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NEUROPHARMACOLOGY
-1 Receptor Gene and Protein Expression in Brain Regions Involved in Addiction and Reward
College of Pharmacy (Y.L., G.-D.C., R.R.M.) and Department of Surgery (M.R.L., D.J.B.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Veteran's Affairs Medical Center, Oklahoma City, Oklahoma (M.R.L., D.J.B.); and University of Mississippi, University, Mississippi (R.R.M.)
Received February 7, 2005; accepted May 3, 2005.
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Abstract |
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Receptors have recently been implicated in the actions of cocaine, and antagonists of these receptors prevent many acute and subchronic cocaine effects. A previous study revealed that the immediate early gene fra-2 is up-regulated after cocaine administration, and this effect is prevented by the -1 receptor antagonist BD1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine]. In the present study, the effects of cocaine and BD1063 on the expression of six fos and jun genes were evaluated in mouse brains using cDNA microarrays. Several of these genes were altered by cocaine, but only the alteration in fra-2 was prevented by BD1063. The time courses of fra-2 and -1 receptor gene and protein expression in different brain regions were also determined. Cocaine up-regulated fra-2, which was followed by a later up-regulation of -1 receptors. The cocaine-induced up-regulation of fra-2 and -1 receptor genes and proteins were detected in whole brain, striatum, and cortex, but not in cerebellum. All of these cocaine-induced effects were prevented by BD1063. The interaction between cocaine, fra-2, and -1 receptors involves brain regions that are established components of the neural circuit for reward, suggesting that they may contribute to the enduring changes that underlie the cellular basis of drug abuse.
; Matsumoto et al., 2003), depending on its dosage. Furthermore, repeated cocaine exposure may cause sensitization of the behavioral responses to cocaine (Post and Rose, 1976).
Many neurotransmitter systems and ion channels are involved in the behavioral effects of cocaine. They include neurotransmission systems for dopamine (Sorg and Kalivas, 1993; Chausmer et al., 2002), glutamate (Brackett et al., 2000), serotonin (Muller et al., 2002), and GABA (Suzuki et al., 2000). Calcium channels play an important role in the locomotor-stimulating effects of cocaine (Han et al., 2002), and sodium and potassium channels mediate some toxic effects of the drug (Bauman and DiDomenico, 2002).
Recently, receptors have been implicated in the actions of cocaine and are suggested to be a promising medication development target for cocaine abuse (Maurice et al., 2002; Matsumoto et al., 2003). Of the two established receptor subtypes, -1 and -2, the -1 subtype seems to have the predominant role in modulating the actions of cocaine. Cocaine has preferential affinity for the -1 subtype, at concentrations that are physiologically relevant (Matsumoto et al., 2003). -1 Receptors are widely distributed in brain and peripheral tissues and have been localized to plasma membrane as well as intracellular structures, including endoplasmic reticulum (McCann et al., 1994; Alonso et al., 2000). Stimulated dopamine release has been reported to be modulated by -1 receptors through the protein kinase C signaling pathway (Nuwayhid and Werling, 2003). In addition, cocaine-induced effects on acute and subchronic behavioral activity are attenuated by various -1 receptor antagonists and antisense oligodeoxynucleotides (Maurice et al., 2002; Matsumoto et al., 2003). However, the mechanisms through which -1 receptor antagonists convey anticocaine actions have not yet been fully characterized.
In a previous study combining behavioral pharmacological approaches with cDNA microarray analysis and RT-PCR confirmations, we discovered that fra-2, an immediate early gene (IEG) and member of the Fos family of transcription factors, is up-regulated by cocaine and prevented by behavioral protective doses of BD1063, a -1 receptor antagonist (Matsumoto et al., 2003). In addition to our study, the acute administration of cocaine has been shown by others to induce the up-regulation of many IEGs and transcription factors, such as c-fos, fosB, 
FosB, and fra-2 (Rosen et al., 1994; Zhang et al., 2002), and the gene expression seems to be regulated through dopamine receptors (Zhang et al., 2002). Several studies have also shown that -1 receptor ligands, such as E-5842 and EMD 57445 (panamesine) can induce IEGs, particularly c-fos (Dahmen et al., 1996; Guitart and Farre, 1998). These results indicate that the protective effect of receptor antagonists may involve modulation of IEG-induced transcription cascades.
