Recovering from cocaine: Insights from clinical and preclinical investigations

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Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

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ecovering from cocaine: Insights from clinical and preclinical investigations

olleen A. Hanlona,b,∗, Thomas J.R. Beveridgea, Linda J. Porrinoa

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC 29425, USA

a r t i c l e i n f o

rticle history:eceived 19 November 2012eceived in revised form 26 March 2013ccepted 17 April 2013

eywords:ocaine

a b s t r a c t

Cocaine remains one of the most addictive substances of abuse and one of the most difficult to treat.Although increasingly sophisticated experimental and technologic advancements in the last severaldecades have yielded a large body of clinical and preclinical knowledge on the direct effects of cocaine onthe brain, we still have a relatively incomplete understanding of the neurobiological processes that occurwhen drug use is discontinued. The goal of this manuscript is to review both clinical and preclinical datarelated to abstinence from cocaine and discuss the complementary conclusions that emerge from these

bstinenceeuroimagingddictionhite matter

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different levels of inquiry. This commentary will address observed alterations in neural function, neuralstructure, and neurotransmitter system regulation that are present in both animal models of cocaineabstinence and data from recovering clinical populations. Although these different levels of inquiry areoften challenging to integrate, emerging data discussed in this commentary suggest that from a struc-tural and functional perspective, the preservation of cortical function that is perhaps the most importantbiomarker associated with extended abstinence from cocaine.

© 2013 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Imaging the brain of cocaine abstainers: clinical research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.1. Beyond the striatum: altered activity in the prefrontal cortex of users and abstainers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. The survivor effect? Altered neural structure among active users and abstainers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Investigating the consequences of abstinence from cocaine: preclinical research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Is there evidence for recovery? Dopamine systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Does the structure of the brain change? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Can we bridge preclinical and clinical research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1. Investigating the role of BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. Imaging neurochemistry non-invasively . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Introduction hardships. Although there have been many efforts to developeffective treatments, whether pharmacological or cognitive and

Please cite this article in press as: Hanlon, C.A., et al., Recovering from coBiobehav. Rev. (2013), http://dx.doi.org/10.1016/j.neubiorev.2013.04.007

Chronic cocaine use is a seemingly intractable public healthroblem worldwide. Whether cocaine is snorted, injected, ormoked as crack, users often suffer serious negative consequenceso their health, social relationships, as well as severe economic

∗ Corresponding author at: Departments of Psychiatry and Neurosciences, Centeror Advanced Imaging Research, Medical University of South Carolina, USA.el.: +1 843 792 5732; fax: +1 843 792 7457.

E-mail address: [email protected] (C.A. Hanlon).

149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.neubiorev.2013.04.007

behavioral, rates of relapse continue to be alarmingly high. More-over, these relapse rates continue to be among the highest of allillegal drugs (Vocci, 2007). One substantial obstacle to the discoveryof successful treatment approaches has been our rather incompleteunderstanding of the neurobiological processes that naturally occurwhen drug use is discontinued (likely best modeled in animals) as

caine: Insights from clinical and preclinical investigations. Neurosci.

well as any unique features of the small population of addicts thatare able to successfully abstain from cocaine for extended periods oftime. Without a more complete picture of these structural and func-tional neuroadaptations, it is difficult to direct effective strategies

dx.doi.org/10.1016/j.neubiorev.2013.04.007


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oward targets with the greatest potential for promoting abstinencend reducing harm.

To understand the natural neural adaptations that follow dis-ontinuation of drug use as well as neurological features thatromote successful abstinence in humans, it is first necessary tonderstand the changes that directly result from cocaine exposure.ecades of robust molecular, genetic, cellular, and neural systems

evel studies have provided important insights in this area. Onemportant approach that has been used in both human and ani-

al models of chronic cocaine use is neuroimaging. This approachncompasses a wide range of in vivo and in vitro techniques capablef assessing neural function and structure, such as positron emis-ion tomography (PET), functional magnetic resonance imagingfMRI), diffusion tensor imaging, tissue morphometry, metabolic

apping, and receptor autoradiography, among others. Not only dohese approaches have the advantage of being able to sample multi-le brain regions simultaneously, but many in vivo approaches cane applied to human drug users and animal models alike providingor substantial translation and cross-validation of findings. Here,e focus on the insights and perspectives that imaging approachesave contributed to the issues that surround the long-term neuraldaptations that follow discontinuation of cocaine use after chronicbuse and dependence.

Although there are many unanswered questions, this briefommentary will consider two fundamental questions about absti-ence from continued cocaine use that we believe neuroimagingtudies can in part address:

1) To what extent do the neurostructural and functional abnor-malities that accompany chronic cocaine use either improve orpersist following discontinuation of cocaine?

2) Are there patterns of neural function or structure that can beused as predictors of successful abstinence when given thechoice to use?

A broad perspective is required in order to address these ques-ions. In this commentary we examine complementary insightsrom clinical addiction research and preclinical animal models ofrug use. When considered together these data give us a deepernderstanding of the neurofunctional and structural adaptationshat are present in both early and extended periods of abstinence.

. Imaging the brain of cocaine abstainers: clinical research

As with many psychiatric diseases, the neuropathology presentn cocaine-dependent individuals is not restricted to a single brainegion, a single cell type, or a single neurotransmitter system.ather substance dependence is frequently associated with disrup-ions in at least three major systems that contribute to behavior –imbic processing, cognition, and basic motor control. These sys-ems span both cortical and subcortical regions of the brain andherefore are vulnerable not only to pathology in a local popula-ion of cells, but also in the white matter tracts that connect theseegions.

