1521-0103/356/3/534–548$25.00 http://dx.doi.org/10.1124/jpet.115.229922 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 356:534–548, March 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Minireviews The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs Gerard J. Marek, Mark Day, and Thomas J. Hudzik Astellas Pharma Development, Northbrook, Illinois (G.J.M.); Alexion Pharmaceuticals, Cheshire, Connecticut (M.D.); and AbbVie, North Chicago. Illinois (T.J.H.) Received October 8, 2015; accepted December 22, 2015 ABSTRACT Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and in- creased impulsivity. Accordingly, a translational medicine para- digm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been system- atically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter- response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impul- sivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. Introduction Given the wealth of diverse symptoms characterizing major depressive illness, providing optimal translation from pre- clinical animal studies to experiments with healthy volun- teers or dysthmic individuals to clinical antidepressant trials may require understanding the core features of major depres- sive episodes. Anhedonia, an inability to experience pleasure is one of the key symptoms of depression that has been used to model depression in animal studies. Another potential core symptom is hopelessness, a symptom related to poorly adap- tive cognitive processing. In recent years cognitive dysfunction is increasingly recognized as being impaired in major depres- sive disorders (MDDs). Given the heterogeneity of MDD, preclinical screening paradigms based on multiple core/key symptoms are warranted to provide optimal predictions to- ward testing in clinical populations, since it is unlikely that any single preclinical paradigm can adequately predict trans- lation to positive and negative clinical trials. The cognitive symptoms of mood disorders include hopeless- ness, feelings of worthlessness or inappropriate guilt, dimin- ished ability to think or concentrate, indecisiveness, and recurrent thoughts of death and suicidal ideation/attempts. In the mid-to-late 1960s, Beck (2008) described a negative triad for depressed patients including a negative interpretive bias toward oneself, the world, and one’s future. Cognitive behavioral therapy was derived from this theoretical under- pinning of ruminative cognitive misperceptions pervading the life of depressed patients and has been widely used in the The authors are employed by Astellas Pharma Development (G.J.M.), AbbVie (T.J.H.) and Alexion Pharmaceuticals (M.D.), but they received no internal or external funding for this work. dx.doi.org/10.1124/jpet.115.229922. ABBREVIATIONS: DAT, dopamine transporter; DRL, differential reinforcement of low rate; 5,7-DHT, 5,7-dihydroxytryptamine; 5-CSRTT, five- choice serial reaction time task; IL, infralimbic cortex; IRT, inter-response time; MAM, methylazoxymethanol acetate; MDD, major depressive disorder; MK-801, dizocilpine; M100907, volinanserin; mPFC, medial prefrontal cortex; NET, norepinephrine transporter; NMDA, N-methyl-D- aspartate; PFC, prefrontal cortex; PL, prelimbic cortex; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; VH, ventral hippocampus. 534 at ASPET Journals on February 19, 2016 jpet.aspetjournals.org Downloaded from
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1521-0103/356/3/534–548$25.00 http://dx.doi.org/10.1124/jpet.115.229922THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 356:534–548, March 2016Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics
Minireviews
The Utility of Impulsive Bias and Altered Decision Making asPredictors of Drug Efficacy and Target Selection: RethinkingBehavioral Screening for Antidepressant Drugs
Gerard J. Marek, Mark Day, and Thomas J. HudzikAstellas Pharma Development, Northbrook, Illinois (G.J.M.); Alexion Pharmaceuticals, Cheshire, Connecticut (M.D.); andAbbVie, North Chicago. Illinois (T.J.H.)
Received October 8, 2015; accepted December 22, 2015
ABSTRACTCognitive dysfunction may be a core feature of major depressivedisorder, including affective processing bias, abnormal responseto negative feedback, changes in decision making, and in-creased impulsivity. Accordingly, a translational medicine para-digm predicts clinical action of novel antidepressants byexamining drug-induced changes in affective processing bias.With some exceptions, these concepts have not been system-atically applied to preclinical models to test new chemicalentities. The purpose of this review is to examine whether anempirically derived behavioral screen for antidepressant drugsmay screen for compounds, at least in part, by modulating animpulsive biasing of responding and altered decision making.The differential-reinforcement-of-low-rate (DRL) 72-secondschedule is an operant schedule with a documented fidelityfor discriminating antidepressant drugs from nonantidepressant
drugs. However, a theoretical basis for this empirical relationshiphas been lacking. Therefore, this review will discuss whetherresponse bias toward impulsive behavior may be a criticalscreening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare andcontrast DRL behavior with the five-choice serial reaction timetask, a test specifically designed for assessing motoric impul-sivity, with respect to psychopharmacological testing and theneural basis of distributed macrocircuits underlying these tasks.This comparison suggests that the existing empirical basis forthe DRL 72-second schedule as a pharmacological screen forantidepressant drugs is complemented by a novel hypothesisthat altering impulsive response bias for rodents trained onthis operant schedule is a previously unrecognized theoreticalcornerstone for this screening paradigm.
IntroductionGiven the wealth of diverse symptoms characterizing major
depressive illness, providing optimal translation from pre-clinical animal studies to experiments with healthy volun-teers or dysthmic individuals to clinical antidepressant trialsmay require understanding the core features of major depres-sive episodes. Anhedonia, an inability to experience pleasureis one of the key symptoms of depression that has been used tomodel depression in animal studies. Another potential coresymptom is hopelessness, a symptom related to poorly adap-tive cognitive processing. In recent years cognitive dysfunction
is increasingly recognized as being impaired in major depres-sive disorders (MDDs). Given the heterogeneity of MDD,preclinical screening paradigms based on multiple core/keysymptoms are warranted to provide optimal predictions to-ward testing in clinical populations, since it is unlikely thatany single preclinical paradigm can adequately predict trans-lation to positive and negative clinical trials.The cognitive symptoms ofmood disorders include hopeless-
ness, feelings of worthlessness or inappropriate guilt, dimin-ished ability to think or concentrate, indecisiveness, andrecurrent thoughts of death and suicidal ideation/attempts.In the mid-to-late 1960s, Beck (2008) described a negativetriad for depressed patients including a negative interpretivebias toward oneself, the world, and one’s future. Cognitivebehavioral therapy was derived from this theoretical under-pinning of ruminative cognitive misperceptions pervading thelife of depressed patients and has been widely used in the
The authors are employed by Astellas Pharma Development (G.J.M.),AbbVie (T.J.H.) and Alexion Pharmaceuticals (M.D.), but they received nointernal or external funding for this work.
