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. Author manuscript; available in PMC: 2011 Jun 22.
Published in final edited form as: J Neurochem. 2008 Jan 21;104(6):1440–1449. doi: 10.1111/j.1471-4159.2008.05240.x

Regulation of Psychostimulant-induced Signaling and Gene Expression in the Striatum

Jacqueline F McGinty 1, Xiangdang D Shi 1, Marek Schwendt 1, Alicia Saylor 1, Shigenobu Toda 1
PMCID: PMC3120109  NIHMSID: NIHMS294439  PMID: 18221378

Abstract

Amphetamine and cocaine are indirect dopamine agonists that activate multiple signaling cascades in the striatum. Each cascade has a different subcellular location and duration of action that depend on the strength of the drug stimulus. In addition to activating D1 dopamine-Gs-coupled-protein kinase A signaling, acute psychostimulant administration activates extracellular-regulated kinase transiently in striatal cells; conversely, inhibition of extracellular-regulated kinase phosphorylation decreases the ability of psychostimulants to elevate locomotor behavior and opioid peptide gene expression. Moreover, a drug challenge in rats with a drug history augments and prolongs striatal extracellular-regulated kinase phosphorylation, possibly contributing to behavioral sensitization. In contrast, amphetamine activates phosphoinositide-3 kinase substrates, like protein kinase B/Akt, only in the nuclei of striatal cells but this transient increase induced by amphetamine is followed by a delayed decrease in protein kinase B/Akt phosphorylation whether or not the rats have a drug history, suggesting that the phosphoinositide-3 kinase pathway is not essential for amphetamine-induced behavioral sensitization. Chronic amphetamine or cocaine also alters the regulation of inhibitory G-protein-coupled receptors in the striatum, as evident by a prolonged decrease in the level of regulator of G protein signaling 4 after non-contingent or contingent (self-administered) drug exposure. This decrease is exacerbated in behaviorally-sensitized rats and reversed by re-exposure to a cocaine-paired environment. A decrease in regulator of G protein signaling 4 levels may weaken its interactions with metabotropic glutamate receptor 5, Gαq, and phospholipase C β that may enhance drug-induced signaling. Alteration of these protein-protein interactions suggests that the striatum responds to psychostimulants with a complex molecular repertoire that both modulates psychomotor effects and leads to longterm neuroadaptations.

Keywords: Akt/PKB, amphetamine, brain-derived neurotrophic factor, cocaine, dynorphin, enkephalin, ERK MAP kinase, striatum, opioid peptides, RGS4, PI3-kinase, SGK1

Psychostimulants Alter Multiple Signaling Cascades in the Striatum

Psychostimulants causes behavioral activation and changes in gene/protein expression by stimulating dopamine release that triggers synaptic activity and intracellular signaling in striatal medium spiny neurons. At the cellular level, D1 dopamine-Gs-coupled-PKA signaling recruits multiple signaling cascades, such as the extracellular-regulated MAP kinase (ERK) and phosphoinositide-3 kinase (PI3-K) cascades, but the intracellular mechanisms involved in this crosstalk are unclear. For example, these kinase cascades are downstream from multiple G-protein-coupled receptors and neurotrophin (also called receptor tyrosine kinase) receptors expressed by medium spiny neurons (Freeman et al., 2003; McGinty, 2006). Ligands for these receptor classes are activated indirectly by psychostimulants (Wang and McGinty, 1998; Meredith et al., 2002; Le Foll et al., 2005), leading to complex interactions that may determine the signaling profile of medium spiny neurons after acute and repeated exposure to stimulants. Further, cocaine and amphetamine (AMPH) may alter the functioning of inhibitory G-protein-coupled receptors, as suggested by prolonged changes in the level of Regulator of G-protein Signaling (RGS) 4, in response to acute and chronic drug exposure. A decrease in RGS4 may alter its interactions with multiple, Gαq, and Gαi-coupled receptors that contribute to enhanced stimulant-induced signaling in behaviorally-sensitized rats. This review focuses on the less well-known changes in ERK, PI3-K, and RGS4 induced by acute and chronic AMPH and cocaine and the potential consequences of altering their interactions in the striatum.