Additionally, just as addiction is not limited to one spatially dis-inct disruption, there is also an important temporal component tohe addiction process. That is, addiction exists on a continuum thatikely extends from a vulnerable, drug-naïve individual that casu-lly uses a drug, to an individual that becomes dependent, attemptsbstinence and, typically, relapses. While several research groupsave isolated traits that predict better than average treatment out-


omes in cocaine users (Kampman et al., 2002; Poling et al., 2007;inha et al., 2007) there are still no FDA approved medications forocaine dependence. Moreover, relapse rates are among the highestf all illegal drugs (Vocci, 2007).

PRESSavioral Reviews xxx (2013) xxx– xxx

Longitudinal studies of neural activity during this continuumare very difficult to perform in substance-dependent individualsfor pragmatic reasons (e.g. identifying vulnerable individuals, lossto follow-up due to frequent changes in phone numbers, livingarrangements, lack of transportation). There is, however, a grow-ing body of research that has tried to address these questions. Inthis review we will discuss several studies which have investigatedindividuals at each stage of this continuum. In order to determinewhether patterns of brain activity predict treatment success orrelapse, however, it is important to first understand common struc-tural and functional abnormalities present in the brain of a cocainedependent individual.

2.1. Beyond the striatum: altered activity in the prefrontal cortexof users and abstainers

Cocaine’s primary mechanism of action in the brain involvesbinding to the dopamine transporter which is highly concentratedin the basal ganglia (or striatum). Dopamine disruption in the stri-atum has been robustly studied in animal models of cocaine useand in several human imaging studies. Additionally however, manyhighly-cited human neuroimaging studies have revealed signifi-cantly lower rates of functional activity in the frontal cortex ofcocaine users relative to non-drug using controls. This ‘hypofrontal-ity’ was first documented in PET imaging studies which measuredbaseline glucose metabolism throughout the brain of cocaine users(Goldstein et al., 2004; Goldstein and Volkow, 2002; Volkow et al.,1991a, 1992, 2005).

Volkow and colleagues were also among the first to demonstratethat, in addition to a lower metabolic rate of glucose utilization,both currently active and recently abstinent cocaine users havelower levels of dopamine D2 receptors in both frontal and lim-bic regions of the cortex (Volkow et al., 1993). Baseline cerebralblood flow (CBF) is also significantly lower in chronic cocaine userscompared with non-drug using controls, in the prefrontal and tem-poral cortices (Goldstein and Volkow, 2002; Holman et al., 1993;Strickland et al., 1993; Volkow et al., 1988).

Although many studies have assessed alterations in cognitivefunction of cocaine abusers after the cessation of drug use (Bollaet al., 2004, 2003; Gottschalk et al., 2001), few studies have directlyaddressed the question of the persistence or potential changes inthese abnormalities over the course of abstinence. One of the firstand only longitudinal studies in this field was done by Volkowet al. (1991a,b). They demonstrated that cerebral metabolism in thebasal ganglia and ventral prefrontal cortex of cocaine abusers waselevated above control levels during the first week of abstinence(Volkow et al., 1991b). After 1–6 weeks of abstinence however,these acutely elevated cerebral metabolic rates had decreased.These decreases persisted in a subset of subjects tested again after 3months, suggesting that many neurofunctional abnormalities per-sist after extended abstinence from cocaine.

It is yet unclear however, if more protracted periods of absti-nence (greater than 6 months) are associated with better affectiveand neurofunctional outcomes. As demonstrated in metham-phetamine abstainers (Wang et al., 2004), significant neocorticalrecovery may not occur until several months after abstinencebegins. Emerging data from several laboratories, including our own,suggests that individuals who are able to maintain abstinence fora long period of time may in fact have higher levels of frontal cor-tex activity. A recent functional MRI study by Connolly et al. (2012)demonstrated that during a response inhibition task, individualsthat had been abstinent from cocaine for 10–25 months (long term)


had significantly higher blood oxygen level dependent (BOLD) sig-nal in the prefrontal cortex during a response inhibition task thanshorter term abstainers (1–5 weeks). Furthermore, whereas currentcocaine users typically have lower prefrontal activity than controls


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Fig. 1. Preliminary data demonstrating alterations in cerebral glucose metabolism in among a cohort of former cocaine users living in a residential treatment facility (n = 23)relative to age, gender and education matched controls (n = 14). These individuals had been abstinent for either less than 1 month (short-term, n = 6), between 1–5 months(middle-term, n = 10), or 10–20 months (long-term, n = 7). The colors superimposed on the gray-scale template indicate the areas of significant increases (red colormap, t-values) and decreases (blue colormap, t-values) in regional glucose metabolism in these subgroups relative to age, gender, and education matched controls (p < 0.05, correctedc n in a

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lusters). The numbers above the images indicate the location of the coronal sectiof the references to color in this figure legend, the reader is referred to the web ver

uring this task, both groups of successful abstainers had signif-cantly greater prefrontal activity than controls (Connolly et al.,012).