treatment of depressed and/or anxious patients. Impulsivenessmay be another expression of disturbed executive functions inpatients withmood disorders; motoric impulsivity may interactwith depression severity to moderate suicidal ideation in atleast some depressed patients (Westheide et al., 2008; Wanget al., 2015).This current review posits that one frequently used empir-
ically derived behavioral screen for antidepressant drugs maydepend on improving cognition. After describing the clinicalunderstanding for neurocognitive dysfunction in MDD, re-search directed at utilizing drug-induced changes in emotionalprocessing as a translational tool for predicting the clinicaleffects of drugs in randomized clinical trials will be outlined.This will then lead to a discussion of how altering impulsivity(action or motoric impulsivity) may be an underlying basis forthe positive predictability of the differential-reinforcement-of-low-rate (DRL) 72-second schedule with respect to antide-pressant drug development. Specifically, the pharmacologyand neurocircuitry underlying motoric impulsivity in rodentsperforming the five-choice serial reaction time task (5-CSRTT)will be compared with the DRL schedules since the 5-CSRTTwas developed in part to specifically assess specific aspectsof impulsivity. The hypothesis will be advanced that thebiasing of impulsive behavior toward longer periods of waitingbehavior may be a critical feature underlying the positivepredictive feature of the DRL 72-second schedule of reinforce-ment with respect to discrimination of antidepressant drugsfrom nonantidepressant drugs.Cognitive Dysfunction and Depression. Rather than
attempting to incorporate as many possible endpoints withface validity for depression into preclinical models/screens forantidepressant drugs, another recently suggested approachis to understand the factors leading into, and maintaining,a negative mood state (Holtzheimer and Mayberg, 2011).Increased clinical attention is being paid to the cognitivecharacteristics of depression involving dysregulation of exec-utive control, memory, temporal perception, affective process-ing bias, and feedback sensitivity (Bschor et al., 2004; Clarket al., 2009). Not only have the neuroimaging studies ofdepressed patients highlighted distributed cortical-subcorticalcircuits underlying depressive symptoms (Mayberg, 1997);Drevets et al., 2008; Price and Drevets, 2010), but aspects ofthese distributed cortical-subcortical circuits also appear tounderpin the dysregulated processing of affectively chargedinformation (Phillips et al., 2003). However, rather than apervasive deficit seen across most cognitive functions forsyndromes such as schizophrenia, included among mostsalient cognitive deficits in depressed patients may be distor-tions in managing the affective valence of information pro-cessing. These distortions of emotional information processingare intimately related to hopelessness in a manner consistentwith earlier notions advanced by Beck (2008) and Gvion et al.(2015).Negative Response Bias and Depression. If emotional
information processing is altered in depression, this raises thequestion as to whether drugs that alter emotional informationprocessing biases in healthy subjects and dysthymic or de-pressed volunteers may predict antidepressant activity inclinical trials. As reviewed by Pringle et al. (2011), biases inattention, memory, and interpretation have been reported aspredicted from the cognitive theories of depression advancedby Beck (2008). These negative biases in depression extend to
depressed patients’ handling of positive or negative emotionalexpression. In a series of studies pioneered by Harmer et al.(2011), and then extended in an academic/industrial collabo-ration with the clinical research organization P1Vital (Oxford,United Kingdom). Harmer and colleagues has produced anemotional test battery that does appear to predict activityof known antidepressants (after a single dose or single weekof administration); drugs lacking these effects also are notknown to produce antidepressant action in the clinic (Harmeret al., 2011).Modeling Depressive Cognitive Dysfunction and Re-
sponse Bias in Animals. Depressed subjects are impairedin go/no-go tasks, as described previously, and also exhibitnegative cognitive affective biases in such tasks. There are arange of go/no-go tasks and choice procedures that can beexplored for dimensional readouts of executive function. Theseissues have been examined preclinically. Harding et al. (2004)trained rats to associate two different auditory cues withdifferent emotional states associated with reward or punish-ment. When presented with an ambiguous tone, intermediateto the two that were trained, bias was exhibited toward thetone associated with the negative affective state under circum-stances of chronic stress, much as has been shown in depressedhumans (Harmer et al., 2009). There have since been manyvariants of these negative biasing procedures in rodents,notably the affective bias test (Stuart et al., 2013), and ingeneral antidepressants predictably appear to reverse thebias induced by stressors.Impulsivity and Mood Disorders. In addition to find-
ings implicating a negative bias of informational processing inmood disorders, there are also reports describing an increasein impulsivity (including motor impulsivity) in mood disor-ders. Research has focused more frequently on the clinicallyobvious increase in impulsivity in patients with bipolardisorders; however, patients with major depression have alsobeen found to exhibit greater impulsivity than healthy controlsubjects (Swann et al., 2008). Even euthymic patients withMDD show greater motor impulsivity than healthy controlsubjects. Recently, these findings have been extended tosimilar relationships in children and adolescents with MDD(Peluso et al., 2007). Akiskal et al. (2005) have suggested thatapproximately 20% of depressed patients may present with anagitated unipolar depression that shares some features of adepressive mixed state with distractibility, racing thoughts,an irritable mood, talkativeness, risky behavior, and in-creased suicidality. Impulsivity appears to discriminate de-pressed subjects without a history of suicide attempts fromthose with a positive personal history (Perroud et al., 2011).Thus, increased impulsivity appears to be another aspect ofexecutive function impairment in patients with mood disor-ders, and especially in those at increased risk for suicide(Westheide et al., 2008; McCullumsmith et al., 2014; Sancheset al., 2014; Wang et al., 2015).While not being frequently examined on impulsivity in
depressed patients per se, antidepressant drugs such asthe selective serotonin reuptake inhibitor (SSRI) sertraline[1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine] have been demonstrated to decrease impulsivity(Dunlop et al., 2011). Suicidality may be considered in part aproxy for impulsivity, given the previously discussed relation-ships between depression, impaired cognition (including rumina-tive thoughts), hopelessness, and suicidal ideation/behavior.