The induction of IEG expression by drugs of abuse is hypothesized to be an initial step by which these drugs alter the expression of late genes to produce long-lasting changes in neuronal function. Since IEGs have been suggested to play an important role in drug addiction and our initial microarray studies and RT-PCR confirmations (Matsumoto et al., 2003) revealed that fra-2 is significantly induced by cocaine and prevented by pretreatment with the -1 receptor antagonist BD1063, the present study was undertaken to further examine the relationship between cocaine-induced IEGs and -1 receptors.
In the first part of this study, the expression of genes in the Fos and related Jun family were investigated to determine whether the anticocaine effects produced by BD1063 are specific to fra-2 or can be generalized to other members of this family of transcription factors. Numerous studies now show that members of the Fos family of IEGs form heterodimers with members of the Jun family of IEGs (Foletta, 1996). These heterodimers can then bind together to a specific DNA sequence known as the AP-1 site (Foletta, 1996; Hope, 1998). Earlier studies have shown that the -1 receptor gene has an AP-1 sequence in its promoter, suggesting that it may serve as a target gene for Fra-2 (Seth et al., 1997). The second part of this study focused on the time course of fra-2 and -1 receptor gene expression in different brain regions after acute cocaine administration, and the effect of BD1063 on the expression of these genes. Finally, the third part of this study characterized the time course of Fra-2 and -1 receptor protein expression in different brain regions after acute cocaine administration and the effect of BD1063.
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Materials and Methods |
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Drug Application. Cocaine hydrochloride (Sigma Chemical Co., St. Louis, MO) was injected at a dosage of 10 mg/kg (1 mg/ml solution i.p.). BD1063 (Tocris Cookson Inc., Ellisville, MO) was injected at a dosage of 30 mg/kg (3 mg/ml solution i.p.). Saline (10 ml/kg i.p.) was used as the control.
Locomotor Activity Measurement. Horizontal locomotor activity was measured using an automated activity monitoring system (San Diego Instruments, San Diego, CA) as described in previous studies (Matsumoto et al., 2001, 2002). Mice were individually adapted to testing chambers for 15 min, after which they received two injections separated by a 15-min interval of one of the following combinations of treatments: saline + cocaine, BD1063 + cocaine, saline + BD1063, saline + saline, or without treatment. Locomotor activity recording started immediately after the second injection and continued for 20 min for the microarray studies. This testing duration was selected because it corresponded to the time at which the locomotor stimulatory effects of cocaine were maximal in earlier time course measurements (Post and Rose, 1976). For the time-course studies in the second part of the investigation, locomotor activity was recorded for 10, 20, 40, or 80 min.
Brain Tissue Sampling. Immediately after the locomotor recordings, brain tissues were collected whole for the microarray studies or dissected into different regions (left half brain, right cortex, right cerebellum, right hippocampus, and right striatum) for the time-course study in different brain regions. The brain samples were immediately frozen in liquid nitrogen and stored in a freezer at -80°C before RNA and protein isolation.