Extending these task-based findings to measurements of base-ine neural activity, a preliminary study from our group hasemonstrated that longer-term abstainers have significantly higherates of baseline glucose metabolism in the frontal cortex thanhorter term abstainers. For this FDG-PET study we enrolled 23ormer cocaine users that were currently active participants inommunity-based outpatient and inpatient treatment programs,s well as 14 age-matched controls with no history of psychi-tric illness or substance dependence. The former cocaine users inhis study had been abstinent from cocaine for up to 14 months.or preliminary analysis these 23 individuals were divided intoroups of short term (1–5 weeks), middle term (1–5 months),nd long term (10–14 months) abstinence, similar to the groupseported by Connolly et al. (2012). Preliminary analysis of theseata demonstrates that, consistent with the original PET studies inhis area, short term abstainers have lower neural activity in bothhe frontal cortex and subcortical areas relative to the matched con-rols (Fig. 1). Similar to the aforementioned functional MRI results,he individuals that had maintained abstinence for 10 or more

onths had significantly higher rates neural activity (as measuredy baseline glucose metabolism) in the frontal cortex relative tohorter term abstainers and age, gender, and education matchedontrols. The functional activity in the subcortical areas, however,id not vary as a function of length of abstinence. While theseata are preliminary, cross-sectional, and from a limited sample,


he results complement Connolly et al. (2012) and suggest thatong-term abstinence from cocaine in humans may be more relatedo neural activity in the frontal cortex rather than the subcorticalreas.

standardized human template (Montreal Neurologic Institute). (For interpretationf the article.)

When considering the relative role of the frontal cortex versussubcortical areas on the maintenance of abstinence, it is importantto acknowledge that nearly all behaviors in the human repertoireare the result of complex interactions among neural systems whichspan multiple brain regions. The mesolimbic and mesocorticaldopamine systems, for example, differentially contribute to moti-vational and cognitive aspects of cocaine dependence and relapse.Whereas they both depend on projections from the prefrontal cor-tex to subcortical areas, these circuits are both anatomically andfunctionally segregated, with the mesolimbic systems receivingmore input from the medial prefrontal cortex and the mesocorticalcircuit receiving input from the lateral prefrontal cortex.

Several studies have now documented specific disruptions ofbaseline frontal-striatal circuitry in cocaine users (Gu et al., 2010;Hanlon et al., 2011b; Ma et al., 2010). Although there are mul-tiple ways to measure functional connectivity in the brain, onemethod that is actively being used in the addiction literature isresting-state BOLD imaging. By combining this technique withsophisticated data modeling and analysis it is possible to isolatecombinations of neural regions which oscillate together, poten-tially aberrantly in substance users. Through this technique severalgroups have demonstrated that, at baseline, cocaine users haveless functional connectivity within the mesolimbic dopamine sys-tem relative to controls. Furthermore, lower network connectivityamong these limbic regions is correlated with longer histories ofcocaine use (Gu et al., 2010; Ma et al., 2010). These disruptions incortical-subcortical connectivity appear to be present after shortperiods (1–2 weeks) of abstinence (Kelly et al., 2011). There are


however, currently no longitudinal investigations of resting stateconnectivity through the course of dependence and abstinence.Additionally, while the most pronounced differences in neuralstructure between cocaine users and controls tend to be in cortical


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reas, Barros-Loscertales et al. (2011) recently demonstrated thatocaine-dependent men have significantly lower gray matter vol-mes in the striatum, compared to controls.

.2. The survivor effect? Altered neural structure among activesers and abstainers

Finally, in addition to aberrant patterns of functional activitybserved in cocaine users and abstainers, there is a growing bodyf evidence demonstrating structural pathology in the brains ofocaine users which may not be present among successful abstain-rs (Bartzokis et al., 2000; Fein et al., 2002; Liu et al., 1998; Moellert al., 2005). Magnetic resonance imaging studies among cocainesers consistently report smaller volumes and lower tissue density

n the prefrontal cortex of cocaine users relative to non-drug usingontrols, which may be correlated with length of use (O’Neill et al.,001). Bartzokis et al. (2002) investigated white matter volume in

large cohort of cocaine dependent individuals and demonstratedhat cocaine dependent individuals did not have the same age-elated increases in white matter volume observed in non-drugsing controls. These data suggest that there may be an arrestedevelopment of white matter among users (Bartzokis et al., 2002).ranklin et al. (2002) were the first to demonstrate lower density ofray matter in cocaine users using voxel-based morphometry. Theyeported lower gray matter density in the insula cortex, medialrbitofrontal cortex, superior temporal cortex, and right anterioringulate (Franklin et al., 2002). Sim et al. (2007) recently reportedower white matter density in the right cerebellum and lower gray

atter density in the premotor cortex, temporal cortex, frontal cor-ex, left thalamus, and cerebellum in current cocaine users (Simt al., 2007).

Given that neural structure is largely inherited and is sensi-ive to many other environmental stressors that coexist in chronicocaine users (such as alcohol abuse, chronic hypertension, peri-atal stress), however, it is difficult to interpret these data. An

nnovative study by Ersche et al. (2012), provided some insightnto the potential heritability of these neurostructural abnormali-ies. They investigated gray matter tissue density and white matterntegrity among 50 sibling pairs (one cocaine dependent, one witho history of drug dependence), and 50 unrelated healthy con-rols. Relative to the controls, the sibling pairs (both the user andon-user) had region specific differences in gray matter density inultiple brain regions that are implicated in addiction (e.g. lower

ray matter density in the posterior insula and higher density inhe caudate). Between the siblings, the stimulant dependent indi-idual had significantly lower tissue density in the vicinity of therbitofrontal cortex. These data suggest that while some of thelterations in neural structure observed in chronic cocaine usersay be related to an endophenotype that was inherited, the drug-

sing sibling may have significantly lower gray matter than theon-drug using sibling in the orbitofrontal cortex, a brain regionritical to the motivational and compulsive aspects of addictionVolkow and Fowler, 2000).