Meta-analyses have consistently found that SSRIs, tricyclicantidepressants (TCAs), venlafaxine (1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol) (see Fig. 1), and the atypicalantipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) attenuate sui-cidality (as measured by single items of depression rating scales)with an effect size of 0.21–0.29 (Faries et al., 2000; Entsuah et al.,2002; Reimherr et al., 2010; Hieronymus et al., 2015). Thismakes the 17-item Hamilton depression rating scale suicideitem among the 4 to 5 itemsmost sensitive to pharmacologicalchange. This is a remarkable finding in light of patients withclinically significant suicidal ideation generally being ex-cluded from large multicenter MDD trials conducted byindustry sponsors. Like depressed mood, suicidal ideation
may show significant improvement within the first severalweeks of treatment, unlike the case for a number of neuro-vegetative symptoms such as early insomnia and appetite(Shelton et al., 2007; Reimherr et al., 2010). Preliminary datafor adjunctive treatment with low-dose (0.25–2 mg) risper-idone (3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]etyl]-6,7,8,9-tetrahydro-2-metyl-4H-pyridol[1,2-a]pyrimidin-4-one)also suggested a relatively rapid effect of this 5-HT2A/dopamine D2 receptor antagonist on decreasing suicidality aswell as depressedmoodwithin the first fewweeks of treatment(Reeves et al., 2008). In an attempt to improve the pharma-cological sensitivity of the full-length 17-item Hamiltondepression rating scale, addition of the suicidality item tothe six-item Hamilton depression rating scale results in evengreater pharmacological sensitivity than for the Beck subscale(Santen et al., 2008). Thus, a range of antidepressants appearto improve suicidality as assessed using a single suicide itemfrom depression scales (Santen et al., 2008).The issue of suicidality and antidepressants has been
especially controversial dating back to the introduction ofblack box warnings on suicidality for antidepressant drugs,although a systematic review of clinical and epidemiologicstudies converge on the finding that antidepressants overallhave a beneficial effect on suicidality in depressed patients(Möller, 2006). A large prospective, naturalistic, multicenterstudy involving 1014 patients has clearly demonstrated abeneficial effect on suicidal ideation since the improvementof suicidal ideation was reported in 91% of hospitalizedinpatients, compared with 3% and 15% of patients withworsening or no change, respectively, in suicidal ideation(Seemüller et al., 2009). Thus, antidepressant drugs have anoverwhelming beneficial effect on suicidality from a pop-ulation perspective. This conclusion is consistent with a webof overlapping relationships between major depression,impulsivity, and other executive dysfunctions, hopeless-ness, and suicidality (Westheide et al., 2008; Clark et al.,2011; Carver et al., 2013; Keilp et al., 2013; Joormann andQuinn, 2014).DRL Operant Schedules and Impulsive Response
Bias. The improvement of response efficiency of rats respond-ing under a DRL 72-second schedule has been extensivelyused as an empirically derived behavioral screen for antide-pressant drugs (O’Donnell et al., 2005). Mice, rats, and non-human primates can be trained on DRL schedules, resultingin stable baseline behavior on which to explore drug effects.Either water or food can be used to differentially reinforcelonger inter-response times (IRTs) (all IRT intervals $72seconds) versus shorter IRTs. When rats are trained to astable baseline of behavior, most antidepressant drug classes,including electroconvulsive shock, have been found to increasethe reinforcement rate, decrease response rates, and cohe-sively shift to the right the IRT distributions (Fig. 2; Table 1).Most classes of nonantidepressant drugs tested, assuming anadequate background reinforcement rate (baseline reinforce-ment rate $7 reinforcers/hour), do not share this commonbehavioral profile on the DRL 72-second schedule, as pre-viously reviewed by O’Donnell et al. (2005). A theoretical basisexplaining why DRL behavior appears to predict antidepres-sant activity was not explicitly evident when this behavioralscreen was initially described in the 1980s by Seiden andcolleagues (McGuire PS and Seiden, 1980; O’Donnell andSeiden, 1983; Seiden et al., 1985).
Fig. 1. Correlations of antidepressant drug effect size for individual itemsof the 17-item Hamilton depression rating scale (HAMD-17) derived frompublished meta-analyses and reviews. The top graph shows the correla-tion between the effect sizes for SSRIs (Hieronymus et al., 2015) versusTCAs (Faries et al., 2000). For this correlation, r2 = 0.051 and P = 0.0005.The lower graph shows the correlation between the effect sizes for SSRIs(Hieronymus et al., 2015) versus the serotonin-norepinephrine reuptakeinhibitor venlafaxine (Entsuah et al., 2002). For this correlation, r2 =0.0.778 and P , 0.0001. The suicidal ideation item, one of the top fivepharmacologically sensitive items, is demarcated by the number 3. Theother items are represented by the following numbers: 1, mood; 2, guilt; 4,early insomnia; 5, middle insomnia; 6, late insomnia; 7, work/activities; 8,retardation; 9, agitation; 10, psychic anxiety; 11, somatic anxiety; 12,gastrointestinal somatic symptoms; 13, general somatic symptoms; 14,genital symptoms; 15, hypochondriasis; 16, loss of weight; and 17, insight.