Psychostimulants stimulate ERK/MAP kinase signaling

The ERK MAPK pathway, including ERK1 (44 KDa) and ERK 2 (42 KDa), is a complex intracellular signaling cascade that is activated by phosphorylation and regulates various neurobiological adaptations thought to be involved in drug addiction (Berhow et al., 1996; Mazzucchelli et al., 2002; Zhai et al., 2007). Although acute AMPH and cocaine transiently and modestly increase ERK phosphorylation (Valjent et al., 2000; Shi and McGinty, 2006), studies differ about whether inhibition of ERK activation blocks acute AMPH and cocaine-induced behavior despite inhibition of downstream neurochemical effects. For example, systemic and intra-striatal infusion of the selective MEK inhibitors, SL327 or U0126, respectively, significantly attenuated acute AMPH-induced hyperlocomotion, vertical activity, as well as blocked opioid [preproenkephalin (PPE) and preprodynorphiin (PPD)] gene expression in rats (Figure 1A–D; Shi and McGinty 2006). In contrast, another study found that SL327 did not affect acute AMPH-induced locomotion in mice (Ferguson et al., 2006) although it attenuated AMPH-induced c-fos expression in srtiatopallidal neurons (Ferguson and Robinson, 2004). However, Valjent and colleagues (2000) showed that SL327 partially inhibited acute cocaine-induced locomotion in mice. The site of action of MEK inhibition after systemic injection in rats is not likely the ventral tegmental area (VTA) because Pierce and colleagues (1999) showed that intra-VTA infusions of a different MEK inhibitor, PD90859, did not decrease acute cocaine-induced locomotion. Thus, depending on the type and dose of MEK inhibitor and its site of action, ERK is differentially activated by acute cocaine or AMPH. In contrast, there is more widespread agreement about ERK involvement in stimulant-induced behavioral sensitization because MEK inhibition decreased the development and the expression of cocaine or AMPH-induced behavioral sensitization consistently in both mice and rats (Pierce et al., 1999; Valjent et al., 2005; Ferguson et al., 2006).

Figure 1.

Figure 1

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ERK inhibition suppresses acute AMPH-induced behavioral activity and opioid gene expression in the striatum and repeated AMPH alters the phosphorylation of ERK MAP kinase and CREB. (A) U0126 attenuates AMPH-induced total distance traveled. (B) U0126 attenuates AMPH-induced vertical activity. *p<0.001 vs. DMSO/Saline; # P< 0.01, ## P<0.001 vs. DMSO/AMPH group. (C) U0126 blocks AMPH-induced PPE mRNA induction. (D) U0126 blocks AMPH-induced PPD mRNA induction. *p<0.05, **P<0.01 vs. DMSO/Saline; #P<0.05 vs. DMSO/AMPH. (E) Striatal phospho-ERK1/2 and phospho-CREB immunoreactivity was increased 15 min (E, F) and 2 h (G, H) after amphetamine sensitization. Insets above graphs: representative western blots for striatal phospho-protein (top) and total protein (bottom) levels from the striatum of saline- or AMPH-pretreated rats after challenge injection of AMPH. Bar graphs represent the mean ± S.E.M. integrated density ratio (n=6–8 samples/group from three independent determinations). *p<0.05 and ***p<0.001 as compared to respective control group. #p<0.05 as compared to SAL + AMPH group. *p<0.05 as compared with SAL + SAL group. (A–D modified from Shi and McGinty, 2006 with permission; E–H modified from Shi and McGinty, 2007 with permission).

Because D1 receptors are positively coupled to adenylate cyclase, it had been assumed in the early 1990s that the cAMP/PKA cascade was sufficient for calcium and cAMP response element (CaCRE)-mediated gene expression subsequent to CREB phosphorylation by dopaminergic agonists. However, it is known now that CREB is a common phosphorylation target of many kinases, including the ERK MAPK signaling cascade, which is activated by cooperative interactions between dopamine and glutamate receptors (Girault et al., 2007). In AMPH-pretreated rats, 15 min or 2 hr after an AMPH challenge (1 mg/kg, i.p.), phospho-ERK and phospho-CREB levels were significantly greater than in saline-pretreated rats whereas two hours after an AMPH challenge in saline-pretreated rats, phospho-ERK immunoreactivity and phospho-CREB had returned to normal levels (Figure 1E–H-Shi and McGinty, 2007). Thus, signaling from ERK to CREB is positively correlated with and may contribute to behavioral sensitization.