Microarrays. Total RNA was isolated using the Atlas pure total RNA labeling system (BD Biosciences Clontech, Palo Alto, CA) from each brain: saline + saline (n = 3), saline + cocaine (n = 3), BD1063 + cocaine (n = 3), and BD1063 + saline (n = 3). Probes were made from total RNA using a reverse transcription reaction and labeled with [
-32P]dATP. The extracted and labeled cDNA probes from each sample were hybridized overnight to 1.2K cDNA microarrays (Atlas Arrays; BD Biosciences Clontech). After a high stringency wash, the resulting data were quantified using a Storm 820 PhosphorImager (Amersham Biosciences, Inc., Piscataway, NJ), and the expression levels of individual genes from each of our 12 samples were quantified from the cDNA microarrays as optical density readings with background subtraction using Array Vision software (Imaging Research, St. Catharine's, ON, Canada). Of the 1176 genes spotted on the membranes, six fos and jun family genes were represented on the microarray: fra-2, c-fos, fosB, c-jun, junB, and junD. Statistical analysis was performed using analysis of variance and Bonferroni's post hoc analysis.
RT-PCR. After the behavioral recordings for 10, 20, 40, and 80 min, brain tissues (half brain, striatum, cortex, hippocampus, and cerebellum) were immediately sampled (n = 4 for each data point). The expression of fra-2 and -1 receptor genes was determined in the different treatment groups and brain regions.
Total RNA was prepared from each brain sample using TRIzol reagents (Invitrogen, Carlsbad, CA) following the standard protocol for RNA extraction. First strand cDNA synthesis was performed using Superscript II RNase H reverse transcriptase and Oligo(dT)12-18 (Invitrogen). PCR reactions were performed as suggested by the manufacturer (Invitrogen). The oligos that were used as primers for each of our targeted genes, and their PCR reaction conditions are listed in Table 1. The oligos were synthesized by Integrated DNA Technologies, Inc. (Coralville, IA) using a standard desalting purification method.
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The following cycling parameters were used to perform the PCR amplification: denature for 45 s at 94°C, anneal as indicated in Table 1 (the specific temperature was determined based on the Tm indicated on the oligo synthesis report and adjusted based on initial PCR results), and extend for 1 min at 72°C for the number of cycles indicated in Table 1. The number of cycles for each reaction was selected to allow linear amplification of the cDNA under study. 
-Actin was used as the housekeeping gene for normalization. Amplified products were analyzed by electrophoresis on 1.5% agarose gel and stained with 0.5 µg/ml ethidium bromide. The gel was then photographed using a UV transilluminator to visualize the ethidium bromide-stained bands. The RT-PCR reactions were repeated a minimum of three times to validate the results. The expression levels of the individual genes were assessed by Scion Image software (Frederick, MD) and expressed in optical density units. The data from each of the assays were subject to analysis of variance, and Bonferroni's multiple comparisons post hoc tests to determine whether the differences between the experimental groups were statistically significant.
Western Blots. At 20, 80, 160, and 320 min and 24 h after the drug treatments, brain tissues (half brain, striatum, cortex, hippocampus, and cerebellum) were immediately sampled (n = 3–9 for each data point). The protein levels for Fra-2 and -1 receptors were measured in the different treatment groups and brain regions.
Pulverized samples were homogenized in T-PER tissue protein extraction reagent (Pierce Chemical, Rockford, IL) using a ratio of 
1 g of tissue to 20 ml of T-PER reagent. The samples were centrifuged at 10,000 rpm for 5 min, and the supernatants were collected. For small brain regions, like the striatum and hippocampus, tissues from three mice were pooled for protein extraction. Protein concentration was determined using a Bio-Rad protein assay kit (Bio-Rad, Hercules, CA), and each sample was normalized to its total protein concentration.
