in the
FIGURE 15.3 Working model for effect of BDNF on cocaine-induced D1 receptor expression. Repeated administration of cocaine is known to increase striatal BDNF levels. BDNF binds to TrkB receptor and increases transcription of D1 receptor gene via the PI-3K signaling pathway. While this pathway exhibits post-transcriptional regulation, the D1 receptor proteins levels and function are also enhanced following BDNF treatment. This model provides a mechanistic explanation for BDNFmediated behavioral and physiological effects of cocaine.
50 untranslated region, intron-less coding region and B1600 bp 3’ untranslated region. The D1R receptor gene can be transcribed from two different promoters that lack the consensus TATA and CAAT boxes. The upper promoter is located between nucleotides 1154 and 1336 relative to the start codon, and the lower promoter is located in the single intron (Lee, Yajima, & Mouradian, 1999; Minowa, Minowa, Monsma, Sibley, & Mouradian, 1992). The D1 receptor mRNA transcripts from the upper promoter are found only in neuronal cell types, whereas the shorter mRNA transcripts from the lower intron promoter are found in both neurons and kidney cells. The D1 receptor mRNA transcripts from the upper promoter are less stable (Lee, Minowa, & Mouradian, 1996). Several studies have shown that the transcription of D1 receptor gene is finely regulated by a combination of trans-activators (Meis2, Sp1, and Brn4) and trans-repressors (TGIF, Zic2, Sp3, and AP2β) as depicted in Fig. 15.4 (Hwang et al., 2001; Okazawa et al., 1996; Takeuchi et al., 1999; Yang et al., 2000a; Yang, Hwang, Junn, Lee, & Mouradian, 2000b). In addition, the dopamine receptor regulating factor (DRRF) plays a context-dependent dual role in which it can either act as a repressor or activator by competing with the above-mentioned transcription factors for binding to the Act/AR1 DNA element (Hwang et al., 2001). Interestingly, studies have shown that DRRF expression is downregulated by cocaine and it is possible that this downregulation contributes to the cocaineinduced increase in D1 receptor mRNA levels. We have shown that the BDNF-induced increase in D1 receptor mRNA occurs at the transcriptional level and is
FIGURE 15.4 Trans-acting factors and cis-DNA elements that are known to regulate transcription of D1 receptor gene. The D1 receptor gene has a single intron in the 5´ untranslated region. The gene has two promoters: an upstream promoter that generate a long transcript from the upstream initiation site (U) and an intron promoter that generates a shorter transcript from the downstream initiation site (I). Transcription factor binding sites Act and AR1 in the upstream promoter region and another element in exon 1 has been identified. The sites bind transcription factors that can increase (Meis2; Sp1; Brn-4) or decrease (TGIF; Zic2; Sp3; Ap2β) transcription. DRRF is a cocaine-sensitive transcription factor that competes with other factors to bind to the Act and AR1 sequence; hence it can have a context-dependent positive or negative effect on D1 receptor gene transcription. The BDNF response element in the D1 receptor promoter is located in a 2700 bp region. The base pair numbering is relative to the translation initiation codon (ATG).
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mediated by cis-elements in the D1 receptor promoter between 4700 and 2000, relative to the ATG initiation codon (Do et al., 2007a). The transcription factor(s) mediating BDNF-induced D1 receptor mRNA transcription remains to be identified and could be a key mediator of the effect of cocaine on D1 receptor expression.
15.5 POSTTRANSCRIPTIONAL REGULATION OF D1 RECEPTOR EXPRESSION We have shown that the expression of D1 receptor is posttranscriptionally regulated during postnatal brain development and also during differentiation of CAD cells (Pasuit, Li, & Kuzhikandathil, 2004; Tobo´n, Chang, & Kuzhikandathil, 2012). Recently we have also shown that D1 receptor expression is posttranscriptionally regulated in the caudate-putamen of cocaine-sensitized mice (Tobon et al., 2015). Sensitized mice express higher levels of D1 receptor mRNA but not protein; however, when cocainesensitized mice are challenged with cocaine, the levels of D1 receptor increase rapidly within 30 minutes. The rapid cocaine-induced increase of D1 receptor protein expression in sensitized mice requires de novo protein synthesis and is inversely correlated with the levels of microRNAs miR142-3p and miR-382, both of which, we have shown, posttranscriptionally regulate D1 receptor expression in vitro and in vivo in a mouse model of alcohol (Li et al., 2013; Tobo´n et al., 2012). Our working model shown in Fig. 15.5
FIGURE 15.5 Working model for post-transcriptional regulation underlying cocaine-induced locomotor hyperactivity in sensitized animals. The levels of D1 receptor mRNA (green (double dashed line)) and miRNA 383 and 142-3p (purple (dashed line)) in the striatum is high in sensitized animals; however, prior to cocaine administration in sensitized animals, the steady-state protein levels (red (solid gray line)) and the locomotor activity (blue (solid black line)) are low. Administration of cocaine to sensitized animals (up arrow) results in a rapid-decrease in microRNA levels within 5 min which relieves the translational suppression of D1 receptor mRNA, resulting in a rapid increase in D1 receptor protein levels within 30 min. The elevated D1 receptor protein levels contribute to the sustained cocaine-induced hyperactivity in the sensitized animals.
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is that expression of D1 receptor mRNA is elevated in the caudate-putamen of cocaine-sensitized mice; however the levels of D1 receptor protein are low due to miRNAmediated translational suppression. This translational suppression of D1 receptor mRNA is rapidly relieved upon cocaine challenge due to a rapid loss of microRNA suppression brought about by a combination of active miRNA decay and/or expulsion of miRNA via exosomes. The newly synthesized D1 receptor protein provides a sustained response to cocaine-elevated synaptic dopamine, manifested as enhanced locomotor activity in the sensitized mice. An interesting aspect of the posttranscriptional regulation of D1 receptor expression in the cocaine-sensitized mice is that it is observed in the caudate-putamen but not the nucleus accumbens. Given the role of caudate-putamen in habit formation, induction of a posttranscriptional mechanism for regulating D1 receptor expression following repeated cocaine administration strongly suggests that such mechanisms might be important for relapse and cueinduced cocaine-seeking behaviors.
