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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Pharmacopsychiatry. Author manuscript; available in PMC 2010 May 1.
Published in final edited form as:
PMCID: PMC2734446

Molecular Mechanisms of Psychostimulant-induced Structural Plasticity


Drug addiction is characterized by persistent behavioral and cellular plasticity throughout the brain's reward regions. Among the many neuroadaptations that occur following repeated drug administration are alterations in cell morphology including changes in dendritic spines. While this phenomenon has been well documented, the underlying molecular mechanisms are poorly understood. Here, within the context of drug abuse, we review and integrate several of the established pathways known to regulate synaptic remodeling, and discuss the contributions of neurotrophic and dopamine signaling in mediating this structural plasticity. Finally, we discuss how such upstream mechanisms could regulate actin dynamics, the common endpoint involved in structural remodeling in neurons.


Drug addiction is characterized by persistent behavioral and cellular plasticity throughout the brain's reward regions. During the transition from initial drug use to addiction, people experience tolerance and sensitization to varying aspects of drug action, reward dysfunction, escalation of drug intake, and, finally, compulsive use in the face of severely adverse physical or psychosocial consequences [24, 43, 46, 67, 82]. Although the neurobiological mechanisms driving addiction are not known with certainty, it is hypothesized that molecular and cellular changes occur during initial drug exposure, which then accumulate over time and, in vulnerable individuals, drive compulsive drug use. Several long-term molecular and cellular changes induced by drugs of abuse have already been shown throughout diverse neuronal populations within the brain reward circuit (An external file that holds a picture, illustration, etc.
Object name is nihms-126286-ig0001.jpg Fig. 1). Despite these advances, only a few studies have definitively linked a specific molecular change with structural and behavioral plasticity. A more detailed understanding of this relationship could lead to the development of more effective treatments that target specific behavioral features of addiction by reversing the drug-induced restructuring of neurons.

Fig. 1
Neuronal subtypes in the neural circuitry underlying addiction. Projections of VTA dopamine neurons (shown in solid red lines) innervate directly NAc and mPFC neurons, as well as amygdala and hippocampal neurons (the latter projections are not shown in ...

Several molecular and cellular changes induced by drugs of abuse have been implicated in regulating drug-induced structural plasticity and behavioral responses to cocaine [67, 68, 84]. These include changes in protein kinase A (PKA), cyclin-dependent kinase 5 (Cdk5), and protein kinase B (also known as Akt) as well as downstream transcription factors such as ΔFosB, nuclear factor kappa B (NFκB), and myocyte enhancing factor 2 (MEF2). Through the use of pharmacological antagonists and agonists, genetic mutant mice, and viral gene transfer, each of these molecules has been shown to mediate structural plasticity in several brain regions, including the reward circuitry. However, the direct relationship between synaptic alterations and addictive behaviors remains much more complex.

In this review, we discuss new advances in our understanding of the molecular mechanisms of structural plasticity in psychostimulant addiction. Additionally, recent work indicates the need to reevaluate the hypothesis that psychostimulant-induced increases in dendritic spines on brain reward neurons are necessary for behavioral sensitization after repeated exposure to drugs of abuse. Based on these published studies, we will propose new areas of research that warrant further investigation.

Psychostimulants and structural plasticity of brain reward circuitry

The brain's reward circuit evolved to direct one's resources to obtain natural reward, such as food, sex, and social interaction, but this system can be corrupted or hijacked by drugs of abuse. Within this circuit, drug-induced plasticity has been shown to involve altered dendrite branching or arborization as well as changes in the density or morphology of dendritic spines. A large literature, over the past decade, has characterized the effects of long-term psychostimulant administration on structural plasticity of brain reward regions. Most of these studies are correlative, and associate structural changes in specific brain regions with a behavioral phenotype (for review see [82]) As depicted in An external file that holds a picture, illustration, etc.
Object name is nihms-126286-ig0002.jpg Table 1, psychostimulants such as amphetamine and cocaine have been shown to increase dendritic spines and neurite complexity in NAc (nucleus accumbens) medium spiny neurons, VTA (ventral tegmental area) dopaminergic neurons, and PFC (prefrontal cortex) pyramidal neurons [51, 71, 79-81, 88].

Table 1
This table describes the morphological changes, which occur in a number of different neuronal cell types in the brain's reward circuitry following chronic exposure to psychostimulants.7

Neurotrophic factor signaling and psychostimulant-induced structural plasticity

Changes in levels of BDNF (brain derived neurotrophic factor) protein and mRNA have been examined in multiple brain regions following administration of many classes of addictive substances. Psychostimulants produce a widespread, but transient, induction of BDNF protein in the NAc, PFC, VTA, and central (CeA) and basolateral [111] nuclei of the amygdala [31, 32, 50]. Both contingent and non-contingent (i.e., animals yoked to self-administering animals) cocaine administration causes transient yet significant elevation of BDNF protein in the NAc [31, 53, 117]. While the increase in BDNF during cocaine administration appears to be dynamic in nature, there is a more stable and long-term induction of BDNF protein in the NAc, VTA, and amygdala [32, 75] following prolonged withdrawal from cocaine, and there is evidence that epigenetic regulation at the bdnf gene may be involved in mediating this persistent induction [49]. Interestingly, BDNF application has been shown to increase spine density and induce plasticity through some of the same signaling pathways that are activated by drug exposure, providing a possible mechanism for both induction and maintenance of structural and functional changes described with psychostimulants [2, 12, 42, 107].