Cognition may be a link between DRL behavior andpredicting antidepressantlike potential of approved and noveldrugs. While drugs may alter different aspects of DRLbehavior, including temporal discrimination, an impulsivelever-response bias is another behavioral dimension that maybe impacted by antidepressant drugs. When lever pressing onlong DRL schedules—if rodents have avoided early bursts ofresponding during the initial seconds following the previousresponse—the IRT distribution for individuals or groups ofsubjects usually peaks around 35–60 seconds. The frequencyof longer IRTs progressively declines, although sometimeswith another peak with very long pauses .120 seconds. Theshape of the IRT distribution means that usually less than15% of total lever presses are followed by availability of awater (or food) reinforcer. Under control conditions, Fowleret al. (2009) have suggested that rats responding on a DRL72-second schedule locate themselves away from the operantlever and tend to exhibit very little movement. Only inthe approximately last 8 seconds prior to a reinforced or un-reinforced response did the rats exhibit an increased amountof horizontal locomotion. In contrast to baseline behavior,psychomotor stimulants such as amphetamine (1-phenylpropan-2-amine) increase the response rate, decrease the reinforcementrate, and cause a leftward shift in the IRT distribution. Thispattern is consistent with expectations for an increased biastoward impulsive responding.The 5-CSRTT: Visual Attention and Impulsivity. The
5-CSRTT, as employed in preclinical species such as rodents,is a paradigm designed to measure visual attention, motoricimpulsivity, and compulsivity. It was originally inspired tostudy analogous neural processes as those in the humancontinuous performance task used in healthy volunteers andpatients with schizophrenia or attention deficit hyperactivitydisorder (Robbins, 2002). This task provides a means to studyvigilance or sustained attention without potential confoundsof impaired motor behavior. Similarly, nose pokes prior to thepresentation of the stimulus starting a new trial is a pre-mature response that may be analogous to leftward-shiftedIRTs on a DRL schedule, particularly when omissions inresponding during the trial or perseverative responses are notobserved. While there are some significant differences be-tween typical 5-CSRTTs with inter-trial intervals of 5–10seconds compared with the DRL 72-second schedule, whereanimals must withhold responding for 72 seconds followingtheir last response, we will discuss the similarities withrespect to the psychopharmacology and underlying neuro-circuitry between impulsive behavior in the 5-CSRTT andDRL schedules previously suggested by Dalley et al. (2011).
Pharmacological Similarities between the DRL72-Second Schedule and the 5-CSRTT
An important initial psychopharmacological comparisonbetween the DRL 72-second schedule and 5-CSRTT is thesystemic administration of channel blocking N-methyl-D-aspartate (NMDA) receptor antagonists such as dizocilpine(MK-801), 5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (Table 1). MK-801 results in anincrease in premature responses and response omissions onthe 5-CSRTT during a time frame where the rats exhibit anincrease in locomotor activity (Higgins et al., 2003; Paine et al.,
2007; Paine and Carlezon, 2009; Smith et al., 2011; Benn andRobinson, 2014). Local infusion of competitiveNMDA receptorantagonists have also been frequently examined to mitigatebehavioral confounds of noncompetitive channel blockingNMDA receptor antagonists, such as prevalent omission inresponding during extended periods that animals make no orfew responses. This is discussed in the subsequent section onthe underlying neuroanatomy of the 5-CSRTT. For DRL72-second behavior, systemic administration of MK-801induces a dose-dependent increase in total responses and aleftward shift of the IRT distribution consistent with in-creased impulsivity (Ardayfio et al., 2008; Hillhouse andPorter, 2014). At high doses MK-801 can completely suppresslever pressing, probably analogous to increased omissionsseen on the 5-CSRTT.The effects of another channel blocking NMDA receptor
antagonist, ketamine (2-(2-chlorophenyl)-2-(methylamino)cyclohexanone), can be at least partially discriminated fromMK-801 on both the 5-CSRTT and DRL 72-second behavior.Unlike a stimulant- or psychotomimeticlike action of MK-801on DRL 72-second behavior, ketamine increases the reinforce-ment rate, decreases the total response rate, and induces arightward shift of the IRT distribution similar to antidepres-sant drugs (Hillhouse and Porter, 2014; G.J. Marek, un-published data). In only a single study has ketamine beenfound to increase premature responding with the 5-CSRTT,and this was in only one of two mouse strains tested (Oliveret al., 2009). In contrast, systemic administration of ketaminefailed to increase premature responding in several studieswhere MK-801 did increase premature responding (Smithet al., 2011; Benn and Robinson, 2014). In another study,ketamine failed to increase premature responding as well(Nikiforuk and Popik, 2014). There are several potentialexplanations for the differential effects of ketamine and MK-801. The first explanation may be the relatively short pharma-cological half-life of ketamine in rodent and human studies,where dissociation may be seen with respect to early acutepsychomimetic effects and antidepressantlike