After activation, ERK1/2 proteins are translocated to the nucleus, resulting in phosphorylation and activation of transcription factors such as CREB and Elk-1 in medium spiny neurons (Choe et al. 2002; Valjent et al., 2000, 2005; Zhang et al. 2004). These nuclear events initiate cell-specific gene expression programs necessary for synaptic remodeling and long-term changes in synaptic efficacy (Mazzucchelli et al., 2002). These events are prevented by blocking both D1 dopamine and NMDA receptors as well as by inhibiting ERK phosphorylation (Valjent et al., 2000; 2005). Thus, the evidence suggests that ERK activation by dopamine and glutamate neurotransmission induces rapid phosphorylation of transcription factors, like CREB and Elk1, that regulate striatal gene expression and the behavioral responses to repeated psychostimulant administration.

Psychostimulants stimulate phosphoinositide 3-kinase signaling

Similar to the rapid effects of AMPH on phospho-ERK and phospho-CREB described above, phospho-Akt was transiently elevated 15 min after acute AMPH and augmented after AMPH challenge in sensitized rats (Figure 2A and B-Shi and McGinty, 2007). Further studies in our laboratory have demonstrated that PI3-K activity (but not its protein level) and phospho-Akt1 were increased in the nuclei of striatal cells 15 min after acute AMPH when levels of the phosphoinositide phosphatase, PTEN and phospho-PTEN were decreased (Toda and McGinty, submitted; Figure 2C and D). However, 2 hr after an AMPH challenge when prolonged augmentation of phospho-ERK and phospho-CREB was observed, phospho-Akt was significantly below saline values to the same extent whether or not the rats had an AMPH history (Figure 2A and B-Shi and McGinty, 2007). Similarly, Beaulieu and colleagues (2004) reported that Akt1 phosphorylation was decreased 60–90 min after acute AMPH in mice, suggesting that Akt1 inactivation is a late biochemical response to dopamine receptor stimulation. (However, these investigators did not investigate changes in Akt1 phosphorylation in striatal lysates earlier than 30 min.) The “rapid” Akt1 activation in rats is mediated by D1 receptors (Shi and McGinty, in preparation) whereas the “late” Akt1 de-activation in mice is mediated by D2 receptors that stimulate an Akt1-β-arrestin-PP2A inactivation complex (Beaulieu et al., 2005).

Figure 2.

Figure 2

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AMPH-induced changes in striatal PI3-K signaling. (A) Striatal phospho-Akt immunoreactivity in whole cell lysates was increased more in AMPH-sensitized rats than in rats with no AMPH history 15 min after AMPH challenge. (B) Striatal phospho-Akt immunoreactivity in whole cell lysates was decreased below saline values equally in AMPH-sensitized rats and in rats with no AMPH history 2 h after AMPH challenge. Insets above graphs: representative western blots for striatal phospho-protein and total protein immunoreactivity. Integrated density ratio (n=6–8 samples/group from three independent determinations). *p<0.05 and ***p<0.001 as compared to respective control group. #p<0.05 as compared to SAL + AMPH group. *p<0.05 as compared with SAL + SAL group. (A and B modified from Shi and McGinty, 2007 with permission). (C) Alterations in the level of phospho-Akt, Akt, phospho-SGK and SGK in striatal nuclear fractions after acute AMPH. Fifteen min after AMPH, phospho-Akt and Akt were increased whereas phospho-SGK was decreased; 30 min after AMPH, Akt and SGK were increased in striatal nuclei; no changes were detected at 60 min. Insets above graphs: representative western blots for striatal phospho-protein and total protein immunoreactivity. Bar graphs represent the mean ± S.E.M. (D) Schematic illustrating the major changes in the rapid nuclear PI3-K pathway 15 and 30 min after acute AMPH treatment.