The relationship between cocaine abstinence and neural tissuentegrity however, is unclear and has not been studied in a longitu-inal manner. Matochik et al. (2003) demonstrated that individualsbstinent from cocaine for approximately 20 days had lower grayatter density in the cingulate gyrus, lateral prefrontal cortex, andedial and lateral aspects of the orbitofrontal cortex than con-

rols (Matochik et al., 2003). A study of polydrug abusers thateported abstinence from cocaine for approximately 4 years alsoemonstrated lower gray matter volume in the orbitofrontal cortex


ompared with controls (Tanabe et al., 2009). Whereas these stud-es suggest that in both short and longer tem abstinence, cocainesers have significantly lower tissue density in the orbitofrontalortex, a recent study by our group demonstrated individuals that


are able to remain abstinent for more than 30 days have greater grayand white matter density in many other cortical areas than currentusers or rigorously matched controls (Hanlon et al., 2011a).

One interpretation of these data is that that structural abnor-malities associated with chronic cocaine use may be reversed withextended abstinence. Elevated gray and white matter integrity iswell documented in individuals abstaining from alcohol. In theseindividuals, lower gray and white matter volumes recover to base-line levels after a several weeks of abstinence (Gazdzinski et al.,2005a,b; Pfefferbaum et al., 1995, 1998). Gray matter density alsoincreases during methamphetamine abstinence in the striatum,nucleus accumbens, and parietal cortex (Jernigan et al., 2005).Positron emission tomography studies have revealed elevatedglucose metabolism throughout the cortex of methamphetamineabstainers with the greatest increase (≥20%) in the parietal cortex(Berman et al., 2008; London et al., 2004).

Although the mechanism through which gray matter densityincreases is unclear, it is possible that, in the absence of chronicstimulation by cocaine, dendritic spine density is able to increase inthe prefrontal cortex and/or the afferent axons are able to arborize,creating a greater density of local connections. A likely mecha-nism through which white matter density may increase followingdiscontinuation of cocaine is through the maturation of oligoden-drocytes which are sensitive to levels of both glutamate (Gallo et al.,1996) and dopamine (Bongarzone et al., 1998; Howard et al., 1998)(via AMPA and D2/D3 receptors). While chronic cocaine use is asso-ciated with lower levels of myelin, in abstinence these immatureoligodendrocytes are likely able to develop thereby increasing theintegrity and density of the myelin sheaths in the brain.

Alternately, however, beyond basic neurobiological explana-tions, it is possible that elevated neural tissue density amonglong-term abstainers may be a “survivor effect.” That is, the lackof differences in neural structure observed in longer term abstain-ers is because these individuals represent a unique sub-populationof drug users that have a greater level of frontal cortical integrityat the beginning of abstinence. This elevated cortical integrity inbrain regions involved in self-control may enable them to main-tain abstinence for a longer time. This ‘survivor’ effect may alsoexplain the elevated levels of frontal glucose metabolism thathave been observed in these long term abstainers (Connolly et al.,2012).

Considered together, there are several themes that emerge from thisresearch. First, in chronic users functional and structural abnormal-ities in the brain extend beyond dopamine-rich subcortical areas tothe glutamate and GABA-rich areas of the prefrontal and temporalcortices which in turn project to the striatum. Second, individualsthat remain abstinent for several months likely have higher lev-els of functional and structural integrity in these cortical areas –possibly a “survivor effect.” Finally third, the high levels of individ-ual variability in substance abuse treatment success and relapsemay be associated with neural endophenotypes and variations inthe integrity of the prefrontal cortex. While these endophenotypesmay increase one’s likelihood of using stimulant drugs (as in thestudy of Ersche et al., 2012), they may alternatively increase thelikelihood that an individual will remain abstinent (as in the studyof Connolly et al., 2012).

Although these three themes in the human imaging literatureprovide a unique window into the neurobiologic ‘fingerprint’ ofaddiction and abstinence, there are multiple aspects of human sub-stance abuse research which make it very challenging to examinethese themes with more rigorous scientific detail. From a clinicalperspective, cocaine dependent individuals often have psychiatric


comorbidities including depression and post-traumatic stress dis-order, and often abuse other legal and illegal drugs. It is alsovery difficult to perform longitudinal studies on human cocaineusers. This challenge results in most of the studies of individuals


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bstaining from cocaine to be limited to the scope of the typical–4 week timeframe of a treatment programs.

. Investigating the consequences of abstinence fromocaine: preclinical research

There is no question that studies in human drug abusers, cur-ent and abstaining, can provide the best evidence about the coursef this disorder. Among others, the ability to obtain verbal reportsf the feelings engendered by the drug, factors that lead to drugse, the sources of drug craving, or the factors that lead to theotivation to quit, are among some of the obvious advantages of

tudies in human users. But there are many questions that can-ot be readily answered, especially some of the questions posedere about abstinence. The interpretation of studies of human drugbusers is limited by such factors as the highly variable drug histo-ies among the participants, current and prior history of legal andllegal drug use other than cocaine, and frequently co-morbid psy-hiatric conditions including depression and post-traumatic stressisorder. Another issue that is often limiting is the considerable dif-erences in inclusion criteria for drug use and abstinence, as well ashe reliance on self-reported drug use history. Longitudinal studiesf abstinence are further hampered by the socioeconomic chal-enges faced by many of these individuals including lack of steadyousing, adequate nutrition, and access to mental health care ser-ices necessary to fund treatment. But from the perspective ofnderstanding structural and functional brain changes associatedith abstinence, an important problem is distinguishing between

hose effects produced by the cessation of cocaine use and thoseffects that predate the initiation of drug use. This is a questionest addressed by preclinical studies in animal models.