effects that maybe present in humans and rodents after the psychotomimeticeffects have resolved. A second pharmacodynamic-based expla-nation for the differential effects of ketamine versus MK-801may be based in the commonly held view that ketamine acts ona number of other pharmacological sites, perhaps includingm-opioid receptors and sigma1 binding sites (Sanacora andSchatzberg, 2015). At the present time there is widespreadagreement that single ketamine doses producing measurablepsychomimetic responses also produce an antidepressantlikeresponse in patients, beginning several hours after ketamineadministration with a duration of up to nearly two weeks(Berman et al., 2000; Iadarola et al., 2015; McGirr et al., 2015).However, it is not clear that any other more selective NMDAreceptor antagonist tested in the clinic produces comparable orimproved efficacy as has been demonstrated with ketamine(Sanacora and Schatzberg, 2015). Despite the psychomimeticeffects and cognitive impairment that may be produced withinthe first 30–45minutes following ketamine administration, theclinical use of ketamine in depressed patients does appear todecrease suicidality (DiazGranados et al., 2010; Zarate et al.,2012; Ballard et al., 2014; Price et al., 2014).Striking similarities also exist between the DRL 72-second
schedule and the 5-CSRTT with respect to the serotonergicsystem and serotonin-glutamate interactions. This is most
obvious with the widely replicated finding that the 5-HT2A
receptor antagonist volinanserin (M100907), (R)-a-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, blockedthe impulsivelike NMDA receptor antagonist–induced disrup-tion of 5-CSRTT (Higgins et al., 2003;Mirjana et al., 2004; Carliet al., 2006; Pozzi et al., 2010; Fletcher et al., 2011; Agnoli andCarli, 2012). M100907 similarly attenuates the impulsivelikeaction of MK-801 on DRL 72- or 24-second behavior (Higginset al., 2003; Ardayfio et al., 2008). The 5-HT2A receptorantagonists M100907 or ketanserin (3-[2-[4-(4-fluorobenzoly)piperidin-1-yl]ethyl]-1H-quinazoline-2,4-dione) alone havebeen reported to improve impulsive performance of ratstrained on the 5-CSRTT (Talpos, 2006; Fletcher et al.,2011). However, selective 5-HT2A receptor antagonistsM100907, ketanserin, or pipamperone (1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidin-1-ylpiperidine-4-carboxamide) have moreconsistently been demonstrated to improve impulsivity ofrats performing on the DRL 72-second schedule in a dose-dependent fashion (Marek and Seiden, 1988; Marek et al.,1989, 2005; Balcells-Olivero et al., 1998; Ardayfio et al.,2008). Furthermore, activation of the 5-HT2C receptor actssimilarly, and in at least an additive fashion, with blockadeof the 5-HT2A receptor on both the 5-CSRTT and DRL72-second behavior (Martin et al., 1998; Fletcher et al., 2007;Navarra et al., 2008a; Agnoli and Carli, 2012). This func-tional antagonism between 5-HT2A and 5-HT2C receptorswith respect to impulsivity induced by MK-801 was con-firmed for the 5-CSRTT and DRL 24-second behavior (Higginset al., 2003).With respect to clinical effects, pipamperone is the only
5-HT2A receptor antagonist with at least modest selectivitythat has been tested for adjunctive treatment of MDD. In arandomized, multicenter, placebo-controlled trial, a dose ofpipamperone probably blocking no more than ∼60% of brain5-HT2A receptors appeared to exert an antidepressant effectwhen added onto citalopram, especially during treatmentweeks 1–4 (Wade et al., 2011). However, the common phar-macological action shared by approved antidepressants tra-zodone (2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridine-3-one), nefazodone (2[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazol-3-one), and mianserin [(6)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine] in addition tothe approved atypical antipsychotics aripriprazole, olanzapine(2-methyl-4-(4-methylpiperazin-1-yl)-5H-thieno[3,2-c][1,5]benzodiazepine), risperidone, and quetiapine (2-[2-(4-benzo[b][1,4]benzothiazepin-6-ylpiperazin-1-yl)ethoxy]ethanol) is block-ade of 5-HT2A receptors. All of these drugs, except risperidone,have been approved by regulatory agencies for either mono-therapy or adjunctive treatment of MDD. However, furtherevidence is required before definitively concluding that selec-tive blockade of 5-HT2A receptors exerts antidepressanteffects in patients with MDD.
Fig. 2. Antidepressantlike effects of drugs in rats performing on the DRL72-second schedule exemplified by the TCA desipramine. The top graphshows the dose-dependent increase (0.625–10 mg/kg, i.p.) in the re-inforcement rate for a group of eight male Sprague-Dawley rats expressedas the mean + S.E.M. reinforcers obtained during a 60-minute behavioralsession. The middle graph displays the dose-dependent decrease in thetotal responses relationship for desipramine in this same group of rats.The increase in the reinforcement rate and the decrease in response rate
are characteristic of most antidepressant drugs including electroconvul-sive shock. * P , 0.05; ** P , 0.01; *** P , 0.001. The bottom graphdisplays the IRT distribution (measured in seconds) derived from theentire group of rats shown in the top and middle graphs. The cohesiverightward shift in the peak of IRTs close to the reinforcement timerequirement (72 seconds) is characteristic of antidepressant drugs andmay reflect, at least in part, an effect of antidepressant drugs on motoricimpulsivity.