15.6 POSTTRANSLATIONAL REGULATION OF D1 RECEPTOR EXPRESSION Following synthesis of D1 receptor protein, it undergoes posttranslational modifications including glycosylation and phosphorylation. This can affect both the expression of the receptor on the cell membrane as well as its function. Transport from the endoplasmic reticulum (ER) to cell membrane is a multistep process that involves different types and levels of glycosylation and disruption of these mechanisms results in rapid elimination of the receptor. In the case of D1 dopamine receptor, an ERmembrane-associated protein, dopamine receptor interacting protein 78 (DRiP78), regulates the transport to the cell surface (Bermak, Li, Bullock, & Zhou, 2001). Overexpression of DRiP78 significantly slows the maturation of the early forms of D1 receptor to the mature form. Similarly, overexpression of neurofilament-M protein was shown to decrease cell surface expression of D1 receptors (Kim, Ariano, Lazzarini, Levine, & Sibley, 2002). It is not known if cocaine administration affects the expression and function of DRiP78 or neurofilament-M and consequently D1 receptors. Generally, the D1 receptor protein is enriched in detergent-resistant membrane fractions where lipid raft and caveolar proteins are found; however, repeated cocaine administration over a 7-day period shifted the D1 receptor protein from the detergent-resistant fractions to detergent-soluble membrane and cytoplasmic fractions (Voulalas, Schetz, & Undieh, 2011). This suggests that cocaine administration might affect posttranslation mechanisms that regulate D1 receptor cell surface expression.
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D1 receptor cell surface expression is also regulated by an agonist-dependent internalization mechanism that is driven by phosphorylation of the receptor. G-protein receptor kinases (GRKs) mediate agonist-induced phosphorylation of D1 receptors, followed by β-arrestin-mediated receptor internalization. It has been shown that mutation of threonine 360, a residue in the GRK2 phosphorylation site, in D1 receptor abolished the rapid agonist-induced desensitization, while mutation of residue, threonine 446, abolished agonist-induced receptor internalization (Lamey et al., 2002). Recently, it was shown that serine 421 is a key residue for cell surface expression of D1 receptors and phosphorylation of this site by protein kinase D is critical for mediating the behavioral effects of cocaine administration (Wang et al., 2014).
MINI-DICTIONARY OF TERMS G
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Behavior sensitization: Repeated administration of cocaine over a period of 47 days to animals results in enhanced behavioral response to the same dose of cocaine. Typically, locomotor behavior in a monitoring arena is used to assess behavior sensitization. Binge administration: A cocaine administration protocol used to induce behavior sensitization. Typically animals are administered three daily doses of cocaine (1020 mg/kg, i.p.), 1 hour apart for 12 weeks. Exosomes: Membranous secreted vesicles that can contain RNA, microRNA, protein, or other cytoplasmic material. Found in plasma and other bodily fluids. Extracellular cAMP-adenosine pathway: A signaling pathway with ecto-proteins present on the extracellular side of cell membrane that generated adenosine from cAMP, AMP, and ATP. Ecto-phosphodiesterases breakdown cAMP into AMP. Ecto-nucleotidases, such as CD73 and TNAP, generate adenosine from AMP and ATP. This pathway has been described in brain, kidney, and many other tissues. G-protein coupled receptors: Seven transmembrane receptor proteins that signal to cytoplasmic effectors via heterotrimeric G-proteins (Galpha, Gbeta, and Ggamma). Conformational changes induced by ligand binding to receptors results in G-protein exchanging the bound GDP with GTP, which is one of the first steps in the activation of the signal transduction cascade. Levamisole: Originally approved for treating parasitic infections, it was removed from market due to side effects. It is still widely used in veterinary practice as a dewormer and is being assessed for treating cancer in human patients. A 2011 assessment by the US Drug Enforcement Agency found that levamisole was an adulterant in B80% of cocaine seized on the street. Monoamine transporters: Proteins that are responsible for transporting monoamines such as dopamine,
G
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norepinephrine, and serotonin across the cell membrane. They reuptake the monoamine neurotransmitters from the synaptic space and facilitate the termination of neurotransmitter function. Cocaine blocks these transporters and prevents the reuptake of monoamines released by the neurons, prolonging their actions. Posttranscriptional: Molecular events that occur after the transcription of a gene. Typically includes mechanisms that regulate stability, trafficking, and processing of RNA. Posttranslational: Molecular events that occur after the translation of mRNA into protein. Typically includes mechanisms that regulate stability, trafficking, and processing of proteins and their function. Transgene: An exogenous recombinant DNA construct containing various elements of a gene (promoter, noncoding, and/or coding regions) that is introduced into the genome of animal models for the express purpose of creating a transgenic animal.