With animal models, precise control over drug experience inerms of duration of exposure, total intake, and use of other drugsan be carefully controlled. Systematic manipulation of these andther variables can ensure that the results are attributable to theariables in question and provide a framework for mechanistictudies. Another important advantage is the use of well-matchedontrol groups in preclinical studies. It is often much more difficulto match subjects in human studies on key demographic variables.his is an important strength of animal models that is frequentlyverlooked. Finally, studies of the neurobiological consequencesf abstinence in animal models have the important advantage ofnsuring abstinence from both the drug in question and any otherrug.

Animal models of drug self-administration have proven to bealid predictors of multiple aspects of human drug abuse (Johansonnd Fischman, 1989; Schuster and Johanson, 1981) and havellowed us to investigate the neurochemistry of use and absti-ence more precisely than is possible in human cocaine abusers.urthermore, animal models enable us to identify behavioral, phar-acological, and neurobiological variables that mediate cocaine

se and abuse. These include decreases in dopamine D2 receptorsBeveridge et al., 2009; Nader et al., 2002b), alterations in dopamineelease dynamics (Bradberry, 2000; Bradberry et al., 2000; Wheelernd Carelli, 2009), white matter impairments (Nielsen et al., 2012),nd disruptions of glutamate signaling (Kalivas, 2008; Wolf, 2010),s well as changes in a myriad of other systems. While studies inumans have demonstrated differences between cocaine users andealthy controls on many of these same measures, animal mod-ls are able to uniquely describe the neuroadaptations that are airect result of drug exposure rather than a consequence of dif-


erences that predate drug use, as is a common caveat in clinicalesearch.

But are such neuroadaptations permanent even with the ces-ation of cocaine exposure? Does the cessation of drug use lead

PRESSavioral Reviews xxx (2013) xxx– xxx 5

to a restoration of structure and function disrupted during expo-sure? Again, these are questions where animal models can provideimportant insights into the process and consequences of abstinenceby allowing for the systematic manipulation of environmentalvariables, ensuring the absence of cocaine use, removing the com-plications that come from other legal and illicit drug use, andavoiding the confounds of co-morbid psychiatric disorders.

3.1. Is there evidence for recovery? Dopamine systems

One of the most robust findings from imaging studies of cocainedependent individuals, and certainly among the most studied incocaine abusers as well as in animal models, is the dysregulationof the dopamine system. Dopamine D2 receptors have been shownconsistently to be significantly lower in cocaine dependent indi-viduals (Martinez et al., 2004; Volkow et al., 1993), whereas thelevels of dopamine transporters have been found to be elevated(Malison et al., 1998; Mash et al., 2002; Staley et al., 1994) comparedto healthy controls. These differences in the dopamine system areaccompanied by decreases in stimulated dopamine release, againas measured with PET (see Volkow et al., 1997; Martinez et al.,2007). Data from investigations in animal models largely corrob-orate these findings (Letchworth et al., 2001; Mateo et al., 2005;Nader et al., 2002a; Nader et al., 2006), suggesting that the alter-ations are a consequence of drug use, rather than any pre-existingconditions.

Rodent studies have provided strong evidence for dysregula-tion of the dopamine system following abstinence. Samuvel et al.(2008), for example, investigated the molecular mechanisms ofDAT regulation following 3 weeks abstinence from cocaine self-administration and found significantly higher uptake of dopaminein the caudate putamen and nucleus accumbens, higher surfaceexpression of DAT and decreased serine phosphorylation in thecaudate-putamen (Samuvel et al., 2008). Similarly Jones and hercolleagues demonstrated that 7 days after the cessation of bingecocaine self-administration, basal levels of dopamine were reducedin the nucleus accumbens, as was electrically and cocaine stimu-lated release in this same brain region (Mateo et al., 2005). Althoughlonger withdrawal periods were not tested, these data support sig-nificant functional dysregulation of the dopamine system duringthe early stages of abstinence.

Studies in nonhuman primates have shown similar dysreg-ulation in the early stages of withdrawal. Elevations in theconcentrations of dopamine D1 receptors evident after chroniccocaine self-administration remained after cessation of drug use.But, 30 days after exposure to cocaine was discontinued, the den-sities of dopamine D1 receptors were higher throughout both thedorsal and ventral striatum to levels well beyond the already ele-vated concentrations resulting from cocaine self-administrationexperience (Fig. 2; Beveridge et al., 2009). The levels of dopaminetransporters followed a very similar pattern. However, if the periodof drug withdrawal was extended to 90 days, there was evi-dence of a return to control levels in both systems. These findingsstrongly suggest that alterations in dopamine systems associatedwith cocaine exposure are not necessarily permanent and that withextended abstinence may be re-regulated to more normal levels offunctioning.