Several proteins in neurotrophin signaling cascades are regulated within the mesolimbic dopamine system by drugs of abuse; these include drug effects on IRS (insulin receptor substrate) 1 & 2, PI3K (phosphatidylinositol-3-kinase), Akt, PLCγ (phospholipase Cγ), the Ras–ERK (extracellular signal regulated kinase) pathway, and NFκB signaling (An external file that holds a picture, illustration, etc.
Object name is nihms-126286-ig0005.jpg Fig. 2). Psychostimulants dramatically increase ERK phosphorylation in numerous brain regions, including the NAc, VTA, and PFC, following acute or chronic drug administration [41, 63, 73, 91, 92, 96, 108, 109]. These findings are consistent with stimulant-induced increases in neuronal branching and spine number, given Ras–ERK's established role in neurite outgrowth (discussed in more detail below). The effects of psychostimulants on the IRS–PI3K–Akt pathway are more complex, and inconsistencies in the literature are often accounted for by differences in the interval after drug administration and heterogeneity of the tissue sampled. For example, chronic cocaine increases PI3 K activity in the NAc shell, with decreases observed in the NAc core [118]. These data are in line with a previous report showing that chronic cocaine selectively increased BDNF mRNA levels in the NAc shell and decreased TrKB (tyrosine receptor kinase B) receptor mRNA in the NAc core [26]. Thus, shell and core differences in PI3 K activity could be explained by differential upstream regulation of BDNF and TrKB by cocaine. Interestingly, when a more general dissection of striatum is used (including NAc and CPu [caudate putamen]), it has been shown that amphetamine decreases Akt activity in synaptosome preparations [110, 111], and we have observed similar effects of chronic cocaine in the NAc without distinguishing between core and shell [76]. Although the antibodies used here were not selective, it should be noted that given the predominance of the Akt1 versus Akt2 isoform in brain, these changes are likely to be specific to Akt1. Additionally, comparison among these studies is complicated by the time-course used to study Akt signaling changes, as recent work by McGinty and colleagues suggests that chronic amphetamine causes a transient and nuclear-specific change in Akt phosphorylation in striatum [59]. At early timepoints after amphetamine administration there is a nucleus-specific increase in Akt phosphorylation, however, after two hours Akt phosphorylation is decreased, suggesting a compensatory mechanism to turn off this activity. Although it is unclear whether adaptations in NAc Akt signaling are driving drug-induced structural plasticity, as we have shown in the case for the VTA77, understanding the patterns of psychostimulant induction of Akt signaling in distinct subregions of NAc, in combination with functional studies using viral vectors to manipulate Akt signaling directly, we can define with greater precision, the distinct molecular networks driving structural plasticity in NAc.

Fig. 2
Molecular pathways implicated in the structural changes that occur as a result of exposure to drugs of abuse. Transcription factors, such as NFκB, ΔFosB, CREB, and MEF2 play a role in regulating changes in dendritic spines, and can be ...

Alterations in the PLCγ and NFκB signaling pathways in drug abuse are not as well studied as ERK and Akt; however, recent work shows that both pathways are regulated by cocaine. Graham and colleagues [31] observed increased phosphorylation of PLCγ in the NAc following acute, chronic yoked, or chronic self-administered cocaine, an effect that was dependent on BDNF. Additionally, It is unknown whether this cocaine-induced regulation of PLCγ results in activation of NFκB; however, based on in vitro studies, there may be significant crosstalk between these pathways [52, 74]. An earlier study from our group showed that the NFκB subunits p105, p65, and IκB are increased in the NAc in response to chronic cocaine administration [4]. This is consistent with findings from Cadet and colleagues [5], who demonstrated that methamphetamine induces NFκB binding activity in striatal regions. We have more recently shown that chronic cocaine induces NFκB-dependent transcription in the nucleus accumbens of NFκB-LacZ transgenic mice. This induction of NFκB activity is accompanied by increased expression of several NFκB genes (p105, p65, and IKBβ), the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their transcriptional activation [85]. In addition, functional studies show that viral-mediated overexpression of a dominant negative form of I Kappa kinase, that serves as an antagonist of the NFκB pathway in the NAc, prevents the ability of chronic cocaine to increase the density of dendritic spines on NAc medium spiny neurons. Such inhibition of NFκB signaling also blunts sensitization to the rewarding effects of cocaine [85]. These data support a link between increased spine density and behavioral sensitization to cocaine. However, such a link is not supported by studies of other signaling molecules (e.g., Cdk5, see below), emphasizing the complexity of these phenomena and the need for further study.

Dopamine signaling and psychostimulant-induced structural plasticity

The release of dopamine and the subsequent activation of dopamine receptors lead to a cascade of intracellular events, which may play an important role in structural plasticity during exposure to psychostimulants. Dopamine receptors are generally classified into a D1-like or D2-like receptor family based on whether they are positively or negatively coupled to adenylyl cyclase activity [reviewed in 62] and are thought to be localized to largely distinct populations of neurons within the NAc and CPu [1, 29, 30, 99]. Receptors in the D1-like family (D1 and D5) are positively coupled to adenylyl cyclase through Gs/olf proteins and, upon stimulation, increase cytosolic levels of cyclic AMP (cAMP) and downstream activation of PKA [98]. Once active, PKA can influence numerous intracellular targets, including activation of dopamine- and cAMP-dependent phosphoprotein of 32 kDa (DARPP-32) [100], altered function and trafficking of glutamate receptors [34, 93], and activation of the transcription factor cAMP-responsive element binding protein (CREB) [68]. Dopamine D2-like receptors (D2, D3, and D4 receptors) are coupled to Gi/o proteins, which inhibit adenylyl cyclase [34, 95]. In contrast to D1-like receptors, activation of the D2 family of dopamine receptors can lead to activation of PLC generating diacylglycerol (DAG) and protein kinase C (PKC) activation, and subsequent IP3 activation and the mobilization of intracellular calcium stores [98]. D2 receptor activation also results in enhancement of potassium conductance [62] and, like D1 activation, can lead to changes in calcium channel properties, glutamatergic signaling, and regulation of the Ras-ERK cascade [33, 39].