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Minowa, M. T., Minowa, T., Monsma, F. J., Jr, Sibley, D. R., & Mouradian, M. M. (1992). Characterization of the 50 flanking region of the human D1A dopamine receptor gene. Proceedings of the National Academy of Sciences of the United States of America, 89 (7), 30453049. Mu¨ller, C. P., & Homberg, J. R. (2015). The role of serotonin in drug use and addiction. Behavioural Brain Research, 277, 146192. Okazawa, H., Imafuku, I., Minowa, M. T., Kanazawa, I., Hamada, H., & Mouradian, M. M. (1996). Regulation of striatal D1A dopamine receptor gene transcription by Brn-4. Proceedings of the National Academy of Sciences of the United States of America, 93(21), 1193311938. Pasuit, J. B., Li, Z., & Kuzhikandathil, E. V. (2004). Multi-modal regulation of endogenous D1 dopamine receptor expression and function in the CAD catecholaminergic cell line. Journal of Neurochemistry, 89(6), 15081519. Schmidt, K. T., & Weinshenker, D. (2014). Adrenaline rush: The role of adrenergic receptors in stimulant-induced behaviors. Molecular Pharmacology, 85(4), 640650. Sidhu, A., Olde, B., Humblot, N., Kimura, K., & Gardner, N. (1999). Regulation of human D1 dopamine receptor function and gene expression in SK-N-MC neuroblastoma cells. Neuroscience, 91(2), 537547. Song, R., Zhang, H. Y., Li, X., Bi, G. H., Gardner, E. L., & Xi, Z. X. (2012). Increased vulnerability to cocaine in mice lacking dopamine D3 receptors. Proceedings of the National Academy of Sciences of the United States of America, 109(43), 1767517680. Takeuchi, S., Imafuku, I., Waragai, M., Roth, C., Kanazawa, I., Buettner, R., . . . Okazawa, H. (1999). AP-2beta represses D(1A) dopamine receptor gene transcription in neuro2a cells. Brain Research. Molecular Brain Research, 74(1-2), 208216. Tobo´n, K. E., Catuzzi, J. E., Cote, S. R., Sonaike, A., & Kuzhikandathil, E. V. (2015). Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice. The European Journal of Neuroscience, 42(2), 18491857. Tobo´n, K. E., Chang, D., & Kuzhikandathil, E. V. (2012). MicroRNA 142-3p mediates post-transcriptional regulation of D1 dopamine receptor expression. PLoS One, 7(11), e49288. Tobo´n, K. E., & Kuzhikandathil, E. V. (2014). Preadolescent drd1-EGFP mice exhibit cocaine-induced behavioral sensitization. Neuroscience Letters, 558, 2025. Voulalas, P. J., Schetz, J., & Undieh, A. S. (2011). Differential subcellular distribution of rat brain dopamine receptors and subtype-specific redistribution induced by cocaine. Molecular and Cellular Neurosciences, 46(3), 645654. Wang, N., Su, P., Zhang, Y., Lu, J., Xing, B., Kang, K., . . . Wang, Y. (2014). Protein kinaseD1-dependent phosphorylation of dopamine D1 receptor regulates cocaine-induced behavioral responses. Neuropsychopharmacology, 39(5), 12901301. Yang, Y., Hwang, C. K., D’Souza, U. M., Lee, S. H., Junn, E., & Mouradian, M. M. (2000a). Three-amino acid extension loop homeodomain proteins Meis2 and TGIF differentially regulate transcription. The Journal of Biological Chemistry, 275(27), 2073420741. Yang, Y., Hwang, C. K., Junn, E., Lee, G., & Mouradian, M. M. (2000b). ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene. The Journal of Biological Chemistry, 275(49), 3886338869. Zhang, Y., Schlussman, S. D., Ho, A., & Kreek, M. J. (2003). Effect of chronic “binge cocaine” on basal levels and cocaine-induced increases of dopamine in the caudate putamen and nucleus accumbens of C57BL/6J and 129/J mice. Synapse (New York, N.Y.), 50(3), 191199.
Mechanisms That Regulate the Expression of Dopamine D1 Receptor in Cocaine Addiction E.V. Kuzhikandathil Rutgers—New Jersey Medical School, Newark, NJ, United States
SUMMARY POINTS
KEY FACTS
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This chapter focuses on mechanisms that regulate expression of the dopamine D1 receptor in the context of cocaine addiction. The dopamine D1 receptor is centrally involved in cocaine-induced locomotor activity, cocaine selfadministration, cocaine-induced behavioral sensitization, cue-elicited cocaine-seeking behavior, and the reinforcing effects of cocaine. Acute and repeated cocaine administration alter the expression of the D1 receptor gene. The D1 receptor gene is regulated at the level of transcription, posttranscription, and posttranslation. The adenosine signaling pathway potentially acts as an autoinhibitor mechanism for downregulating D1 receptor expression. Levamisole, an adulterant in street cocaine, is an inhibitor of the adenosine signaling pathway and could increase D1 receptor expression and accentuate effects of cocaine. Cocaine-induced increase in BDNF levels could mediate the sustained elevation of D1 receptor mRNA and potentially induce the posttranscriptional mechanism observed in cocaine-sensitized animals. The cocaine-sensitive transcription factor, DRRF, competes with positive and negative transcription factors to regulation D1 receptor gene transcription. Posttranscriptional mechanisms involving microRNAmediated translational suppression might underlie the physiological and behavioral responses to cocaine challenge in a sensitized animal. Posttranslational mechanisms affecting D1 receptor trafficking and turnover rates are also likely affected in cocaine-sensitized animals.
The Neuroscience of Cocaine. DOI: http://dx.doi.org/10.1016/B978-0-12-803750-8.00015-4 © 2017 Elsevier Inc. All rights reserved.