A surprising finding 1 hr, but not 3 hr, after acute AMPH identified as a result of cDNA array analysis was the transient upregulation of the mRNA encoding for Serum and Glucocorticoid-regulated Kinase, SGK1 (Gonzalez-Nicolini and McGinty 2002). SGKs are members of the cAMP dependent, cGMP dependent, and protein kinase C serine-threonine kinase superfamily that includes Akt1/PKB (Firestone et al. 2003). Both SGK1 and Akt1 are substrates of the PI3-K cascade that requires PtdIns (3,4,5) P3 and PDK1 activation and is regulated by the phosphoinositide phosphatase, PTEN (Kobayashi and Cohen 1999; Sheid et al 2005; Yamada and Araki 2001). Further studies in our laboratory have demonstrated that AMPH causes a transient increase in total SGK1 in the nuclei of striatal neurons (Toda and McGinty, submitted; Figure 2C and D). Furthermore, when the phosphorylation of Akt1 was increased in striatal nuclei 15 min after AMPH, SGK was actively dephosphorylated, suggesting preferential and transient activation of nuclear Akt and simultaneous inactivation of nuclear SGK followed by increased synthesis (Gonzalez-Nicolini and McGinty, 2002) after acute AMPH stimulation.

SGK1 is distinct from PKB/Akt in that it is an immediate early gene controlled by stimulus dependent-transcriptional activity and it lacks a PH domain that binds to PI-3,4,5-P3 (Webster et al. 1993a,b; Park et al. 1999). The SGK1 promoter has functionally active glucocorticoid and MeCP2 response elements and several other putative DNA binding sites including a cyclase response element, Sp-1, and AP-1 elements (Firestone et al., 2003; Nuber et al., 2005; Tessier and Woodgett, 2006). Recently, functional specificity of multiple SGK1 isoforms has been identified; long forms (49 and 47 kDa) are localized preferentially to the endoplasmic reticulum membrane where they are quickly ubiquitinated whereas shorter forms (42 and 45 kDa) are located in the cytoplasm and nucleus and have longer half-lives (Arteaga et al., 2007). Upon stimulation, SGK1 (presumably the short forms) and Akt1 translocate to the nucleus and promote cell survival (Buse et al. 1999; Park et al 1999). Both Akt1 and PDK1 have nuclear export sites but SGK1 has a nuclear import site regulated by importin-α (Firestone et al 2003; Saji et al 2005; Scheid et al 2005). Different stimuli induce tissue-specific patterns of nucleocytoplasmic shuttling of these and other proteins that represent an additional level of signal regulation (Firestone et al. 2003). Both phosphorylation and nuclear translocation of SGK can be blocked by the PI3-K inhibitors, wortmannin or LY294002, in non-neuronal cells (Park et al. 1999) but this has not been demonstrated in neurons in vivo. Further, glucocorticoids and hyperosmotic stress cause SGK1 retention in the nuclei of non-neuronal cells (Buse et al. 1999).

The physiological targets and neurobiological functions of SGKs overlap but also are distinct from Akt1 (Sakada et al., 2003). SGK1 and Akt1 can phosphorylate cyclase response element binding protein (Du and Montminy, 1998; David and Kalb, 2005) and they share several negatively regulated targets, like the FoxO subfamily of forkhead transcription factors and glycogen synthase kinase 3 but different phosphorylation sites may be preferred by each enzyme (Brunet et al., 2001; Kobayashi and Cohen, 1999).

Crosstalk between the PI3-K and the ERK pathways may depend on the type and strength of stimulation. Perkinton et al (2002) demonstrated in striatal cultures that PI3-K inhibitors blocked NMDA-induced phospho-ERK but MEK inhibitors did not block NMDA-induced phospho-Akt1, suggesting that PI3-K is upstream of ERK. However, both MEK and PI3-K inhibitors blocked glutamate-induced CREB phosphorylation. Further, PI3-K inhibitors did not block the BDNF-stimulated increase in phospho-ERK, indicating independence of the ERK and PI3-K pathways after neurotrophin stimulation. In contrast, Brami-Cherrier et al (2002) demonstrated that D1 agonist-induced phospho-Akt1 is insensitive to PI3-K inhibition but is inhibited by the selective MEK inhibitor, U0126, in striatal cultures. Because there is a calmodulin binding site in PI3-K, another proposal is that NMDA-mediated calcium signaling to CAMK II is upstream of PI3-K (Wang et al. 2004). Recently, a family of GTPases that are PI3-K enhancers (PIKEs) has been discovered and shown to activate PI3-K and stimulate the phosphorylation of Akt1 (Ye et al. 2000; Ahn et al 2004). The long form of PIKE (PIKE-L) binds to Homer and couples mGluR1/5 to PI3-K (Guhan and Lu 2004; Rong et al. 2003). However, the ability of PIKE isoforms to enhance PI3-K activity in the nuclei and/or cytoplasm of neurons in vivo has not yet been demonstrated.