In the NAc, intracellular signaling stimulated by D1 receptor activation has been implicated in behavioral and biochemical responses to drugs of abuse in part mediated through activation of CREB [13, 14, 70, 90, 106]. Given the large amount of data to suggest that CREB activity in the NAc regulates an individual's sensitivity to a broad range of emotional stimuli including the rewarding properties of drugs of abuse [6, 7, 15], one can imagine a role of CREB in mediating drug-induced structural plasticity. In one such study, Murphy and Segal [64] report that spine density changes are mediated through cAMP-PKA-CREB activation in cultured rat hippocampal neurons and, based on data showing that antisense knockdown of CREB regulated spines only at long-term time points, they suggest that the lasting effects may occur through repression of a CREB target. Evidence such as this implicates CREB and certain of its target genes in the structural plasticity that occurs in brain reward regions after drug administration. However, despite the wealth of information demonstrating CREB's role in learning and memory as well as in drug addiction, two fields in which changes in dendritic spine number and shape have been well documented, few studies have directly examined the role of CREB in synaptic remodeling.

The Ras-ERK pathway may also contribute to structural plasticity induced by psychostimulants in brain reward regions [19, 61]. As stated earlier, these drugs induce a transient but dramatic activation of ERK in numerous reward-associated brain regions after acute or chronic administration, with effects seen in the NAc, VTA, and PFC, [108, 109]. Studies performed in vitro suggest that ERK activation is critical for the formation, but not the stability, of new spine protrusions induced by temporally spaced K+-induced depolarizations [112], while blockade of ERK activation via inhibition of Ras signaling leads to a significant suppression of hippocampal spine number and length [86]. In line with the notion that ERK regulates the proliferation or induction of new spines, but not the stability of dendritic outgrowths, pharmacological inhibition of ERK in CA1 hippocampal neurons prevents BDNF-induced spine proliferation without causing a reduction in spine number. These observations suggest that ERK activation may be necessary for neurotrophic factors such as BDNF, or dopamine receptor activation, to induce plastic changes [2], although this remains to be demonstrated directly.

Additional signaling molecules, known to interact with dopamine receptors, may also be involved. D2-class dopamine receptors can function through an Akt-GSK-3 (glycogen synthase kinase 3) signaling cascade that has previously been implicated in morphological alterations such as changes in the size of VTA dopamine cell bodies following chronic exposure to opiate drugs of abuse [8, 83]. Beaulieu and colleagues (2005) have demonstrated that amphetamine alters the formation of signaling complexes containing the scaffolding protein β-arrestin2, and the negative regulator of Akt, PP2A (protein phosphatase 2A), ultimately leading to dephosphorylation and deactivation of Akt and subsequent activation of GSK-3. These molecular events then regulate dopamine activity and have been implicated in psychiatric diseases such as schizophrenia, bipolar disorder, and drug addiction [3, 9].

Consistent with the involvement of dopamine in these cellular and behavioral processes associated with addiction, it is not surprising that induction of dendritic spines after repeated treatment with psychostimulants occurs in both D1- and D2-expressing MSNs (medium spiny neurons) [49]. Interestingly, however, the long-term stability of new spines appears to be greater in D1 + compared to D2 + neurons. The persistence of increased dendritic spines in D1-containing MSNs correlates with the stable induction of ΔFosB [61]. through the D1/DARPP-32/PP1 signaling pathway [51, 116]. A member of the Fos family of genes, ΔFosB is a highly stable transcription factor that accumulates following drug administration in brains areas associated with rewarding aspects of drugs of abuse, including the NAc [40, 69]. Overexpression of ΔFosB increases the rewarding properties of several classes of drugs of abuse, including psychostimulants, while blockade of ΔFosB causes a reduction in drug reward [66, 68]. Given the considerable evidence for an obligatory role of ΔFosB in behavioral and molecular adaptations to drugs of abuse, investigation of how ΔFosB directly mediates dendritic plasticity is a high priority. Preliminary data from our laboratory has indeed found that overexpression of ΔFosB increases dendritic spine density in medium spiny neurons of the NAc.

Furthermore, several studies have elucidated some interesting candidates downstream of ΔFosB that may mediate the synaptic remodeling which occurs in response to psychostimulant exposure. Using genome wide analysis, our group has shown that ΔFosB overexpression leads to changes in several genes known to mediate spinogenesis [58]. One such target induced by ΔFosB is NFkB [3], which as noted above increases spine density on NAc neurons. Another target induced by ΔFosB is Cdk5. Inhibition of Cdk5 prevents the cocaine-induced spine proliferation in the NAc [71] while also paradoxically potentiating the behavioral responses to cocaine [10, 103]. Additionally, Pulipparacharuvil et al. [76] have recently demonstrated that a direct downstream target of Cdk5, MEF2, appears to directly regulate cellular adaptations that are involved in cocaine-induced increases in dendritic spine density. Viral-mediated overexpression of MEF2 inhibits, while knockdown of MEF2 potentiates, the cocaine-induced increases in MSN spine density. Reduction of MEF2 activity in response to cocaine, achieved via phosphorylation by Cdk5, may allow for transcription of cytoskeleton associated genes such as the neural Wiskott-Aldrich syndrome proteins (N-WASP) and WASP-family verprolin homologue (WAVE) proteins which were identified as having putative MEF binding sites in their proximal promoter regions [76]. There is also considerable evidence to suggest that one particular WAVE protein, WAVE1, regulates spine morphogenesis in a Cdk5-dependent manner [45, 97]. In this way, Cdk5 activation, induced by chronic cocaine administration via ΔFosB, could result in regulation of WAVE activity, while MEF2 may regulate its expression level to mediate longer-term changes involved in drug addiction.