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In the brain, D1 receptor expression levels are highest in the caudate-putamen (dorsal striatum), nucleus accumbens, substantia nigra, olfactory bulb, amygdala, and medial prefrontal cortex. Lower levels of expression occurs in the hippocampus, cerebellum, thalamic areas, and hypothalamic areas. Synthetic ligands with selectivity for D1 receptors include agonists such as A77636, SK38393, A 68930, CY 208-243, and dihydrexidine and antagonists such as SKF 83566, SCH23390, LE 300, and SCH 39166. Fenoldopam is a clinically used peripheral D1 receptor partial agonist for treating hypertension. The D1 receptors are seven transmembrane G-protein coupled receptors that couple to and stimulate adenylyl cyclase to increase intracellular cAMP levels through the activation of Gαs/olf family of G-proteins. Activation of D1 receptors results in protein phosphorylation, increases in intracellular calcium, and activation of gene expression. Expression of a gene can be regulated at transcriptional, posttranscriptional, or posttranslational levels. Transcriptional regulatory mechanisms involve transcription factors activing via cis regulatory regions in a gene. The transcription factors can activate or inhibit the synthesis of mRNA from the gene. Posttranscriptional regulatory mechanisms can regulate the stability of mRNA and rate of protein synthesis via RNA-binding proteins or regulatory RNAs such as microRNAs. Posttranslational regulatory mechanisms regulate the stability of proteins and trafficking of proteins to various subcellular compartments. 143
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Regulation of gene expression at transcriptional, posttranscriptional, and posttranslational level can be celland tissue-specific, regulated by extrinsic and intrinsic signaling pathways and altered during development, disease, and treatment of disease.
LIST OF ABBREVIATIONS ATP BDNF CAD cAMP drd1a DRiP78 DRRF EGFP ER GRK mRNA miRNA PI-3K
adenosine triphosphate brain-derived neurotrophic factor cath A derived cyclic AMP dopamine D1 receptor gene dopamine receptor interacting protein 78 dopamine receptor regulating factor enhanced green fluorescent protein endoplasmic reticulum G-protein receptor kinase messenger RNA microRNA phosphatidylinositol-4,5-bisphosphate 3-kinase
15.1 INTRODUCTION Cocaine’s physiological effects are primarily due to its ability to block monoamine uptake transporters. The blockade results in elevated levels of synaptic dopamine, serotonin, and norepinephrine (Mu¨ller & Homberg, 2015; Schmidt & Weinshenker, 2014; Zhang, Schlussman, Ho, & Kreek, 2003). Acute and repetitive elevation of these monoamine neurotransmitters, due to cocaine administration, results in both immediate and long-term changes in function and expression of the monoamine receptors. Among monoamines, the effect of cocaine on dopamine and its receptors has been thoroughly studied (Anderson & Pierce, 2005). Most drugs of abuse, including cocaine, increase extracellular dopamine affecting the mesocorticolimbic reward and reinforcement pathway, which ultimately causes the physiological and behavioral phenotypes associated with drug addiction. Results from pharmacological and genetic knockout studies strongly suggest that the dopamine D1 receptor is a key mediator of the effects of cocaine and various drugs of abuse (Hummel & Unterwald, 2002). Studies using behavioral and electrophysiological approaches with D1 receptor agonist SKF38393 and antagonist SCH23390 have shown that the D1 receptor is essential for mediating the effects of cocaine (Henry, Greene, & White, 1989; Hummel & Unterwald, 2002). Molecular-level studies have shown that the cocaine-induced changes in signaling and gene expression are also mediated by the D1 receptor (Hummel & Unterwald, 2002). Studies using D1 receptor knock-out mice have established the role of the D1 receptor in mediating the cocaine-induced locomotor activity,
cocaine-self administration, behavioral sensitization, cueelicited cocaine-seeking behavior, and the reinforcing effects of cocaine (Caine et al., 2007; Chen & Xu, 2010; Karlsson, Hefner, Sibley, & Holmes, 2008). Acute and chronic cocaine administration of cocaine alter expression of various genes, including the D1 receptor. The effects of cocaine on expression of D1 receptor mRNA and protein expression are brain region specific (Hummel & Unterwald, 2002). The studies to date have often reported contradictory results because of differences in cocaine administration protocols, species/strains of rodents, time of assessment, brain regions investigated, and assays for measuring D1 receptor mRNA and protein levels (Table 15.1). The general consensus is that intermittent cocaine treatment increases D1 receptor mRNA expression, but does not change D1 receptor protein (Table 15.1). Overall, these disparate descriptive studies have clearly established that cocaine alters the expression of D1 receptors; however, the extracellular factors, signaling pathways, and molecular mechanisms that regulate cocaine-induced changes in D1 receptor expression remain to be determined. This knowledge deficit needs to be addressed as, despite being a therapeutic target for treating addictive disorders, clinically viable ligands that directly modulate D1 function have been difficult to develop. Given the well-documented cocaine-induced changes in D1 receptor expression, indirect manipulation of D1 receptor expression provides an alternate approach to treating cocaine addiction. In this chapter, the various mechanisms that have been reported to regulate expression of D1 receptor and their potential relevance to cocaine addiction are discussed.