In human cocaine abusers, the reductions in D2 receptor concen-trations persist into abstinence (Volkow et al., 1993). It is difficult todraw conclusions about the duration of this effect, however, sinceall of the participants had relapsed by the end of a few months.Furthermore, it is possible that lower D2 receptor concentrations


may have predated drug use. In animal models where greatercontrol over environmental and pharmacological variables can beexercised, Nader and colleagues have reported that D2 receptoravailability following limited (less than a month) cocaine exposure


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6 C.A. Hanlon et al. / Neuroscience and Biobehavioral Reviews xxx (2013) xxx– xxx

Fig. 2. Representative autoradiograms of [3H]SCH 23390 binding to dopamine D1 receptors (top panel) and [3H]WIN 35,428 binding to dopamine transporters (bottomp al respw 0 days

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dapted from Beveridge et al. (2009).

n nonhuman primates, recovered to control levels after only 1–3eeks. However, this was not the case when longer periods (12onths) of exposure to cocaine self-administration were investi-

ated. Here, recovery was found in only 60% of the monkeys within months, whereas in the other 40% there was no evidence of recov-ry even after as long as a year after the cessation of cocaine use.hese data emphasize the significance of the exposure period prioro the discontinuation of drug use. It is likely that because of theelatively short periods of exposure used in many studies using ani-al models, the intensity and duration of many neuroadaptationsay be underestimated.The critical element in these studies, however, is the range of

ndividual differences in the degree of normalization of dopamineystems, particularly in those studies that considered long dura-ions of withdrawal from cocaine use. Martinez et al. (2011) haveecently shown that among treatment seeking cocaine abusersetter treatment outcomes were associated with higher levels ofopamine stimulated release as measured with PET. Whether theigher dopamine transmission was due to recovery of the system

ollowing drug cessation or a “survivor” effect as described ear-ier, dopamine transmission may provide an important marker foruccessful abstinence.

.2. Does the structure of the brain change?

Mirroring findings in human cocaine abusers, a number oftudies have reported that cocaine exposure produces significanthanges in the structure of gray and white matter. Terry Robin-on and Bryan Kolb, along with their colleagues, have shownhat there are significant modifications in the architecture of den-rites and dendritic spines, particularly in the prefrontal cortexnd nucleus accumbens, of rats after exposure to psychostimu-ants including both cocaine and amphetamines (Robinson andolb, 1999). Repeated exposure to cocaine, whether administeredontingently, or non-contingently by the experimenter, producedncreased spine density of medium spiny neurons in the accumbensnd pyramidal cells in the medial prefrontal cortex (Robinson et al.,001). These structural changes in dendritic organization have been


hown to persist for up a month following the cessation of cocaineelf-administration (Robinson and Kolb, 1999) and for as long as.5 months after amphetamine exposure (Li et al., 2003). There

s some evidence, however, that these cocaine-associated changes

onding for food-reinforcement. Panels B and E: cocaine self-administration animal abstinence.

may be reversible after longer periods of abstinence (Kolb et al.,2003). The observation that alterations in neural spine density fol-lowing extended cocaine exposure may return to baseline levelsonly after extended periods of abstinence, is consistent with thepattern observed in the white matter of cocaine users–namely, asmentioned above, lower white matter integrity observed in chronicusers is present in short term abstainers but not in individuals thathave been abstinent for several months (Hanlon et al., 2011a). In thecase of human abstainers, many of the cognitive deficits observedin active users and short term abstainers are also not present inlong-term abstainers (Hanlon et al., 2011a).

Several investigations have also documented changes in theintegrity of white matter in the corpus callosum of rats exposed tochronic cocaine (Ma et al., 2009; Narayana et al., 2009). Four weeksof cocaine exposure via minipump resulted in significant changesin fractional anisotropy in the splenium of the corpus callosum,as measured with diffusion tensor imaging. This was accompa-nied by decreases in myelin basic protein (Narayana et al., 2009).Preliminary findings from our lab have demonstrated that pro-longed cocaine exposure in rhesus monkeys was associated withreductions in both myelin basic protein and proteolipid protein(Smith et al., 2011, 2012). However, the decreases in this studywere restricted to more anterior regions of the corpus callosum,more consistent with those observed in humans, as described ear-lier in this review. More recent studies have addressed the questionof the persistence of these changes by measuring DNA methylationof genes for transcription factors that regulate myelination in ratsfollowing 14 days of cocaine self-administration. These investiga-tors report that within 24 h of drug cessation there is an increasein methylation, followed by a hypomethylation observed 30 daysafter withdrawal from cocaine self-administration (Nielsen et al.,2012). These findings highlight the importance of the time afterdrug withdrawal as a critical factor in determining the nature of theadaptations. Early in the withdrawal phase, the changes observedare most likely to be the direct result of compensatory actions inresponse to drug removal. While later in the withdrawal phase, thechanges are much more likely to represent more stable persistentalterations in brain structure.


Whether these structural changes result in altered functionaland behavioral outcomes is the key question that remains to beinvestigated further. Although very preliminary, studies in our lab-oratory have begun to address the question of persistent alterations


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n basal levels of functional activity, as assessed with the 2DGethod, following the cessation of cocaine use in nonhuman pri-ate models of cocaine exposure. In these studies functional

ctivity was measured in a neutral environment not associated withhe availability of drug or other reinforcers. Persistent reductions inasal activity were observed in the striatum and prefrontal cortex as

ong as 30 days after the cessation of drug use. Of interest, the func-ional activity within the prefrontal cortex of these monkeys wasighly variable as measured 30 days after the last cocaine exposure.his variability may reflect a different temporal course of recoveryn some animals as compared to others, reminiscent of the differ-ntial restoration of dopamine systems observed by Nader et al.2006).

It is tempting to speculate that these animals with higher basalates of glucose metabolism in the prefrontal cortex may be mostikely to exhibit greater behavioral recovery, based on findingsescribed earlier in human cocaine abusers. Those able to remainbstinent for long periods of time (10 months or greater) appearedo have greater cortical functional activity, again suggesting thathis may be an important indicator of successful abstinence. Thisranslational line of research however, is clearly preliminary andeeds further investigation. Nonetheless, the value of these stud-

es in animal models is clearly the identification of the molecularnd cellular events that lead to the changes which, in the long term,ay result in the development of strategies to reverse, compensate

r prevent such deficits that can have a very profound impact onognitive function.