Interestingly, as in the case of Cdk5 inhibition, overexpression of a constitutively active form of MEF2 reduced the density of dendritic spines on MSNs while paradoxically increasing sensitivity to cocaine's behavioral effects. Given the large amount of prior correlative data suggesting a link between sensitized behavioral responses to psychostimulants and an increase in spine number, these data on Cdk5 and MEF2 suggest a functional uncoupling between the two phenomena and argue that this dogma needs much further investigation. In addition, these data underscore the importance of studying complex molecular systems and moving beyond the analysis of single components. As suggested by Pulipparacharuvil and co-workers [76], cocaine-induced spine density changes may not lead to increased sensitivity per se, but may be a result of “homeostatic adaptations” to compensate for other changes caused by chronic psychostimulant exposure, such as a reduction in glutamatergic stimulation of medium spiny neurons by prefrontal cortical afferents. Understanding the dynamic changes in molecular systems in the context of structural plasticity of the brain's reward circuitry, will help us to better identify specific forms of maladaptive plasticity important in addictive behaviors.

Actin binding proteins and stimulant-induced structural plasticity

While changes in the density of dendritic spines following exposure to drugs of abuse has been well characterized, very little investigation into alterations in the morphology of these spines has been carried out to date. Spine morphology is an important factor in considering functional connectivity within neuronal circuitry, as it is highly correlated with synaptic function. Dendritic spines come in various shapes and sizes, which can be divided into general categories such as stubby, thin, and mushroom-like that are thought to reflect differences in functional properties [38]. Along these lines, it has been shown that the size of the spine head is proportional to the size of the postsynaptic receptor density and presynaptic active zone [37, 77, 89, 102], suggesting that larger spines are indicative of stronger connections, and that changes in the structure of dendritic spines can result in an alteration of synaptic function [18, 22, 87, 115]. In addition, the long-term potentiation (LTP) of synaptic responses in hippocampus is facilitated by the amplified membrane potentials that occur in the spine head as a result of the constricted neck of the mushroom-shaped dendritic spine [36]. In this same model of learning and memory, the induction of synaptic potentiation alters the morphology of dendritic spines, by enlarging the spine head or creating new structures [17, 35, 55, 105]. An alteration in the shape of dendritic spines, therefore, can have strong functional consequences and is something that should be investigated more thoroughly in brain reward regions after exposure to drugs of abuse.

Dendritic spines are highly enriched with actin, which is thought to enable these types of structural changes [25, 57]. The polymerization and arrangement of filamentous actin is critical for regulation of spine growth and morphological plasticity [20, 23, 27, 54, 56, 78, 119]. This process is continuous, and even stable spines contain a dynamic architecture of actin [94], which results in “ twitching ” of the spine head that is observed over a timescale of seconds [27]. The dynamic architecture is maintained by the polymerization and depolymerization of actin within the spine head. In general, profilin, an actin monomer sequestering protein, regulates the polymerization of actin, and the Arp2/3 complex is responsible for nucleating actin branches on pre-existing filaments, whereas the depolymerization of actin filaments is regulated mainly by the actin filament severing proteins, ADF/cofilin and gelsolin [16, 78].

Recent work by Toda and colleagues [104] demonstrate changes in some of the actin cytoskeleton regulators in response to drugs of abuse. Their findings show that chronic cocaine exposure increases the amount of polymerized actin (f-actin) in dendritic spines of medium spiny neurons in the NAc. These effects can be long-term, as increases in f-actin can be observed after 3 weeks of withdrawal from repeated cocaine exposure. The long-term changes were also observed in areas of the prefrontal cortex, but not CPu. These changes in actin polymerization occurred in concert with a reduction in the inactive form of cofilin, which may be the result of reduced levels of LIM kinase, known to phosphorylate, and thereby inhibit, cofilin activity [113]. Levels of several other actin-binding proteins were altered in response to pyschostimulant withdrawal. These data suggest that while initial exposure to drugs such as cocaine increases the amount of polymerized actin, repeated exposure results in changes to the baseline cycling of actin. Indeed, pharmacological manipulation of actin cycling to mimic these effects promoted cocaine-induced reinstatement of drug-taking behavior. While this study is the first to examine changes in direct regulators of actin assembly within the context of drug abuse models, it implicates another class of molecular pathways that have yet to be examined following exposure to drugs of abuse. The activity of many of these actin cytoskeleton regulators are known to be governed, at least in part, by the Rho family of small GTPases, namely RhoA, Cdc42, and Rac. The activation of these GTPases leads to the subsequent activation of several protein kinases and protein phosphatases that ultimately control the polymerization and assembly of actin filaments [for review, see 54, 65]. Therefore, further investigation into how these molecules are affected after drug use is greatly needed to understand the mechanism of drug-induced structural plasticity.

Insight into how these pathways may function in drug addiction comes from studies of synaptic plasticity in hippocampus [reviewed in 115]. Induction of LTP causes a similar increase in f-actin [7, 44, 47], and this polymerization of actin is required for LTP, as inhibition of actin dynamics blocks the development of LTP [28, 48]. It has been hypothesized that the “treadmilling” of actin that occurs via the ongoing directional polymerization and depolymerization of actin filaments serves as a route for the trafficking of actin-binding and synaptic proteins to and from the postsynaptic density [11, 56]. Further evidence suggests that it is this regulation of actin assembly in response to changes in synaptic activity that provides a foundation for synaptic plasticity [72]. This mechanism may be universal for induction of plastic changes regardless of the source of activity, whether from artificial electrical stimulation, learning in response to environmental challenges, or exposure to chemical agents such as drugs of abuse.