15.2 COCAINE-INDUCED CHANGES IN D1 RECEPTOR EXPRESSION Acute and repeated chronic cocaine administration have been reported to change D1 receptor expression in rodent models. While a majority of the studies with rodents have used rats, the recent availability of genetically modified mice that express the enhanced green fluorescent protein (EGFP) in cells that endogenously express D1 receptors has facilitated novel studies (Lawhorn, Edusei, Zhou, Ho, & Kreek, 2013; Tobo´n & Kuzhikandathil, 2014). The drd1a-EGFP mouse carries transgenes in which the D1 receptor promoter is fused to the EGFP reporter gene. Fig. 15.1 shows a representative image of a brain slice from the drd1a-EGFP demonstrating robust expression of the D1 receptor mRNA in the striatum and cortex. Numerous studies have shown that administration of cocaine rapidly increases the expression of D1 receptor mRNA (reviewed in Hummel & Unterwald, 2002). A recent study has shown that acute binge administration of
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TABLE 15.1 A List of Representative Studies That Report Cocaine-Induced Changes in D1 Receptor mRNA and Protein Expression Species
Sex/ Age
Cocaine Dose and Administration Protocol
Time of Measurement (After Last Dose)
D1 Receptor mRNA Expression Changes
D1 Receptor Protein Expression Changes
Citations
Fischer rats
Male/ 60 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 2, 7, 14 days
30 min
ND
Increased binding (SCH23390) in NAc, OT, SN & VP
Unterwald et al. (1994). J. Pharmacol. Exp. Therap. 270, 13871397
Fischer rats
Male/ 60 days
15 mg/kg each injection; daily 2 injections, 14 h apart; 14 days
180 min
ND
Increased binding (SCH23390) in NAc and OT
Unterwald et al. (2001). Brain Research, 900, 103109
Long Evans rats
Male, 300 g
4-Week selfadministration; 1 h/day, daily
120 min or 7 days
Increase in striatum, NAc, OT, cortex, hippocampus, thalamus
Decreased binding (SCH23390) in striatum, NAc, OT, cortex, thalamus, hippocampus
Laurier et al. (1994). Brain Research 634, 3140
SpragueDawley rats
Male, 280 g
15 mg/kg each injection; daily 3 injections, 1 h apart; 2, 7, 14 days
60 min
ND
Decreased in vivo binding (PETSCH23390) in striatum
Tskuada et al. (1996) J. Neurosci., 76707677
Wistar rats
Male, 280 g
20 mg/kg daily injection; 10 days
14 h
Increase in striatum, frontal cortex
ND
Scmidt-Mutter, et al. (1999) Neuropsychopharmacol, 21(5), 662669
C57BL/6J mice
Male/ 70 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 14 days
45 min
ND
Increased binding (SCH23390) in caudate but not NAc or OT
Sclussman et al. (2003). Pharmacol. Biochem. Behav. 75, 123131
C57BL/6J & drd1a-EGFP (FVB) mice
Male/ 23 days
15 mg/kg each injection; daily 3 injections, 1 h apart; 7 days
30, 60 min
Increase in caudate but not in NAc
No change in protein expression in caudate or NAc
Tobon et al. (2015) Eur. J. Neurosci. 42(2), 18491857
ND, not determined; NAc, nucleus accumbens; OT, olfactory tubercle; SN, substantia nigra; VP, ventral pallidum; SCH23390, D1 receptor selective antagonist; PET, positron emission tomography.
cocaine rapidly and significantly increases the number of EGFP-expressing cells specifically in the dorsolateral striatum of the drd1a-EGFP mice (Lawhorn et al., 2013); this suggests an increase in transcriptional activity of the dopamine D1 receptor gene. Several studies have consistently shown that repeated cocaine administration alters the expression of D1 receptors in various brain regions (reviewed in Hummel & Unterwald, 2002). Overall, the results suggest that repeated cocaine administration over 714 days
increases the expression of D1 receptor mRNA in the striatum. Using the drd1a-EGFP mouse model, we have recently shown that binge administration of cocaine results in an increase in D1 receptor mRNA, but not D1 receptor protein, expression in the caudate putamen. This change is not observed in the nucleus accumbens (Tobo´n, Catuzzi, Cote, Sonaike, & Kuzhikandathil, 2015). Interestingly, when sensitized mice are administered a single challenge dose of cocaine, there is a rapid increase in D1 receptor protein expression within
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FIGURE 15.1 Representative coronal striatal brain slice from the drd1a-EGFP mice. Brain was isolated from a male drd1a-EGFP mouse on postnatal day 7. Two hundred micrometer coronal section was mounted on glass slide and viewed with an inverted fluorescence microscope. Several overlapping images of one hemisphere were obtained using a 20 3 objective and integrated using Image J.
30 minutes in the caudate putamen. Taken together, from these results, we can infer that the D1 receptor expression is regulated at the transcriptional and posttranscriptional level by cocaine.
15.3 EXTRACELLULAR FACTORS THAT REGULATE D1 RECEPTOR EXPRESSION How cocaine regulates the expression of D1 receptors is not known. Studies distinguishing acute and long-term effects of cocaine suggest that the underlying extracellular factors and signaling mechanism for the acute and longterm effect might be very different. Acutely administered cocaine blocks dopamine, serotonin, and norepinephrine uptake transporters and elevates the levels of these monoamine neurotransmitters (Mu¨ller & Homberg, 2015; Schmidt & Weinshenker, 2014; Zhang et al., 2003). The acute effects of cocaine might be mediated by dopamine, serotonin, and/or norepinephrine acting on their cognate receptors and altering levels of second messengers such as cAMP and calcium.
15.3.1 Adenosine and cAMP Studies in SK-N-MC human neuroblastoma cells, which express endogenous D1 receptors, have shown a bimodal
regulation of D1 receptor expression by dopamine and D1 receptor agonist, SKF38393, wherein an initial upregulation is followed by a downregulation of endogenous D1 receptor mRNA (Sidhu, Olde, Humblot, Kimura, & Gardner, 1999). We have reported that extracellular cAMP via adenosine A2A receptor decreases expression of endogenous D1 receptors in the CAD mouse catecholaminergic cell line (Do, Sun, Beuve, & Kuzhikandathil, 2007b) and in the kidney of type I diabetic rats (Kuzhikandathil, Clark, & Li, 2011). We observed that elevating intracellular cAMP also downregulates the expression of D1 receptors in the CAD cell line (Do et al., 2007b). These studies suggest that D1 receptor-induced elevation of intra- and extracellular cAMP might have an autoinhibitory effect on D1 receptor expression wherein a persistent increase in steady-state cAMP levels might lead to D1 receptor downregulation via the extracellular cAMP-adenosine signaling pathway (Do et al., 2007b). A key component of the extracellular cAMPadenosine signaling pathway is the ecto-protein, tissue nonspecific alkaline phosphatase (TNAP), which generates adenosine from ATP or AMP (metabolite of cAMP or ATP). We have shown that inhibitors of the adenosine signaling pathway can prevent extracellular cAMP from downregulating D1 receptor expression in CAD cell line and in diabetic rat kidneys (Do et al., 2007b; Kuzhikandathil et al., 2011). One of these inhibitors is levamisole, an adulterant, commonly found in street cocaine that causes severe side effects in cocaine addicts (Larocque & Hoffman, 2012). We have shown that levamisole prevents the downregulation of D1 receptor expression in CAD cells and diabetic rat kidneys (Do et al., 2007b; Kuzhikandathil, et al., 2011). Fig. 15.2 shows a working model of how levamisole, by blocking TNAP and preventing the downregulation of D1 receptors, could enhance the behavioral and physiological effects of cocaine.