. Can we bridge preclinical and clinical research?

Throughout this commentary we have mentioned severalays in which well-controlled experiments in animal models of

ddiction can provide valuable interpretations for functional andtructural findings from clinical research (i.e. extended exposureo cocaine leading to variability in the recovery of the dopamineich striatum, and oligodendrocyte maturation as an explanationor elevated white matter in abstinence). There are at least twother promising lines of research however that we would like toention as models for bridging preclinical and clinical research:

.1. Investigating the role of BDNF

One of the ways in which animal models have helped our clin-cal understanding of cocaine addiction is the identification of themportant role of brain derived neurotrophic factor (BDNF). Whilet has been shown to play a role in various forms of plasticity (Black,999; Bramham and Messaoudi, 2005), BDNF is also involved in theurvival of dopamine neurons (Hyman et al., 1991). BDNF knockoutice have reduced locomotor responses to cocaine and diminished

ocaine-induced conditioned place preference, compared to wild-ype littermates (Hall et al., 2003). Subsequently it was shown thatnfusions of BDNF into the medial prefrontal cortex attenuate theeinstatement of cocaine-seeking (Berglind et al., 2007) and pre-ent cocaine-induced alterations in nucleus accumbens glutamateevels (Berglind et al., 2009). Interestingly, levels of BDNF in theentral tegmental area, amygdala and nucleus accumbens haveeen shown to progressively increase following withdrawal fromocaine self-administration (Grimm et al., 2003), suggesting thategulation of the protein may continue to occur even after the ces-ation of drug use. Moreover, elevated BDNF expression occurredn parallel with an enhanced response to cocaine cues (the ‘incuba-


ion of craving’ phenomenon). These data suggest that changes inDNF levels may result directly in changes in behavior.

These rodent data led clinical researchers to investigate whetherDNF levels were altered in human cocaine users (Angelucci et al.,


2007; D’Sa et al., 2011; Jiang et al., 2009). D’Sa et al. (2011) con-ducted a study in 3-week abstinent inpatient cocaine-dependentusers and prospectively followed them up to 90 days followingdischarge. While on the inpatient unit, they reported an elevationin serum BDNF levels compared with healthy controls. Interest-ingly, higher serum levels of BDNF predicted a shorter time torelapse following discharge from the inpatient unit, and greateramount of cocaine used. The authors, and others, posited, there-fore, that BDNF may act as a biomarker that may predict relapseto cocaine use (D’Sa et al., 2011; McGinty and Mendelson, 2011).These clinical data in turn encouraged additional research usinganimal models. This ‘reverse translational’ approach has resultedin a greater understanding the molecular events involved in BDNFregulation following cocaine exposure. Sadri-Vakili and colleagueshave shown recently, for example, that cocaine self-administrationin rodents resulted in elevated levels of BDNF mRNA in the striatumand medial prefrontal cortex. This increase was associated withcocaine-induced alterations in chromatin remodeling, includinghistone acetylation (Sadri-Vakili et al., 2010; Schmidt et al., 2012).

4.2. Imaging neurochemistry non-invasively

Positron emission tomography is clearly the primary meansthrough which we are currently able to translate findings in animalmodels of chronic cocaine use and abstinence (often in non-humanprimates) to clinical populations through various radioligands.Unfortunately however, PET in human users is fairly invasive(requiring that addicts are given a dose of radiation and an arterialor venous line), expensive, and only available at research sites withrapid access to the radioligands. Recently however, there have beensignificant developments in a non-invasive, widely available MRItechnique, magnetic resonance spectroscopy (MRS). This techniqueuses the properties of magnetic resonance to probe the neurochem-ical composition of the tissue being examined and is routinely usedin academic hospitals to investigate tissue composition. While itsreliability initially was limited to markers of neural health, inflam-mation and energy metabolism, such as creatine, myo-inositol, andN-acetylaspartate, it is now possible to isolate levels of glutamateand GABA (Licata and Renshaw, 2010) and can be applied to non-human primates as well as rodent models of addiction. Although ithas not been a primary area of focus in this commentary, both gluta-mate and GABA are very important components to the maintenanceof cocaine taking and are disrupted during abstinence. There havebeen a number of recent reviews detailing many of the changesin this system in animal models of addiction (Kalivas and Volkow,2011; Wolf, 2010).

Several early MRS studies demonstrated that cocaine usershave 30% less GABA in the prefrontal cortex (Ke et al., 2004) and23% less GABA in the occipital cortex than controls (Hetheringtonet al., 2000). Yang et al. (2009) at the National Institute on DrugAbuse were the first to demonstrate that cocaine users havesignificantly lower glutamate/creatine ratios in the anterior cin-gulate cortex than controls, and that this was related to length ofuse. Schmaal and colleagues (2012) administered N-acetylcysteine(which blocks cocaine reinstatement in rodents (Zhou and Kalivas,2008)), to cocaine users and demonstrated that it normalized theelevated glutamate/creatine ratios in these users. Although it isdifficult to rectify the results of these two studies, they both sug-gest that altered glutamate function is not restricted to the nucleusaccumbens in human addicts. Investigating glutamate and GABAconcentrations in human cocaine users however, is still in its


infancy. Future research in this area holds tremendous potential fortranslating many of the basic science results of altered glutamateand GABA activity to new, potentially patient-tailored treatmentoptions for human cocaine users.