The arrangement of actin filaments within the spine head is such that there is a bundle of parallel actin filaments in the neck, and a meshwork of cross-linked actin filaments in the spine head. The meshwork of actin filaments provides a scaffold for postsynaptic proteins such as PSD-95 (postsynaptic density protein of 95 kDa), scaffolding proteins, and glutamate receptors. A major component of the postsynaptic structure, it is interesting that levels of PSD-95 are reduced after repeated exposure to cocaine [114]. Reduced levels of this synaptic protein can be correlated with an enhanced predisposition for the induction of synaptic potentiation, as knockdown of PSD-95 has been shown to result in enhanced LTP [60]. In fact, reduced levels of PSD-95 were also shown to increase dendritic spine instability, reminiscent of the higher rate of turnover that is characteristic during development [21]. This would suggest that the changes observed in response to psychostimulant exposure may in fact indicate a shift in the overall plasticity of the neurons themselves. However, in vitro studies have demonstrated that, while PSD-95 overexpression results in a maturation and stabilization of synapses, it can also increase dendritic spine density [22], which is counter to the reduced expression but increased spine density seen with psychostimulants. These findings suggest that the reduced PSD-95 is perhaps only one of many changes occurring in structural proteins of the dendritic spine of MSNs in the context of drug exposure. Other components of the postsynaptic density, such as members of the homer family of scaffolding proteins that are involved with the maturation of dendritic spines [87], may also play a role in the plasticity associated with exposure to drugs of abuse. Recent studies have shown that the expression of homer genes is altered, albeit in a complex manner, with several drugs of abuse [reviewed in 101]. Further exploration into alterations of these scaffolding proteins after psychostimulant exposure may help to provide a clearer understanding of the mechanisms responsible for long-term changes in the drug-mediated structural plasticity.


The data presented in this review demonstrate that we have made considerable progress in understanding how drugs of abuse mediate changes in postsynaptic complexity. Nevertheless, much remains unanswered. With the exception of a few works cited above, most of the information currently available about drug-induced alterations in dendritic spine number and morphology has been largely phenomenological in nature. We have presented here numerous pathways that appear to be important in regulating dendritic spines, however, many of these pathways are overlapping and involved in a complex mosaic within the cell. Due to the complex nature of these molecular networks, future research is needed to more completely understand how psychostimulants change intracellular signaling pathways to alter actin structure and ultimately influence addictive-like behavior. Indeed, we have only a rudimentary understanding of how drugs of abuse regulate basic actin dynamics that have been so richly studied in other models of plasticity such as hippocampal LTP. Given the progress that has been made in understanding basic spine regulation in these other models, we now need to move beyond correlative assessments to fully understand the molecular mechanisms of drug-induced structural plasticity.

Finally, although this review has focused on plastic changes within the NAc that occur following psychostimulant administration, we should emphasize the importance of investigating morphological changes known to occur in other limbic brain regions, such as VTA and prefrontal cortex, to name just two (An external file that holds a picture, illustration, etc.
Object name is nihms-126286-ig0008.jpg Fig. 1). Additionally, by focusing on the identification of single molecular adaptations in these individual brain regions and ignoring the many dynamic changes, such as the kinetics of protein-protein or protein-DNA interactions that occur in response to drug administration across numerous brain regions and circuits, it is likely that the field has not captured all of the molecular, cellular, and systems level changes that are important in the expression of addictive behaviors. Therefore, a major goal of future research is to understand addictive behavior at the level of the neural and molecular circuit, which requires temporally and spatially localized manipulations of complex molecular networks in vivo integrated over the many brain regions that are known to influence drug reward and motivation. A more complete understanding of how drugs of abuse alter dendritic spines and other features of structural plasticity in these brain regions and across different cell types will give us a greater appreciation on a systems level of how drugs of abuse mediate such powerful and long-lasting behavioral effects (An external file that holds a picture, illustration, etc.
Object name is nihms-126286-ig0009.jpg Fig. 3).

Fig. 3
Actin arrangement in the cytoskeleton. Top panel: Many proteins help regulate the polymerization and arrangement of actin filaments within the cytoskeletal network. Actin sequestering proteins provide a ready pool of actin monomers (globular actin, or ...


This work was supported by grants from the National Institute on Drug Abuse and NARSAD.