15.3.2 Dopamine Among dopamine receptors, the dopamine D3 receptor is a potential candidate for regulation of D1 receptor expression as it couples to Gαi/o G-proteins, which inhibits adenylate cyclase and decreases cAMP levels. Cocaine administration could drive increased D3 receptor signaling resulting in decreased steady-state cAMP levels and increased D1 receptor expression. D3 receptor is coexpressed with D1 receptors in the direct pathway (Beaulieu & Gainetdinov, 2011). Pharmacological and knock-out animal studies have suggested a role for D3 receptors in cocaine addiction (Karasinska, George, Cheng, & O’Dowd, 2005; Song et al., 2012). The levels of D3 receptors are elevated in rodent models of sensitization; in particular, levels of D3 receptors in the dorsal striatum are elevated in rodents addicted to cocaine (Guillin et al., 2001).
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FIGURE 15.2 Working model for effect of adenosine and levamisole on cocaine-induced D1 receptor expression. (A) In animals administered cocaine, elevated dopamine (red (gray in print versions) ellipses) binds D1 receptors (D1R), increases adenylate cyclase (AC) activity, elevates cAMP levels and elicits cocaine-induced behavioral effects. Sustained elevation of intracellular cAMP leads to paracrine export of cAMP and, metabolite, AMP from cells which together with ATP, AMP, and cAMP from exocrine sources is converted to adenosine (green (black in print versions) ellipse) by tissue nonspecific alkaline phosphatase (TNAP). Adenosine binds receptors (AdoR) such as A2A receptors which downregulates the expression of D1 dopamine receptors. This autoinhibitory feedback mechanism for downregulation of D1 receptor is blocked when production of adenosine by TNAP is inhibited by levamisole (B). This results in increased D1 receptor expression and enhanced behavioral and physiological effects of cocaine.
15.3.3 Norepinephrine Among adrenergic receptors, the alpha 1 and alpha 2 receptors couple to Gαq and Gαi/o signaling pathways. The reported rapid increase in calcium levels following an acute dose of cocaine supports a role for a Gαq-mediated signaling process (Luo, Volkow, Heintz, Pan, & Du, 2011). Studies have shown that alpha 1 antagonism decreases and alpha 2 antagonism increases cocaine-induced locomotor response, suggesting that alpha 1 receptors like D1 receptors are important for the cocaine-induced enhanced locomotor response. The alpha 1b receptor subtype couples to Gαq G-proteins and facilitates cocaine-induced sensitization. Specifically, mice lacking the alpha 1b adrenergic receptor have decreased acute and sensitized response to cocaine (reviewed in Schmidt & Weinshenker, 2014).
15.3.4 Serotonin Acute cocaine administration has been reported to increase extracellular serotonin levels in several brain regions (reviewed in Mu¨ller & Homberg, 2015). This coupled with low nanomolar affinity of serotonin for 5-HT receptors suggest a potential role for serotonin in mediating changes in D1 receptor expression. Among serotonin receptors, the 5-HT1 and 5-HT2 receptors are of interest; in particular 5-HT1A and 5-HT2A receptors which have high affinity for serotonin and are coupled to Gαi/o and Gαq G-protein signaling, respectively. Most studies suggest that activation of the 5-HT1A and 5-HT2A receptors facilitates the induction and expression of cocaineinduced sensitization while other subtypes either have an inhibitory effect on cocaine-induced behaviors or have no
effect (reviewed in Mu¨ller & Homberg, 2015). Interestingly, it has been reported that 5-HT2A and alpha1b-adrenergic receptors mediate locomotor response and behavioral sensitization to cocaine and amphetamines (Auclair, Drouin, Cotecchia, Glowinski, & Tassin, 2004).
15.3.5 Brain-Derived Neurotrophic Factor Numerous studies have shown that cocaine administration increases brain-derived neurotrophic factor (BDNF) levels in the striatum (reviewed in McGinty, Whitfield, & Berglind, 2010). Manipulation of BDNF-TrkB signaling in the dorsal striatum by deleting the expression of TrkB in D1- and D2-expressing cells (using drd1a-cre and drd2-cre mice) affects cocaine-induced behaviors (Lobo et al., 2010). However, to date the role of BDNF-TrkB signaling in regulating D1 receptor expression following cocaine administration is not known. We have shown that BDNF-TrkB signaling increases D1 receptor expression in studies using the CAD cell line and TrkB null mice (Do, Kerr, & Kuzhikandathil, 2007a). We have also shown that BDNF-induced upregulation of D1 receptor expression exhibits posttranscriptional regulation. In CAD cells transfected with TrkB receptor, BDNF induces expression of D1 receptor mRNA within 3 hours, while protein levels do not increase until 12 hours later (Do et al., 2007a). The BDNF-TrkB induction of D1 receptor expression is mediated by the PI-3 kinase signaling pathway (Do et al., 2007a). Our working model, shown in Fig. 15.3, postulates that the persistent upregulation of D1 receptor mRNA in cocaine-sensitized animals is mediated by BDNF which might also impart posttranscriptional regulation on D1 receptor expression (Tobon et al., 2015).