Functionally, PI3-K activity is required for the expression of long term potentiation via insertion of AMPA receptors into the postsynaptic membranes of hippocampal neurons (Man et al 2003; Sanna et al 2002). Similarly, Wolf and colleagues (reviewed in 2004) have demonstrated that AMPA receptor insertion into the plasma membranes of nucleus accumbens neurons is required for stimulant-induced behavioral sensitization but the role of PI3-kinase in this event is unknown. Evidence in support of the importance of PI3-K signaling to psychostimulant-induced actions was reported by Izzo et al. (2002) who demonstrated that icv infusion of LY294002 inhibited the expression, but not the induction or maintenance, of cocaine-induced behavioral sensitization. Furthermore, Zhang and colleagues (2006) demonstrated that a cocaine challenge selectively increases PI3-K activity in the accumbens shell in cocaine-sensitized rats. These studies suggest that phosphoinositide signaling are possible triggers neuroadaptations in response to psychostimulant exposure, reinforcing the importance of investigating their functional significance after both acute and repeated stimulant administration.

Psychostimulants alter striatal G-protein signaling by RGS4

Gene expression of many Regulators of G-protein Signaling (RGS) proteins in the brain is altered rapidly by various stimuli including stress and glucocorticoids (Ni et al. 1999), electroconvulsive seizures (Ingi et al. 1999; Gold et al. 2002), opioids (Gold et al. 2003), and psychostimulants (Burchett et al. 1998; 1999; Bishop et al. 2002). RGS proteins are GTPase-activating proteins that increase the rate of GTP hydrolysis of Gαi or Gαq subunits thereby desensitizing receptor-mediated responses (Wieland and Chen 1999; Neubig and Siderovski, 2002). Studies from our laboratory have demonstrated that acute or repeated treatment with AMPH or cocaine downregulates gene and protein expression of RGS4 in the prefrontal cortex and dorsal striatum (Gonzalez-Nicolini and McGinty 2002; Schwendt et al 2006a; Schwendt et al., 2007a,b), thereby potentially modulating GPCR signaling. This unusual regulation (a psychostimulant-driven decrease in gene expression) may be explained through the influence of D1 and D2 receptors on RGS4 gene expression. Either pharmacological blockade of D1 receptors or stimulation of D2 receptors increases RGS4 gene expression in the striatum (Guerts et al. 2002; Schwendt et al. 2006a; Taymans et al. 2003). Because D1 and D2 receptors regulate RGS4 gene expression in opposite directions, it may not be surprising that several authors failed to find any change in RGS4 gene expression in the striatum after acute treatment with AMPH that indirectly stimulates both D1 and D2 classes of dopamine receptors (Burchett et al. 1998; 1999; Bishop et al. 2002; Taymans et al. 2003). In each of these studies, high doses of AMPH (≥7.5 mg/kg) were used whereas we have demonstrated that there is an inverse dose-response curve that, at higher doses, masks a downregulation of striatal RGS4 mRNA found 1–6 hours after a single dose (2.5 or 5 mg/kg) of AMPH by cDNA array and in situ hybridization analysis (Gonzalez-Nicolini and McGinty 2002; Schwendt et al. 2006a).