1. Aizman O, Brismar H, Uhlen P, et al. Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat Neurosci. 2000;3:226–230. [PubMed]
2. Alonso M, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem. 2004;11:172–178. [PubMed]
3. Amar S, Shaltiel G, Mann L, et al. Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia. Int J Neuropsychopharmacol. 2008;11:197–205. [PubMed]
4. Ang E, Chen J, Zagouras P, et al. Induction of nuclear factor-kappaB in nucleus accumbens by chronic cocaine administration. J Neurochem. 2001;79:221–224. [PubMed]
5. Asanuma M, Cadet JL. Methamphetamine-induced increase in striatal NF-[kappa]B DNA-binding activity is attenuated in superoxide dismutase transgenic mice. Mol Brain Res. 1998;60:305–309. [PubMed]
6. Barrot M, Olivier JD, Perrotti LI, et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc Natl Acad Sci USA. 2002;99:11435–11440. [PubMed]
7. Barrot M, Wallace DL, Bolanos CA, et al. Regulation of anxiety and initiation of sexual behavior by CREB in the nucleus accumbens. Proc Natl Acad Sci USA. 2005;102:8357–8362. [PubMed]
8. Beaulieu J-M, Gainetdinov RR, Caron MG. The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends in Pharmacological Sciences. 2007;28:166–172. [PubMed]
9. Beaulieu J-M, Sotnikova TD, Marion S, et al. An Akt/[beta]-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell. 2005;122:261–273. [PubMed]
10. Bibb JA, Chen J, Taylor JR, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature. 2001;410:376–380. [PubMed]
11. Bramham CR. Local protein synthesis, actin dynamics, and LTP consolidation. Curr Opin Neurobiol. 2008;4:5. [PubMed]
12. Bramham CR, Messaoudi E. BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis. Prog Neurobiol. 2005;76:99–125. [PubMed]
13. Brenhouse HC, Howe ML, Stellar JR. Differential activation of cAMP response element binding protein in discrete nucleus accumbens subregions during early and late cocaine sensitization. Behav Neurosci. 2007;121:212–217. [PubMed]
14. Carlezon JWA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci. 2005;28:436–445. [PubMed]
15. Carlezon WA, Jr, Thome J, Olson VG, et al. Regulation of cocaine reward by CREB. Science. 1998;282:2272–2275. [PubMed]
16. Carlisle HJ, Kennedy MB. Spine architecture and synaptic plasticity. Trends Neurosci. 2005;28:182–187. [PubMed]
17. Chang FL, Greenough WT. Transient and enduring morphological correlates of synaptic activity and efficacy change in the rat hippocampal slice. Brain Res. 1984;309:35–46. [PubMed]
18. Chen Y, Bourne J, Pieribone VA, et al. The role of actin in the regulation of dendritic spine morphology and bidirectional synaptic plasticity. Neuro report. 2004;15:829–832. [PubMed]
19. Cunningham ST, Kelley AE. Hyperactivity and sensitization to psychostimulants following cholera toxin infusion into the nucleus accumbens. J Neurosci. 1993;13:2342–2350. [PubMed]
20. Dunaevsky A, Tashiro A, Majewska A, et al. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci USA. 1999;96:13438–13443. [PubMed]
21. Ehrlich I, Klein M, Rumpel S, et al. PSD-95 is required for activity-driven synapse stabilization. Proc Natl Acad Sci USA. 2007;104:4176–4181. [PubMed]
22. El-Husseini AE, Schnell E, Chetkovich DM, et al. PSD-95 involvement in maturation of excitatory synapses. Science. 2000;290:1364–1368. [PubMed]
23. Eom T, Antar LN, Singer RH, et al. Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses. J Neurosci. 2003;23:10433–10444. [PubMed]
24. Everitt BJ, Dickinson A, Robbins TW. The neuropsychological basis of addictive behaviour. Brain Res Rev. 2001;36:129–138. [PubMed]
25. Fifkova E, Delay RJ. Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity. J Cell Biol. 1982;95:345–350. [PMC free article] [PubMed]
26. Filip M, Faron-GÛrecka A, Kusmider M, et al. Alterations in BDNF and trkB mRNAs following acute or sensitizing cocaine treatments and withdrawal. Brain Res. 2006;1071:218–225. [PubMed]
27. Fischer M, Kaech S, Knutti D, et al. Rapid actin-based plasticity in dendritic spines. Neuron. 1998;20:847–854. [PubMed]
28. Fukazawa Y, Saitoh Y, Ozawa F, et al. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron. 2003;38:447–460. [PubMed]
29. Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci. 1992;15:133–139. [PubMed]
30. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science. 1990;250:1429–1432. [PubMed]
31. Graham DL, Edwards S, Bachtell RK, et al. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci. 2007;10:1029–1037. [PubMed]
32. Grimm JW, Lu L, Hayashi T, et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: Implications for incubation of cocaine craving. J Neurosci. 2003;23:742–747. [PubMed]
33. Hakansson K, Galdi S, Hendrick J, et al. Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem. 2006;96:482–488. [PubMed]
34. Hallett PJ, Spoelgen R, Hyman BT, et al. Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking. J Neurosci. 2006;26:4690–4700. [PubMed]
35. Harris KM, Jensen FE, Tsao B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci. 1992;12:2685–2705. [PubMed]
36. Harris KM, Kater SB. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci. 1994;17:341–371. [PubMed]
37. Harris KM, Stevens JK. Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J Neurosci. 1989;9:2982–2997. [PubMed]
38. Hering H, Sheng M. Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci. 2001;2:880–888. [PubMed]
39. Hernandez-Lopez S, Tkatch T, Perez-Garci E, et al. D2 Dopamine receptors in striatal medium spiny neurons reduce L-Type Ca2+currents and excitability via a novel PLC{beta}1-IP3-calcineurin-signaling cascade. J Neurosci. 2000;20:8987–8995. [PubMed]
40. Hope BT, Nye HE, Kelz MB, et al. Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments. Neuron. 1994;13:1235–1244. [PubMed]