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15.4 TRANSCRIPTIONAL REGULATION OF D1 RECEPTOR EXPRESSION The D1 receptor gene has a cell type-specific promoter of B6400 bp with two promoters, a single intron in the
FIGURE 15.3 Working model for effect of BDNF on cocaine-induced D1 receptor expression. Repeated administration of cocaine is known to increase striatal BDNF levels. BDNF binds to TrkB receptor and increases transcription of D1 receptor gene via the PI-3K signaling pathway. While this pathway exhibits post-transcriptional regulation, the D1 receptor proteins levels and function are also enhanced following BDNF treatment. This model provides a mechanistic explanation for BDNFmediated behavioral and physiological effects of cocaine.
50 untranslated region, intron-less coding region and B1600 bp 3’ untranslated region. The D1R receptor gene can be transcribed from two different promoters that lack the consensus TATA and CAAT boxes. The upper promoter is located between nucleotides 1154 and 1336 relative to the start codon, and the lower promoter is located in the single intron (Lee, Yajima, & Mouradian, 1999; Minowa, Minowa, Monsma, Sibley, & Mouradian, 1992). The D1 receptor mRNA transcripts from the upper promoter are found only in neuronal cell types, whereas the shorter mRNA transcripts from the lower intron promoter are found in both neurons and kidney cells. The D1 receptor mRNA transcripts from the upper promoter are less stable (Lee, Minowa, & Mouradian, 1996). Several studies have shown that the transcription of D1 receptor gene is finely regulated by a combination of trans-activators (Meis2, Sp1, and Brn4) and trans-repressors (TGIF, Zic2, Sp3, and AP2β) as depicted in Fig. 15.4 (Hwang et al., 2001; Okazawa et al., 1996; Takeuchi et al., 1999; Yang et al., 2000a; Yang, Hwang, Junn, Lee, & Mouradian, 2000b). In addition, the dopamine receptor regulating factor (DRRF) plays a context-dependent dual role in which it can either act as a repressor or activator by competing with the above-mentioned transcription factors for binding to the Act/AR1 DNA element (Hwang et al., 2001). Interestingly, studies have shown that DRRF expression is downregulated by cocaine and it is possible that this downregulation contributes to the cocaineinduced increase in D1 receptor mRNA levels. We have shown that the BDNF-induced increase in D1 receptor mRNA occurs at the transcriptional level and is
FIGURE 15.4 Trans-acting factors and cis-DNA elements that are known to regulate transcription of D1 receptor gene. The D1 receptor gene has a single intron in the 5´ untranslated region. The gene has two promoters: an upstream promoter that generate a long transcript from the upstream initiation site (U) and an intron promoter that generates a shorter transcript from the downstream initiation site (I). Transcription factor binding sites Act and AR1 in the upstream promoter region and another element in exon 1 has been identified. The sites bind transcription factors that can increase (Meis2; Sp1; Brn-4) or decrease (TGIF; Zic2; Sp3; Ap2β) transcription. DRRF is a cocaine-sensitive transcription factor that competes with other factors to bind to the Act and AR1 sequence; hence it can have a context-dependent positive or negative effect on D1 receptor gene transcription. The BDNF response element in the D1 receptor promoter is located in a 2700 bp region. The base pair numbering is relative to the translation initiation codon (ATG).
Cocaine-Mediated Regulation of D1 Receptor Chapter | 15
mediated by cis-elements in the D1 receptor promoter between 4700 and 2000, relative to the ATG initiation codon (Do et al., 2007a). The transcription factor(s) mediating BDNF-induced D1 receptor mRNA transcription remains to be identified and could be a key mediator of the effect of cocaine on D1 receptor expression.
15.5 POSTTRANSCRIPTIONAL REGULATION OF D1 RECEPTOR EXPRESSION We have shown that the expression of D1 receptor is posttranscriptionally regulated during postnatal brain development and also during differentiation of CAD cells (Pasuit, Li, & Kuzhikandathil, 2004; Tobo´n, Chang, & Kuzhikandathil, 2012). Recently we have also shown that D1 receptor expression is posttranscriptionally regulated in the caudate-putamen of cocaine-sensitized mice (Tobon et al., 2015). Sensitized mice express higher levels of D1 receptor mRNA but not protein; however, when cocainesensitized mice are challenged with cocaine, the levels of D1 receptor increase rapidly within 30 minutes. The rapid cocaine-induced increase of D1 receptor protein expression in sensitized mice requires de novo protein synthesis and is inversely correlated with the levels of microRNAs miR142-3p and miR-382, both of which, we have shown, posttranscriptionally regulate D1 receptor expression in vitro and in vivo in a mouse model of alcohol (Li et al., 2013; Tobo´n et al., 2012). Our working model shown in Fig. 15.5
FIGURE 15.5 Working model for post-transcriptional regulation underlying cocaine-induced locomotor hyperactivity in sensitized animals. The levels of D1 receptor mRNA (green (double dashed line)) and miRNA 383 and 142-3p (purple (dashed line)) in the striatum is high in sensitized animals; however, prior to cocaine administration in sensitized animals, the steady-state protein levels (red (solid gray line)) and the locomotor activity (blue (solid black line)) are low. Administration of cocaine to sensitized animals (up arrow) results in a rapid-decrease in microRNA levels within 5 min which relieves the translational suppression of D1 receptor mRNA, resulting in a rapid increase in D1 receptor protein levels within 30 min. The elevated D1 receptor protein levels contribute to the sustained cocaine-induced hyperactivity in the sensitized animals.