Surprisingly, three weeks after 5 daily AMPH (5 mg/kg, i.p.) injections, RGS4 mRNA and protein levels were still depressed in the striatum (Schwendt and McGinty, 2007a; Figure 3A, B). Similarly, two weeks after 10 days of cocaine self administration, RGS4 mRNA in the striatum was still depressed (Schwendt et al., 2007b-Fig 3C). Surprisingly, an AMPH challenge (1 mg/kg, i.p.) in rats behaviorally-sensitized to AMPH further suppressed RGS4 expression in the striatum (Figure 3A, B), but re-exposure to a cocaine-paired environment normalized striatal RGS4 mRNA (Figure 3C). This prolonged RGS4 decrease during abstinence from psychostimulant exposure may reflect augmented Gαi- and/or Gαq-coupled signaling in sensitized animals. In agreement, while behavioral sensitization to cocaine is not associated with changes in protein levels of four major G-proteins (Perrine et al. 2005), Gαi-protein activity is augmented in sensitized animals in a receptor-specific manner (Schroeder et al., 2004). However, better understanding of the detailed role of RGS4 in regulating reinforcing and stimulating effects of psychostimulants depends on identifying its receptor specificity and cellular functions.

Figure 3.

Figure 3

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Repeated AMPH causes a prolonged suppression of RGS4 mRNA (A) and protein (B) in the striatum and an AMPH challenge 3 weeks after AMPH pretreatment suppresses RGS4 expression further. (C) Re-exposure to cocaine-paired context reversed the decrease of RGS4 mRNA produced by repeated cocaine. Quantitative analysis of RGS4 mRNA in the dorsolateral striatum, dlSTR after cocaine self-administration and 14 d of drug-free abstinence in an alternative environment (−ALT groups) followed by re-exposure to the cocaine-associated environment with (−LA) or without (−NL) levers available for 1 h. Bar graphs represent the percent change in RGS4 mRNA levels when compared to control (SAL, saline) group. **p < 0.01 COC-ALT vs. SAL-ALT group; # p<0.05, ## p<0.01 COC-LA, COC-NL vs. COC-ALT (means ± SEM, n=5). INSETS: Representative grayscale images of RGS4 mRNA brain distribution in selected treatment groups. Schematized coronal brain sections illustrate areas where RGS4 mRNA was quantified. A, B modified from Schwendt and McGinty, 2007a with permission; C modified from Schwendt and McGinty, 2007b with permission.

RGS4 regulates the signaling of several Gαi- and Gαq-coupled receptors, such as metabotropic glutamate receptors (Saugstad et al. 1998), opioid receptors (Xie et al 2005; Georgoussi et al. 2005), and 5-HT1a receptors (Ghavami et al. 2004, Gu et al. 2007) but not dopamine D2 receptors (Ghavami et al. 2004). Recently, we demonstrated that RGS4 co-immunoprecipitates with mGluR5, phospholipase Cβ, and Gαq in rat dorsal striatum (Schwendt and McGinty, 2007a). Downstream from plasma membrane receptors, RGS4 can inhibit MAPKs linked to the activation of Gαi- and Gαq-coupled receptors (Yan et al., 1997). Heterologous expression of RGS4 in neuronal cell lines attenuates both activation of ERK and Akt by Gαi-coupled receptors (Leone et al., 2000). Moreover, preliminary data from our laboratory indicate that overexpression of RGS4 in rat dorsal striatum suppresses AMPH-induced activation of ERK MAPK, suggesting the potential of RGS4-ERK interactions in vivo (Schwendt et al., 2006b). Further investigations will determine whether a diminished inhibitory influence of RGS4 is related to the augmented ERK activation in the dorsal striatum in animals sensitized to AMPH (Shi and McGinty, 2007).

BDNF regulates striatal signaling

Acute injection of cocaine or methamphetamine increases BDNF mRNA in the cerebral cortex (Le Foll et al. 2005) and our data indicate that acute AMPH increases BDNF mRNA in the cingulate cortex (Saylor and McGinty, submitted). However, Meredith et al (2002) reported that repeated, but not acute, AMPH increases BDNF immunoreactivity in the striatum. The normal striatum contains little BDNF mRNA; instead it receives extensive projections from the substantia nigra and cortical pyramidal neurons that synthesize BDNF and transport the protein anterogradely to be released in an action potential and calcium-dependent manner (Sauer et al 1994; Seroogy et al 1994; Altar et al 1997; Conner et al 1997; Altar and DiStefano 1998). The biological effects of BDNF are primarily mediated by its tyrosine kinase receptor, TrkB (Chao 2003), which is abundantly expressed in cortical pyramidal neurons, ventral midbrain dopamine neurons and GABAergic striatal medium spiny neurons (Numan and Seroogy 1999; Freeman et al 2003). BDNF/TrkB signaling is critical for activity-dependent synaptic plasticity, the cellular basis of learning and memory, and the neuroadaptations underlying drug seeking (Lu 2003; Poo 2001; Rattiner et al 2004; Barco et al 2005; Ou and Gean 2006).