Boiled protein samples (40–60 µg) and molecular weight standards (5 µl, Precision Plus protein standards) were resolved on 12 or 15% SDS-polyacrylamide gels, electrophoresed, and transferred onto nitrocellulose membranes. The membranes were then blocked with bovine serum albumin for Fra-2 or nonfat dry milk for -1 receptors. The membranes were incubated with the following primary antibodies: Fra-2 (Q20, sc-604, 1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), -1 receptors (1:1000; Aves Labs, Tigard, OR), and -actin (Santa Cruz Biotechnology, Santa Cruz, CA,). Incubation with the following horseradish peroxidase-conjugated secondary antibodies followed: anti-rabbit IgG for Fra-2, anti-goat IgG for -actin (I19, sc-1616, 1:5000; Santa Cruz Biotechnology, Inc.), and anti-chicken IgY for -1 receptors (Aves Labs). NIH/3T3 nuclear extracts (Santa Cruz Biotechnology, Inc.) were used as a positive control for the Fra-2 antibody, and depleted antibodies against -1 receptor antigens (Aves Labs) were used as a negative control for the -1 receptor antibody. Immunoreactivity was visualized using enhanced chemiluminescence. Western blots for each protein was repeated at least three times.
The optical density reading of each band was quantified using Quantity One software (Bio-Rad) with background subtraction. The data from each experimental band was normalized to -actin and then subjected to analysis of variance. If there was an overall significant effect, Bonferroni's pairwise comparisons were used for post hoc evaluations.
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, 2003). Analysis of variance confirmed a statistically significant difference in the locomotor scores among the treatment groups [F(3,8) = 16.96; p < 0.001].
Analysis of variance also indicated that there were significant differences among the experimental groups in the gene expression patterns of junD [F(3,8) = 6.73; p < 0.05], c-fos [F(3,5) = 6.35; p < 0.05], and fra-2 [F(3,6) = 37.02; p < 0.001]. The expression of genes in the fos and jun families for each experimental group is shown in Fig. 1. Post hoc analysis confirmed that cocaine significantly increased the expression of junD (p < 0.05), c-fos (p < 0.05), and fra-2 (p < 0.001). Moreover, among these cocaine-induced IEGs that were upregulated, post hoc analysis confirmed that only fra-2 was prevented by pretreatment with the -1 receptor antagonist BD1063 (p < 0.001).
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-1 receptor gene expression in the different groups after injection. Although expression levels of the -1 receptor gene remained constant during the postadministration period from 10 to 80 min in the control groups, the cocaine injection caused an up-regulation of the gene, which increased with time gradually. Similar to the behavioral results and fra-2 gene expression, pretreatment with BD1063 diminished the cocaine effect. One-way analysis of variance showed a significant difference only at 80 min (p < 0.01).
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Regional Differences of the Cocaine-Induced Up-Regulation of Fra-2 and -1 Receptor Genes in the Brain. Cocaine up-regulated fra-2 gene expression in the striatum, cortex, and hippocampus (Fig. 5, A–C), but not in the cerebellum (Fig. 5D). One-way analysis of variance revealed that in the striatum and hippocampus, the differences between the treatment groups were significant at all time points (p < 0.05–p < 0.001). In the cortex, the difference between the treatment groups reached statistical significance only at the 20-min time point (p < 0.05), although the gene expression levels in the cocaine groups were consistently higher at all time points. Similar to previous studies, pretreatment with BD1063 diminished the cocaine effect.
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-1 receptor gene was observed in the striatum and cortex but not in the cerebellum and hippocampus (Fig. 6). One-way analysis of variance showed that the differences between the treatment groups reached statistical significance in the striatum and cortex only at the 80-min time point (p < 0.05). Similarly, pretreatment with BD1063 diminished the cocaine effect.
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-1 Receptor Protein Expression in the Brain. Cocaine upregulated Fra-2 protein levels in the whole brain, cortex, striatum, and hippocampus (Fig. 7, A–D) but not in the cerebellum (Fig. 7E). One-way analysis of variance revealed that in the striatum, the differences between the treatment groups were significant at 160 and 320 min (p < 0.05). In the hippocampus, the differences between the treatment groups were significant at 80 and 160 min (p < 0.05–0.01). In the cortex, the differences between the treatment groups were significant at 20, 80, 160, and 320 min (p < 0.05–0.001). In the half brain, the differences between the treatment groups did not reach statistical significance, although the protein levels in the cocaine groups were consistently higher at the 80-, 160-, and 320-min time points. Similar to earlier studies, pretreatment with BD1063 diminished the effects of cocaine.