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is that expression of D1 receptor mRNA is elevated in the caudate-putamen of cocaine-sensitized mice; however the levels of D1 receptor protein are low due to miRNAmediated translational suppression. This translational suppression of D1 receptor mRNA is rapidly relieved upon cocaine challenge due to a rapid loss of microRNA suppression brought about by a combination of active miRNA decay and/or expulsion of miRNA via exosomes. The newly synthesized D1 receptor protein provides a sustained response to cocaine-elevated synaptic dopamine, manifested as enhanced locomotor activity in the sensitized mice. An interesting aspect of the posttranscriptional regulation of D1 receptor expression in the cocaine-sensitized mice is that it is observed in the caudate-putamen but not the nucleus accumbens. Given the role of caudate-putamen in habit formation, induction of a posttranscriptional mechanism for regulating D1 receptor expression following repeated cocaine administration strongly suggests that such mechanisms might be important for relapse and cueinduced cocaine-seeking behaviors.
15.6 POSTTRANSLATIONAL REGULATION OF D1 RECEPTOR EXPRESSION Following synthesis of D1 receptor protein, it undergoes posttranslational modifications including glycosylation and phosphorylation. This can affect both the expression of the receptor on the cell membrane as well as its function. Transport from the endoplasmic reticulum (ER) to cell membrane is a multistep process that involves different types and levels of glycosylation and disruption of these mechanisms results in rapid elimination of the receptor. In the case of D1 dopamine receptor, an ERmembrane-associated protein, dopamine receptor interacting protein 78 (DRiP78), regulates the transport to the cell surface (Bermak, Li, Bullock, & Zhou, 2001). Overexpression of DRiP78 significantly slows the maturation of the early forms of D1 receptor to the mature form. Similarly, overexpression of neurofilament-M protein was shown to decrease cell surface expression of D1 receptors (Kim, Ariano, Lazzarini, Levine, & Sibley, 2002). It is not known if cocaine administration affects the expression and function of DRiP78 or neurofilament-M and consequently D1 receptors. Generally, the D1 receptor protein is enriched in detergent-resistant membrane fractions where lipid raft and caveolar proteins are found; however, repeated cocaine administration over a 7-day period shifted the D1 receptor protein from the detergent-resistant fractions to detergent-soluble membrane and cytoplasmic fractions (Voulalas, Schetz, & Undieh, 2011). This suggests that cocaine administration might affect posttranslation mechanisms that regulate D1 receptor cell surface expression.
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D1 receptor cell surface expression is also regulated by an agonist-dependent internalization mechanism that is driven by phosphorylation of the receptor. G-protein receptor kinases (GRKs) mediate agonist-induced phosphorylation of D1 receptors, followed by β-arrestin-mediated receptor internalization. It has been shown that mutation of threonine 360, a residue in the GRK2 phosphorylation site, in D1 receptor abolished the rapid agonist-induced desensitization, while mutation of residue, threonine 446, abolished agonist-induced receptor internalization (Lamey et al., 2002). Recently, it was shown that serine 421 is a key residue for cell surface expression of D1 receptors and phosphorylation of this site by protein kinase D is critical for mediating the behavioral effects of cocaine administration (Wang et al., 2014).
MINI-DICTIONARY OF TERMS G
G
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Behavior sensitization: Repeated administration of cocaine over a period of 47 days to animals results in enhanced behavioral response to the same dose of cocaine. Typically, locomotor behavior in a monitoring arena is used to assess behavior sensitization. Binge administration: A cocaine administration protocol used to induce behavior sensitization. Typically animals are administered three daily doses of cocaine (1020 mg/kg, i.p.), 1 hour apart for 12 weeks. Exosomes: Membranous secreted vesicles that can contain RNA, microRNA, protein, or other cytoplasmic material. Found in plasma and other bodily fluids. Extracellular cAMP-adenosine pathway: A signaling pathway with ecto-proteins present on the extracellular side of cell membrane that generated adenosine from cAMP, AMP, and ATP. Ecto-phosphodiesterases breakdown cAMP into AMP. Ecto-nucleotidases, such as CD73 and TNAP, generate adenosine from AMP and ATP. This pathway has been described in brain, kidney, and many other tissues. G-protein coupled receptors: Seven transmembrane receptor proteins that signal to cytoplasmic effectors via heterotrimeric G-proteins (Galpha, Gbeta, and Ggamma). Conformational changes induced by ligand binding to receptors results in G-protein exchanging the bound GDP with GTP, which is one of the first steps in the activation of the signal transduction cascade. Levamisole: Originally approved for treating parasitic infections, it was removed from market due to side effects. It is still widely used in veterinary practice as a dewormer and is being assessed for treating cancer in human patients. A 2011 assessment by the US Drug Enforcement Agency found that levamisole was an adulterant in B80% of cocaine seized on the street. Monoamine transporters: Proteins that are responsible for transporting monoamines such as dopamine,
G
G
G
norepinephrine, and serotonin across the cell membrane. They reuptake the monoamine neurotransmitters from the synaptic space and facilitate the termination of neurotransmitter function. Cocaine blocks these transporters and prevents the reuptake of monoamines released by the neurons, prolonging their actions. Posttranscriptional: Molecular events that occur after the transcription of a gene. Typically includes mechanisms that regulate stability, trafficking, and processing of RNA. Posttranslational: Molecular events that occur after the translation of mRNA into protein. Typically includes mechanisms that regulate stability, trafficking, and processing of proteins and their function. Transgene: An exogenous recombinant DNA construct containing various elements of a gene (promoter, noncoding, and/or coding regions) that is introduced into the genome of animal models for the express purpose of creating a transgenic animal.
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