Interactions between the BDNF/TrkB and the dopamine D1/D3 signaling systems have been implied. Like psychostimuants, BDNF directly stimulates opioid peptide gene expression, as exogenous BDNF infused into the striatum (Sauer et al 1994) or substantia nigra (Arenas et al 1996) increases the expression of striatal opioid peptides. In contrast, there is a profound lowering of opioid gene expression in medium spiny neurons in D1 receptor homozygous or BDNF heterozygous mice (Xu et al., 1994; Saylor et al 2006). Interestingly, BDNF positively regulates the expression of both D3 and D1 receptors (Guillin et al., 2001; Do et al., 2007).

Based on these data, we have investigated whether a partial BDNF gene deletion would interfere with the ability of AMPH to increase opioid peptide expression (Saylor and McGinty, submitted). In fact, while basal PPD mRNA levels are less in BDNF+/− mice than in WT mice, a single injection of 5 mg/kg, i.p. AMPH increased PPD mRNA levels proportionally more in the BDNF+/− mice (315%) than in WT mice (210%). In contrast, an AMPH-induced increase of BDNF mRNA occurred in the cingulate cortex of the WT mice only. Thus, although TrkB receptors and G-protein coupled receptors both regulate opioid peptide transcription, the effects of AMPH on opioid peptide expression may be independent of TrkB receptor stimulation in this model.

Summary

In summary, AMPH stimulates G-protein coupled receptors and neurotrophins that activate PKA, MAPK, and PI3-K pathways in medium spiny neurons as a result of a cascade of events indirectly triggered by dopamine release. Future studies will investigate the regulation of G-protein coupled receptors, TrkB receptors, and the functional significance of kinase cascade interactions after psychostimulant exposure (Figure 4).

Figure 4.

Figure 4

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Schematic illustrating that AMPH indirectly stimulates dopamine (DA), glutamate (glu) and BDNF (B) release and stimulation of D1 dopamine, glutamate, and TrkB receptors, respectively, in the striatum. As a result, AMPH activates the major kinase pathways in medium spiny neurons: PKA, MAPK, and PI3-K, as a result of a cascade of events indirectly triggered by dopamine release. Whether or not AMPH stimulates interactions between G-protein coupled receptors and TrkB that contribute to PI3-K and ERK activation of striatal genes is still under investigation. Further, evidence for a nuclear PI3-K signaling pathway rapidly activated by AMPH is proposed. Finally, because acute and repeated AMPH downregulates RGS4, the amplitude and duration of action of a subset of Gi/Go/Gαq-coupled receptors may be upregulated and extended in the striatum. AC=adenylate cyclase, DAT=dopamine transporter, MSK=mitogen-stimulated kinase, PKA=protein kinase A, PLCγ=phospholipase C gamma, RSK=ribosomal S6 kinase.

Acknowledgments

These studies were supported by RO1 DA03982, P50 DA015369, and T32DA07288.

Abbreviations used

AMPH

amphetamine

BDNF

brain-derived neurotrophic factor

CREB

cyclase response element binding protein

ERK

extracellular signal-regulated kinase

MAPK

mitogen-activated protein kinase

MEK

mitogen-activated protein kinase kinase

PDK

PI3-kinase dependent kinase

PI3-K

phosphoinositide-3-kinase

PPD

preprodynorphin

PPE

preproenkephalin

PIKE

PI3-kinase enhancer

PIP

phosphoinositide phosphate

PTEN

phosphatase and tensin homolog

RGS

regulator of G-protein signaling

SGK

serum and glucocorticoid-regulated kinase

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