Globally increasing 5-HT synaptic availability by adminis-tering serotonin transporter inhibitors also suppresses prema-ture responses on the 5-CSRTT (Baarendse and Vanderschuren,2012). While SSRIs probably do not as consistently androbustly demonstrate antidepressant responses in rats per-forming on the DRL 72-second schedule, SSRIs—primarilyfluoxetine (N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine))—can exert cohesive rightward shifts in theIRT distribution (increased peak latency) together with in-creases in the reinforcement rate and decreases in the responserate (Richards et al., 1993b; Balcells-Olivero et al., 1998;Sokolowski and Seiden, 1999; Cousins and Seiden, 2000).These similar effects of SSRIs on impulsivity for the 5-
CSRTT and DRL 72-second schedule are consistent with theliterature on global 5-HT depletions. Earlier findings thatglobal 5-HT depletions with the serotonergic neurotoxin5,7-dihydroxytryptamine (5,7-DHT) increase impulsivity inrodents measured by increased premature responses on the 5-CSRTT have been translated to humans with 5-HT depletionsinduced by the dietary tryptophan depletion paradigm inhealthy volunteers administered an analogous four-choiceserial reaction time test (Harrison et al., 1997; Winstanleyet al., 2004; Worbe et al., 2014). Similarly, global brain 5-HTdepletions in rats with intraventricular 5,7-DHT lesions alsoincrease the response rate with a clear leftward shift in theIRT distribution in subjects responding under a DRL 72-second schedule (Jolly et al., 1999). Thus, this similar patternof changes on presumedmotoric impulsivity for the 5-CSRTTand DRL 72-second behavior with serotonergic depletions,global increases in 5-HT availability by SSRIs, 5-HT2A
receptor antagonists with or without concurrent NMDAreceptor antagonism, and 5-HT2C receptor agonists suggestsa central importance for 5-HT in controlling this aspect ofimpulsivity.Some, but not all, drugs acting to inhibit the norepinephrine
transporter (NET) display apparent anti-impulsive effects onboth the 5-CSRTT and DRL 72-second behavior. SelectiveNET inhibitors such as atomoxetine [(3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine] and reboxetine[(2S)-2-[(S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine], ap-proved for the treatment of attention deficit hyperactivitydisorder and MDD, respectively, both decrease prematureresponding of rodents in the 5-CSRTT (Navarra et al., 2008b;Paterson et al., 2011b; Baarendse and Vanderschuren, 2012;Robinson, 2012). In an analogous manner, selective NETinhibitors reboxetine and (1)-oxaprotiline [(1)-3-(9,10-ethano-9,10-dihydro-9-anthryl)-1-methylamino-2-propanol] increasedthe reinforcement rate, decreased the response rate, andexerted a cohesive rightward shift in the IRT distribution ofrats responding on a DRL 72-second schedule (Marek et al.,1988; Wong et al., 2000; Dekeyne et al., 2002). TCAs such asdesipramine [3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methylpropan-1-amine] potently inhibit the NET but alsoinhibit a range of G-protein-coupled receptors sharing commontransduction pathways such as 5-HT2A/2C, a1-adrenergic, his-tamine H1, and muscarinic cholinergic receptors. Some TCAs,but not desipramine, also potently inhibit the serotonin trans-porter. Desipramine does suppress premature responses in ratstested on the 5-CSRTT (Paine et al., 2007). Desipramine, aswith most TCAs, are among the most reliable antidepressantdrugs tested for producing robust antidepressantlike effects(increased reinforcement rate, decreased responses, and a
cohesive rightward shift in the IRT distribution) in animalsperforming on the DRL 72-second schedule (Marek andSeiden, 1988; Richards and Seiden, 1991; Richards et al.,1993a; Cousins and Seiden, 2000; Ardayfio et al., 2008;Scott-McKean et al., 2008; Paterson et al., 2011a; Hillhouseand Porter, 2014).In contrast to NET inhibitors and TCAs, compounds
inhibiting the NET and dopamine transporter (DAT) or theDAT alone do not appear to attenuate impulsivity, but ratherenhance impulsivity with respect to both the 5-CSRTT andDRL 72-second behavior. Examination of adequate doseranges over adequate 5-CSRTT intertrial intervals tends toshow beneficial effects of methylphenidate (methyl 2-phenyl-2-piperidin-2-ylacetate) on the accuracy or omissions, al-though with increased impulsivity (premature responses)at higher doses (Paine et al., 2007; Navarra et al., 2008b;Paterson et al., 2011a; Robinson, 2012). In rats performingon DRL schedules, methylphenidate also tends to increaseresponse rates and exert cohesive leftward shifts in IRTdistributions, especially at higher doses (Seiden et al., 1979;Orduña et al., 2009; Andrzejewski et al., 2014). Antidepres-sants thought to primarily act as NET/DAT inhibitors, such asnomifensine (2-methyl-4-phenyl-3,4-dihydro-1H-isoquinolin-8-amine) and bupropion [2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one], test as false negatives on the DRL 72-secondschedule and increase the response rate with a cohesive leftwardshift appearing positively biased toward greater impulsivity(O’Donnell and Seiden, 1983; Seiden et al., 1985; Dekeyneet al., 2002; Paterson et al., 2011a). The similar cohesiveleftward shift of the IRT distribution by the DAT inhibitor1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride suggests that DAT inhibition,unlike NET inhibition, is responsible for the apparent in-crease in impulsivity seen with either methylphenidate,bupropion, or nomifensine (Paterson et al., 2011a).Amphetamine appears to increase impulsivity when tested
in rodents both for the 5-CSRTT and DRL behavior, a resultnot surprising considering the apparent role played bydopamine for NET/DAT inhibitors such as methylphenidate,nomifensine, and bupropion. Dopamine release in the nucleusaccumbens appears sufficient for these effects given thatamphetamine increases premature responses on the rat5-CSRTT regardless of a dorsal noradrenergic bundle lesionstatus, sham or active (Cole and Robbins, 1987). Both baselinepremature responses and amphetamine-induced prematureresponses were attenuated by 6-hydroxydopamine–inducedlesions of the nucleus accumbens (Cole and Robbins, 1989).Independent laboratories have replicated amphetamine-induced impulsivity for the 5-CSRTT (Pattij et al., 2007;Paterson et al., 2011b; Baarendse and Vanderschuren, 2012).For DRL 72-second behavior, amphetamine-induced in-creases in impulsivity have been suggested by increasedresponse rates and cohesive leftward shift in the IRT distribu-tion, including decreased peak latency (Balcells-Olivero et al.,1998; Fowler et al., 2009; Paterson et al., 2011a).These observations with amphetamine are important with
respect to predictions for antidepressant efficacy whenmovingfrom rodent DRL 72-second behavior to the clinical treatmentof patients with MDD. Despite anecdotal evidence for antide-pressant effects of amphetamine, double-blind, placebo-controlledstudieswith amphetamine and other stimulants generally havebeen negative (Satel and Nelson, 1989; Abbasowa et al., 2013).