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Cocaine-induced up-regulation of the -1 receptor protein was observed in the half brain, cortex, and striatum (Fig. 8, A–C) but not in the hippocampus and cerebellum (Fig. 8, D and E). One-way analysis of variance showed that the differences between the treatment groups reached statistical significance at the 320-min time point (p < 0.05–0.01). Similarly, pretreatment with BD1063 diminished the effects of cocaine.
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Discussion |
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-1 receptor gene and protein expression in the brain, but with different time courses. The time course of the cocaine-induced locomotor hyperactivity reflects the elimination curve of cocaine in the body (Lau et al., 1991). In contrast, the up-regulation of the fra-2 gene may mediate immediate as well as enduring effects of cocaine on the body, such as addiction and sensitization to cocaine. The up-regulation of the -1 receptor gene on the other hand, with its induction delayed until after much of the cocaine has been eliminated from the body, most likely represents transcriptional regulation by another early gene such as fra-2.
Similar to previous studies, the results demonstrate that cocaine can induce a number of genes in the fos and jun families of transcription factors (Young et al., 1991; Hope, 1998). However, fra-2 is the most sensitive gene of those evaluated to -1 receptor-mediated influences since it was the only one of the six genes evaluated in the microarray analysis whose cocaine-induced expression could be prevented by BD1063, a -1 receptor antagonist. The ability of cocaine to stimulate fra-2 expression through a -1-mediated mechanism most likely involves the activation of intracellular calcium as an intervening step. Receptor agonists have
been reported to increase intracellular calcium, which can be prevented by -1 receptor antagonists (Su and Hayashi, 2001). Since calcium can activate the expression of Fra-2, it is conceivable that the agonist actions of cocaine result in elevations in intracellular calcium and subsequent activation of Fra-2.
The cocaine-induced up-regulation of fra-2 is robust enough to be detected when the entire brain is evaluated, with the up-regulation of fra-2 occurring within minutes of stimulation and persisting for at least 80 min. The onset of fra-2 up-regulation by cocaine precedes the up-regulation of -1 receptor gene expression, suggesting that the -1 receptor gene may be a target for fra-2. Since the promoter of the -1 receptor gene contains an AP-1 sequence to which Fra-2 may bind to activate transcription (Seth et al., 1997), the interaction between fra-2 and -1 receptor genes could start a cascade of further changes with enduring effects on central nervous system function. Similar to that proposed for other IEGs (Goelet et al., 1986; Morgan and Curran, 1989; Sheng et al., 1990; He and Rosenfeld, 1991), this interaction could thus serve as a bridge between the acute effects of cocaine and the long-lasting changes that result after cocaine exposure.
The regional analysis of fra-2 and -1 receptor gene expression after cocaine administration further supports the relevance of this interaction for the cellular basis of drug abuse. Fra-2 and -1 receptor gene expression were found to be up-regulated by cocaine in the striatum and cortex, which contain the terminal fields of dopaminergic neurons that are involved in the neural circuit for reward (Mazei et al., 2002; Porrino et al., 2002). The striatal tissue used in the present study included both the nucleus accumbens in the ventral striatum with its considerable role in reward (Panikkar, 1999; Lu et al., 2003; Sellings and Clarke, 2003), and the dorsal striatum with its established role in locomotor effects (Panikkar, 1999; Lu et al., 2003; Sellings and Clarke, 2003). Similar to when whole brain was analyzed, the up-regulation of fra-2 by cocaine preceded the up-regulation of -1 receptor gene expression in both of these brain regions. In contrast, there was no change in fra-2 or -1 receptor gene expression in the cerebellum, a brain region that is rich in -1 receptors but does not have an established role in drug abuse (Bouchard and Quirion, 1997). This pattern of regional expression of fra-2 and -1 receptor genes in response to cocaine administration suggests that the changes are related to the addictive effects of cocaine and not simply a generalized response to -1 receptor activation.