41. Jenab S, Festa ED, Nazarian A, et al. Cocaine induction of ERK proteins in dorsal striatum of fischer rats. Mol Brain Res. 2005;142:134–138. [PubMed]
42. Ji Y, Pang PT, Feng L, et al. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Nat Neurosci. 2005;8:164–172. [PubMed]
43. Kalivas PW, O'Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology. 2008;33:166–180. [PubMed]
44. Kim CH, Lisman JE. A role of actin filament in synaptic transmission and long-term potentiation. J Neurosci. 1999;19:4314–4324. [PubMed]
45. Kim Y, Sung JY, Ceglia I, et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature. 2006;442:814–817. [PubMed]
46. Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8:1442–1444. [PubMed]
47. Kramar EA, Lin B, Rex CS, et al. Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci USA. 2006;103:5579–5584. [PubMed]
48. Krucker T, Siggins GR, Halpain S. Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc Natl Acad Sci USA. 2000;97:6856–6861. [PubMed]
49. Kumar A, Choi K-H, Renthal W, et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron. 2005;48:303–314. [PubMed]
50. Le Foll B, Diaz J, Sokoloff P. A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. Neuroreport. 2005;16:175–178. [PubMed]
51. Lee KW, Kim Y, Kim AM, et al. Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens. Proc Natl Acad Sci USA. 2006;103:3399–3404. [PubMed]
52. Li X, Hua L, Deng F, et al. NF-[kappa]B and Hsp70 are involved in the phospholipase C[gamma]1 signaling pathway in colorectal cancer cells. Life Sciences. 2005;77:2794–2803. [PubMed]
53. Liu Q-R, Lu L, Zhu X-G, et al. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res. 2006;1067:1–12. [PubMed]
54. Luo L. Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol. 2002;18:601–635. [PubMed]
55. Maletic-Savatic M, Malinow R, Svoboda K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science. 1999;283:1923–1927. [PubMed]
56. Markham JA, Fifkova E. Actin filament organization within dendrites and dendritic spines during development. Brain Res. 1986;392:263–269. [PubMed]
57. Matus A, Ackermann M, Pehling G, et al. High actin concentrations in brain dendritic spines and postsynaptic densities. Proc Natl Acad Sci USA. 1982;79:7590–7594. [PubMed]
58. MacClung CA, Nestler EJ. Regulation of gene expression and cocaine reward by CREB and [Delta]FosB. NatNeurosci. 2003;6:1208–1215. [PubMed]
59. MacGinty JF, Xiangdang D. Shi marek schwendt alicia saylor shigenobu toda. regulation of psychostimulant-induced signaling and gene expression inthe striatum. J Neurochem. 2008;104:1440–1449. [PMC free article] [PubMed]
60. Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature. 1998;396:433–439. [PubMed]
61. Miserendino MJ, Nestler EJ. Behavioral sensitization to cocaine: modulation by the cyclic AMP system in the nucleus accumbens. Brain Res. 1995;674:299–306. [PubMed]
62. Missale C, Nash SR, Robinson SW, et al. Dopamine Receptors: From Structure to Function. Physiol Rev. 1998;78:189–225. [PubMed]
63. Muller DL, Unterwald EM. Invivo regulation of extracellular signal-regulated protein kinase (ERK) and protein kinase B (Akt) phosphorylation by acute and chronic morphine. J Pharmacol Exp Ther. 2004;310:774–782. [PubMed]
64. Murphy DD, Segal M. Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc Natl Acad Sci USA. 1997;94:1482–1487. [PubMed]
65. Nakayama AY, Luo L. Intracellular signaling pathways that regulate dendritic spine morphogenesis. Hippocampus. 2000;10:582–586. [PubMed]
66. Nestler EJ. Is there a common molecular pathway for addiction? Nat Neurosci. 2005;8:1445–1449. [PubMed]
67. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001;2:119–128. [PubMed]
68. Nestler EJ. Molecular mechanisms of drug addiction. Neuropharmacology. 2004;47(Suppl 1):24–32. [PubMed]
69. Nestler EJ. Review. transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci. 2008;363:3245–3255. [PMC free article] [PubMed]
70. Nestler EJ, Carlezon JWA. The mesolimbic dopamine reward circuit in depression. Biol Psychiat. 2006;59:1151–1159. [PubMed]
71. Norrholm SD, Bibb JA, Nestler EJ, et al. Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience. 2003;116:19–22. [PubMed]
72. Okamoto K, Nagai T, Miyawaki A, et al. Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci. 2004;7:1104–1112. [PubMed]
73. Perrine SA, Miller JS, Unterwald EM. Cocaine regulates protein kinase B and glycogen synthase kinase-3 activity in selective regions of rat brain. J Neurochem. 2008;107:570–577. [PMC free article] [PubMed]
74. Petro JB, Khan WN. Phospholipase C-{gamma}2 Couples Bruton's tyrosine kinase to the NF-kappa B signaling pathway in B Lymphocytes. J Biol Chem. 2000:M009137200. [PubMed]
75. Pu L, Liu Q-s, Poo M-m. BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nat Neurosci. 2006;9:605–607. [PubMed]
76. Pulipparacharuvil S, Renthal W, Hale CF, et al. Cocaine regulates MEF2 to control synaptic and behavioral plasticity. Neuron. 2008;59:621–633. [PMC free article] [PubMed]
77. Racca C, Stephenson FA, Streit P, et al. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci. 2000;20:2512–2522. [PubMed]
78. Rao A, Craig AM. Signaling between the actin cytoskeleton and the postsynaptic density of dendritic spines. Hippocampus. 2000;10:527–541. [PubMed]
79. Robinson TE, Gorny G, Mitton E, et al. Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex. Synapse. 2001;39:257–266. [PubMed]
80. Robinson TE, Kolb B. Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine. Eur J Neurosci. 1999;11:1598–1604. [PubMed]
81. Robinson TE, Kolb B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. J Neurosci. 1997;17:8491–8497. [PubMed]
82. Robinson TE, Kolb B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology. 2004;47:33–46. [PubMed]