The primary patient population benefiting from amphetamineappears to be a population of medically ill subjects withdepressive symptoms. This lack of efficacy for amphetaminein controlled randomized clinical studies of patients with MDDmay seem surprising given the interest in anhedonia as amodelfor depression and the relationship of anhedonia to the dopa-mine system. However, despite numerous efforts by industrysponsors, clinical testing of new chemical entities possessingDAT blockade in addition to serotonin transporter and NETinhibition has not resulted in any therapeutic advances beyondthat seen for SSRIs and serotonin-norepinephrine reuptakeinhibitors (Learned et al., 2012; Tran et al., 2012; Bhagwagaret al., 2015). The reason for these relative failures is not clear,although one speculation consistent with the primary thesis ofthis review is that clinically useful antidepressants may needto improve mood and decrease impulsivity (and indirectlydecrease suicidality) on a sustained basis. Nevertheless,rigorous testing of amphetamine and other stimulants, in-cluding triple reuptake inhibitors, implies that simply en-hancing synaptic availability of dopamine does not result intherapeutic effects for depression, as has been seen by over10–30 years of clinical experience with SSRIs or serotonin-norepinephrine reuptake inhibitors.Studies examining specific subtypes or classes of adrenergic
receptors also generally provide convergent evidence for thehypothesis that action or motor impulsivity plays a criticalrole in mediating drug effects for the 5-CSRTT and DRL72-second schedule. The b2-adrenergic agonist clenbuterol[1-(4-amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethanol]suppressed premature responses in rats performing on the5-CSRTT (Pattij et al., 2012). A series of DRL 72-secondexperiments clearly demonstrated that clenbuterol andanother b2-adrenergic receptor agonist salbutamol (4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol)increased the reinforcement rate and decreased the responserate in a manner similar to known antidepressants (O’Donnell,1987, 1990; Dunn et al., 1993; Zhang et al., 2003). Clenbuteroland salbutamol also appeared to shift the impulsivity bias of therats’ lever pressing on the DRL 72-second schedule by acohesive rightward shift toward longer IRTs (O’Donnell, 1987,1990; Dunn et al., 1993; Zhang et al., 2003). While no largeplacebo-controlled multicenter studies of b2-adrenergic ago-nists in patients have been conducted, several preliminarycontrolled trials suggest that i.v. infusion of salbutamol or oraladministration of clenbuterol produces relatively rapid antide-pressant responses in at least a subpopulation of depressedpatients (Lecrubier et al., 1980; Simon et al., 1984).Another interesting candidate G-protein-coupled receptor
to explore is the a1-adrenergic receptor, given the closeneuroanatomical and functional overlap with 5-HT2A recep-tors, and also given that most TCAs potently block this site.The prototypical a1-adrenergic receptor antagonist prazosindoes not have an effect by itself on premature responses inthe rat 5-CSRTT (Koskinen et al., 2003; Liu et al., 2009).Analogously, prazosin ([4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(furan-2-yl)methanone) and several non-selective a-adrenergic receptor antagonists did not increasethe reinforcement rate or exert a cohesive rightward shift ofthe IRT distribution in rats performing on a DRL 72-secondschedule (Marek and Seiden, 1988; Marek et al., 1989).Of further interest, a2-adrenergic receptors appear to
play a critical role in mediating anti-impulsive effects of the
TCA nortriptyline [3-(5,6-dihydrodibenzo[2,1-b:29,19-f][7]annulen-11-ylidene)-N-methylpropan-1-amine] and desipra-mine on an auditory sustained attention test (Roychowdhuryet al., 2012) or DRL 72-second behavior (Zhang et al., 2009).Consistent with these results, the a2-adrenergic receptoragonist guanfacine [N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide] suppressed, while the a2-adrenergic receptorantagonist yohimbine (methyl (1S,15R,18S,19R,20S)-18-hydroxy-1,3,11,12,14,15,16,17,18,19,20,21-dodecahydroyohimban-19-carboxylate) increased, 5-CSRTTpremature responses in rats(Sun et al., 2010; Fernando et al., 2012; Pillidge et al., 2014).Thus, while more work remains to clarify the role of specific a1-and a2-adrenergic subtypes on 5-CSRTT and DRL 72-secondbehavior, converging pharmacological evidence for NET inhib-itors and b2-, a1-, and a2-adrenergic receptor agonists supportsthe hypothesis that motoric impulsivity is an important aspectfor both behavioral paradigms.In addition to MK-801 and other NMDA receptor antago-
nists, the muscarinic cholinergic receptor antagonist scopol-amine (6,7 epoxytropine tropate) is frequently used both inpreclinical and clinical studies as a pharmacological pertur-bation impairing cognition. While a range of scopolamineeffects are seen in rats performing under particular 5-CSRTTconditions with respect to accuracy and omissions, prematureresponses are increased (Jones and Higgins, 1995; de Bruinet al., 2006; Shannon and Eberle, 2006). While scopolamineinduces robust effects on the DRL 72-second behaviorthat may largely reflect a disruption of stimulus control, thedecreased reinforcement rate, increased response rate, andleftward shift in the IRT distribution is also compatible withincreased motoric impulsivity (Jayarajan et al., 2013). Thus,the similar valence of effects for NMDA receptor antagonistssuch as MK-801, psychomotor stimulants, and scopolaminetogether with analogous directional effects for a range ofserotonergic and noradrenergic drugs (many of which areantidepressant drugs) are consistent with the hypothesis thatan overlapping pharmacology and neurocircuitry may medi-ate biasing of motor impulsivity as a key driver for prematureresponses on the 5-CSRTT and DRL 72-second behavior.These preclinical effects of scopolamine do appear contradic-tory to the major thesis advanced in this review sincescopolamine appears to exert antidepressant effects in pa-tients with MDD and bipolar depression from double-blinded,placebo-controlled trials (Furey and Drevets, 2006; Drevetsand Furey, 2010). The reason for this apparent contradictoryfinding remains to be determined. Further work examiningscopolamine effects with longer pretreatment intervals wouldbe one important factor to examine to test for the potentialdissociation of disruptive acute effects and downstream effectswith a slower onset. Potential ancillary pharmacology ofscopolamine may also be a factor in its putative antidepres-sant efficacy.One issue that should be highlighted for the DRL 72-second