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. Conclusions

Here, we have presented a collection of findings (by no meansntended to be exhaustive) from the perspectives of clinical andreclinical science in an attempt to answer two questions about theessation of cocaine use after a prolonged history of drug use: (1)hether the neuroadaptations that result from cocaine exposure

an reverse with abstinence, and (2) whether there are markersr neural signatures that can predict recovery. We have addressedhese questions through examples from both clinical and preclin-cal research.

On the surface, much of what we now know about the pro-ess of recovery from human cocaine abusers and animal modelsay seem to be worlds apart. Human studies address the dis-

ase as it exists, but can be difficult to interpret because theres little knowledge of pre-drug conditions, polydrug abuse andsychiatric co-morbidities. Animal studies can be systematic andarefully control variables, but do not adequately model the pat-ern of human drug use or the route of administration of the drugnd frequently employ very short drug exposure. While humaneuroimaging studies provide us with a lens that can only assessctivity in relatively large areas of the brain, preclinical studiesocus on transmitter systems that elegantly resolve alterations thatccur in pre and postsynaptic densities at the synaptic level. Whilelinical research on abstinence frequently uses “time to relapse” as

dependent measure, preclinical research typically reintroducesocaine at a predetermined time point and uses behavior as theependent measure. Other studies have attempted to examine theersistence of some cellular and molecular processes and how thesehange with time. Despite these seemingly independent lines ofnquiry, there are more and more opportunities for convergence,uch as through the role of BDNF, white matter depletion andestoration, and finally through evolving techniques which allow uso non-invasively quantify neurotransmitter levels in addicts thatre able to successfully abstain from cocaine.

While we have focused on the alterations in brain structure,eurotransmitter system regulation, and functional activity in therains of cocaine users and abstainers, we have not addressed theritical behavioral hallmarks of the addiction and recovery pro-ess. From impulsivity to craving, cognitive set-shifting to measuresf self-control, there is a very large body of research which hasharacterized behavioral phenotypes of addiction in both humansers and in non-human primates following exposure to cocaineBeveridge et al., 2008; Garavan and Hester, 2007; Stalnaker et al.,009). As we attempt to bridge the neurobiological findings fromlinical and preclinical studies of cocaine use and abstinence, itill be important to integrate the literature on behavioral patterns

hat predict successful recovery. Through the integration of theseomponents we will be much more likely to generate individually-ailored therapies, both pharmacologic and behavioral, for thosehat find themselves on this continuum of addiction, from vulner-ble adolescents to treatment-seeking individuals that recurrentlyelapse.

Along these lines, perhaps the most important differenceetween clinical and preclinical investigations of cocaine absti-ence is the inability to address the motivation to remain drug free.nimal models of abstinence cannot effectively model the motiva-

ion for discontinuing drug use and therefore, cannot mimic theuman situation. In animal models, the cessation of drug use is

mposed on the animal. This would be analogous to being placednto a locked ward with no access to drug. In contrast, the moti-ation of human cocaine users to quit generally stems from fear


f negative consequences to their health, welfare, or because of theresence of stronger non-drug reinforcers in the environment (e.g.,ontingency management). In either case, the intrinsic motivationf drug users to quit and remain abstinent is not modeled in most


animal studies. Volition and self-control are not generally consid-ered in animal models. Similarly, neither forced drug withdrawalor extinction procedures mimic the human situation. So as withanimal models of other disorders, it is important to consider theirlimitations along with their strengths and focus on the aspects ofthe neurobiology that are relevant.

Indeed some attempt has been made using animal models tointroduce an element of choice during self-administration (Banksand Negus, 2012; Griffiths et al., 1975; Johanson, 1975; Naderand Woolverton, 1991). These studies typically employ a paradigmin which two levers are presented simultaneously. Responses onone lever result in drug delivery while responding on the otherresults in delivery of an alternate reinforcer (such as food or sweet-ened water). These data have provided important insights; forexample, some animals prefer to respond on the food-associatedlever versus cocaine-associated lever when the magnitude of thealternate reinforcer was sufficient to decrease the potency of thepositive reinforcing effects of cocaine (Lenoir et al., 2007; Naderand Woolverton, 1991). These data suggest that, as with humans,self-administration can be attenuated by increasing the value ofalternate positive reinforcers (contingency management) (Griffithset al., 1980).

Finally, with regard to biomarkers that can predict successfulrecovery from cocaine abuse, we propose here that it is preser-vation of cortical function that is perhaps the most importantpredictor. This is supported by the lack of cortical structural andfunctional deficits in those cocaine abusers that have been able toremain abstinent for long periods of time, often beyond a year atthe time of testing (references). We have argued that these indi-viduals may represent a unique sub-population of drug users thathave been able to remain abstinent because of greater structuralcortical integrity and resulting function. Those that exhibit greaterdegrees of structural and functional cortical damage are far lesslikely to be able to muster the resources to remain abstinent foreven brief periods of time. Longitudinal studies will be necessaryto confirm this hypothesis, but increasing numbers of studies thathave been focused on the biology of successful recovery supportthis idea. While clinical studies will be key, preclinical studies canprovide important insights into the essential processes that areboth necessary and for identification of targets for treatment.

Acknowledgments

Funding for this work was provided by National Institutesof Health grants K01DA027756, DA09085 and DA06634. Theauthors received no compensation from other external organiza-tions related to this manuscript and declare no competing financialinterests.

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Recovering from cocaine: Insights from clinical and preclinical investigations