The gene expression pattern in the hippocampus in response to cocaine also deserves comment. In the hippocampus, cocaine up-regulated fra-2, but not -1 receptor, gene expression. The hippocampus has a well established role in learning and memory (Nestler, 2002) that could have important implications for an animal's ability to learn the association between the administration of cocaine and its related environmental cues and rewarding effects. The up-regulation of fra-2 is expected to alter the transcription of other genes that are involved in this learning process. Since -1 receptors have been implicated in learning and memory processes in previous studies (Maurice et al., 2001), it is possible that the expression of the -1 receptor gene may be up-regulated but with a long delay (>80 min). It is even more likely that after acute cocaine administration, other genes, such as glutamate receptors that have an established role in learning and memory (Nestler, 2002) may serve as targets for fra-2 in the hippocampus.
Time-dependent increases in the expression of Fra-2 and -1 receptor proteins were also observed after cocaine administration. The changes in protein levels followed the changes seen in mRNA, suggesting that the cocaine-induced alterations in gene expression were being translated into protein. Similar to the pattern seen in gene expression, cocaine caused an earlier upregulation of Fra-2 protein levels in half brain, striatum, cortex, and hippocampus, which was followed by a later up-regulation of -1 receptor protein levels in half brain, striatum, and cortex. This temporal and regional pattern of cocaine-induced protein expression was significantly attenuated by the -1 receptor antagonist BD1063, suggesting that some of the behavioral protective effects of -1 receptor antagonists involve modulation of IEG-induced transcriptional cascades.
In summary, cocaine produces many behavioral changes that can be prevented by -1 receptor antagonists (Matsumoto et al., 2001, 2002; Maurice et al., 2002). Cocaine also induces the expression of numerous IEGs (Rosen et al., 1994; Zhang et al., 2002) that can trigger many long-term alterations in brain function. The present data demonstrate that fra-2 is one of these early genes that can be stimulated by cocaine and that it seems to activate the transcription of the -1 receptor gene. These transcriptional changes seem to be translated to protein as seen by the delayed increases in Fra-2 and -1 receptor protein levels after cocaine administration. The interaction between cocaine, fra-2, and -1 receptor gene and protein expression involves brain regions that are established components of the neural circuit for reward. Together, the data suggest a novel mechanism involved in the cellular basis for addiction. Further studies are needed to determine whether these correlational changes reflect causative relationships.
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Acknowledgements |
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-1 receptor antibody for preliminary studies. |
Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: RT-PCR, reverse transcription-polymerase chain reaction; IEG, immediate early gene; BD1063, 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine; fra-2, fos-related antigen 2; E-5842, 4-[4-fluorophenyl]-1,2,3,6-tetra-hydo-1-[4-[1,–2,4-triazol-1-il]butyl]pyridine citrate; AP-1, activator prtoein-1; PCR, polymerase chain reaction.
Address correspondence to: Dr. Rae R. Matsumoto, University of Mississippi, Department of Pharmacology, 303 Faser Hall, University, MS 38677. E-mail: rmatsumo{at}olemiss.edu
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G. Cormaci, T. Mori, T. Hayashi, and T.-P. Su Protein Kinase A Activation Down-Regulates, Whereas Extracellular Signal-Regulated Kinase Activation Up-Regulates {sigma}-1 Receptors in B-104 Cells: Implication for Neuroplasticity J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 202 - 210. [Abstract] [Full Text] [PDF]
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 F. Fumagalli, F. Bedogni, A. Frasca, L. Di Pasquale, G. Racagni, and M. A. Riva Corticostriatal Up-Regulation of Activity-Regulated Cytoskeletal-Associated Protein Expression after Repeated Exposure to Cocaine Mol. Pharmacol., November 1, 2006; 70(5): 1726 - 1734. [Abstract] [Full Text] [PDF]
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