83. Russo SJ, Bolanos CA, Theobald DE, et al. IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates. Nat Neurosci. 2007;10:93–99. [PubMed]
84. Russo SJ, Mazei-Robison MS, Ables JL, et al. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology. 2008
85. Russo SJ, Rental W, Kumar A, et al. NFkB signaling regulates cocaine-induced behavioral and cellular plasticity. Society for Neuroscience; San Diego: 2007.
86. Ryu J, Futai K, Feliu M, et al. Constitutively active rap2 transgenic micedisplay fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction. J Neurosci. 2008;28:8178–8188. [PMC free article] [PubMed]
87. Sala C. Molecular regulation of dendritic spine shape and function. Neurosignals. 2002;11:213–223. [PubMed]
88. Sarti F, Borgland SL, Kharazia VN, et al. Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area. Eur J Neurosci. 2007;26:749–756. [PubMed]
89. Schikorski T, Stevens CF. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci. 1997;17:5858–5867. [PubMed]
90. Shaw-Lutchman TZ, Impey S, Storm D, et al. Regulation of CRE-mediated transcription in mouse brain by amphetamine. Synapse. 2003;48:10–17. [PubMed]
91. Shi X, MacGinty JF. Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum. Neuroscience. 2006;138:1289–1298. [PubMed]
92. Shi XaM. Jacqueline repeated amphetamine treatment increases phosphorylation of extracellular signal-regulated kinase, protein kinase B, and cyclase response element-binding protein in the rat striatum. J Neurochem. 2007;103:706–713. [PubMed]
93. Snyder GL, Allen PB, Fienberg AA, et al. Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo. J Neurosci. 2000;20:4480–4488. [PubMed]
94. Star EN, Kwiatkowski DJ, Murthy VN. Rapid turnover of actinin dendritic spines and its regulation by activity. Nat Neurosci. 2002;5:239–246. [PubMed]
95. Stoof JC, Kebabian JW. Two dopamine receptors: biochemistry, physiology and pharmacology. Life Sci. 1984;35:2281–2296. [PubMed]
96. Sun W-L, Zhou L, Hazim R, et al. Effects of acute cocaine on ERK and DARPP-32 phosphorylation pathways in the caudate-putamen of fischer rats. Brain Research. 2007;1178:12–19. [PMC free article] [PubMed]
97. Sung JY, Engmann O, Teylan MA, et al. WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spines. Proc Natl Acad Sci USA. 2008;105:3112–3116. [PubMed]
98. Surmeier DJ, Ding J, Day M, et al. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trend Neurosci. 2007;30:228–235. [PubMed]
99. Surmeier DJ, Reiner A, Levine MS, et al. Neostriatal dopamine-receptors – reply. Trends in Neurosciences. 1994;17:4–5.
100. Svenningsson P, Nishi A, Fisone G, et al. DARPP-32: An integrator of neurotransmission. Annu Rev of Pharmacol Toxicol. 2004;44:269–296. [PubMed]
101. Szumlinski KK, Ary AW, Lominac KD. Homers regulate drug-induced neuroplasticity: implications for addiction. Biochem Pharmacol. 2008;75:112–133. [PMC free article] [PubMed]
102. Takumi Y, Ramirez-Leon V, Laake P, et al. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci. 1999;2:618–624. [PubMed]
103. Taylor JR, Lynch WJ, Sanchez H, et al. Inhibition of Cdk5 in the nucleus accumbens enhances the locomotor-activating and incentive-motivational effects of cocaine. Proc Natl Acad Sci USA. 2007;104:4147–4152. [PubMed]
104. Toda S, Shen HW, Peters J, et al. Cocaine increases actin cycling: effects in the reinstatement model of drug seeking. J Neurosci. 2006;26:1579–1587. [PubMed]
105. Trommald M, Hulleberg G, Andersen P. Long-term potentiation is associated with new excitatory spine synapses on rat dentate granule cells. Learn Mem. 1996;3:218–228. [PubMed]
106. Turgeon SM, Pollack AE, Fink JS. Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization. Brain Res. 1997;749:120–126. [PubMed]
107. Tyler WJ, Alonso M, Bramham CR, et al. From acquisition to consolidation: on the role of drain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem. 2002;9:224–237. [PMC free article] [PubMed]
108. Valjent E, Pages C, Herve D, et al. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci. 2004;19:1826–1836. [PubMed]
109. Valjent E, Pascoli V, Svenningsson P, et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc Natl Acad Sci USA. 2005;102:491–496. [PubMed]
110. Wei Y, Williams JM, Dipace C, et al. Dopamine transporter activity mediates amphetamine-induced inhibition of akt through a Ca2+/calmodulin-dependent kinase II-dependent mechanism. Mol Pharmacol. 2007;71:835–842. [PubMed]
111. Williams JM, Owens WA, Turner GH, et al. Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine. PLoS Biology. 2007;5:e274. [PMC free article] [PubMed]
112. Wu G-Y, Deisseroth K, Tsien RW. Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat Neurosci. 2001;4:151–158. [PubMed]
113. Yang N, Higuchi O, Ohashi K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature. 1998;393:809–812. [PubMed]
114. Yao WD, Gainetdinov RR, Arbuckle MI, et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron. 2004;41:625–638. [PubMed]
115. Yuste R, Bonhoeffer T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci. 2001;24:1071–1089. [PubMed]
116. Zachariou V, Sgambato-Faure V, Sasaki T, et al. Phosphorylation of DARPP-32 at threonine-34 is required for cocaine action. Neuropsychopharmacology. 2005;31:555–562. [PubMed]
117. Zhang D, Zhang L, Lou DW, et al. The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J Neurochem. 2002;82:1453–1464. [PubMed]
118. Zhang X, Mi J, Wetsel WC, et al. PI3 kinase is involved in cocaine behavioral sensitization and its reversal with brain area specificity. Biochemical and Biophysical Research Communications. 2006;340:1144–1150. [PubMed]
119. Zito K, Knott G, Shepherd GM, et al. Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton. Neuron. 2004;44:321–334. [PubMed]