schedule and 5-CSRTT with respect to measuring modulationof motoric impulsivity and predicting clinical antidepressantaction is that these modulatory effects on impulsivity are seenfollowing a single dose of drug. Furthermore, these antide-pressantlike effects of drugs on theDRL 72-second schedule donot necessarily increase in magnitude with subchronic ad-ministration, with the current relatively small body of workdirected at answering this question. The antidepressantlikeeffects of the TCA imipramine [3-(5,6-dihydrobenzo[b][1]
benzazepin-11-yl)-N,N-dimethylpropan-1-amine] on DRL 18-second behavior appeared to be enhanced by subchronictreatment at a higher (10 mg/kg) but not a lower (5 mg/kg)dose (McGuire and Seiden, 1980). Tachyphylaxis appeared todevelop within a few days for the antidepressantlike effects ofclenbuterol during subchronic treatment (O’Donnell, 1990).However, the observations that acute single doses of antide-pressant drugs may alter emotional information processing inhuman subjects as a translational paradigm for predictingantidepressant activity for new clinical entities (Harmer et al.,2011) appear to parallel the rodent DRL antidepressantscreening paradigm. Presumably, the DRL 72-second sched-ule is measuring the acute antidepressant treatment effects ina subset of the circuitry that must be modified to begin to seea meaningful clinical response within 2–6 weeks of dailyadministration. However, the DRL 72-second schedule alsoappears capable of detecting an acute antidepressant effect ofketamine that may be more similar to the clinical time coursein patients with MDD (Hillhouse and Porter, 2014).Thus, drugs acting at a number of biologically salient and
clinically validated targets (NMDA receptors, 5-HT2A recep-tors, serotonin synthesis/release, and NETs) appear to simi-larly attenuate or enhance impulsivity on the 5-CSRTT andDRL 72-second behavior. These results do not appear surpris-ing, given that withholding of inappropriate responding isat least a component of both tasks. These pharmacologicalsimilarities among the 5-CSRTT and DRL 72-second behaviorare further supported by other procedures that measureresponse inhibition, such as response-duration differentiationin which aspects of impulsivity are clearly produced by anNMDA antagonist and d-amphetamine, and reduced byantidepressant administration, including bupropion andnomifensine (Hudzik and McMillan, 1994a,b).
Candidate Circuitry Sharing Similar Influenceson Impulsivity/Executive Function
The prefrontal cortex (PFC) and its direct and indirectprojections may mediate impulsive responding in both theDRL behavior and 5-CSRTT. The rodent PFC is divided intothemedial PFC (mPFC), the orbital PFC, and themore lateralagranular insular cortex. These areas are further divided intosmaller areas defined by cytoarchitechtonic features andneural connectivity with functional macrocircuits includingthalamo-cortico-striatal loops (Heidbreder and Groenewegen,2003). For the purposes of this review, we will focus upondistinctions between the dorsomedial aspect of the mPFC[including the dorsal anterior cingulate cortex; the dorsalaspect of the prelimbic cortex (PL); and the ventromedialaspect of the mPFC, including the ventral PL, the infralimbiccortex (IL), and the medial orbital cortical areas]. Threedifferent types of thalamic afferents project to these mPFCregions, with discrete topological relationships including themidline and intralaminar thalamic nuclei, the mediodorsalnucleus of the thalamus, and the anterior thalamic nuclei, inwhich these bidirectional thalamocortical connections arethought to play a major role in executive functions andcognition involving the PFC (Bradfield et al., 2013; Mitchellet al., 2014; Saalmann, 2014). Both the midline thalamicnuclei and the anterior thalamic nuclei may relay cognition/executive function–related information between the mPFCT
and the hippocampal formation (Cassel et al., 2013; Prasadand Chudasama, 2013; Vertes et al., 2015). The PFC (and thethalamus) is topographically connected to the dorsal striatumand the ventral striatum (nucleus accumbens core and shell)with return of striatal input to the cortex via the thalamus(Heidbreder and Groenewegen, 2003). These circuits are thenreinforced by themodulatory action of brainstemmonoamines(dopamine, serotonin, and norepinephrine), which projectdiffusely throughout the cortical mantle as well as the sub-cortical regions.
Comparison of Neurocircuitry Underlying5-CSRTT and DRL Behavior
Similar, at least partially, overlapping neurocircuitryappears to underpin the control of impulsivity on the DRL72-second schedule and 5-CSRTT (Table 2). As discussedpreviously, global serotonergic lesions using relatively selec-tive neurotoxins have been found to enhance motoric impul-sivity for both the 5-CSRTT and DRL behavior (Fletcher,1995; Harrison et al., 1997; Jolly et al., 1999). The significanceof this commonality is underscored by a growing body ofevidence supporting the hypothesis that impulsivity in not aunitary construct. With respect to global 5-HT lesions, neitherimpulsive choice quantified by a delay-discounting model norstopping a prepotent response for the stop-signal reaction timetask were impacted by 90% reductions of global forebrain5-HT by intracerebroventircular 5,7-DHT (Winstanley et al.,2004; Eagle et al., 2009).With respect to theDRL behavior and5-CSRTT, decreasing 5-HT locally in the cortex by morethan 80% did not alter impulsivity for either the 5-CSRTTor shorter DRL 20- or 40-second schedules (Fletcher et al.,2009). However, Fletcher et al. (2009) did report one differencebetween the 5-CSRTT and DRL 20-second behavior since local5,7-DHT infusions into the nucleus accumbens increasedimpulsive behavior for the DRL schedule, but not the 5-CSRTT. Nevertheless, the general pattern of results withglobal and local 5-HT depletions seems consistent with thepharmacological similarities between impulsivity measuredby the DRL behavior and 5-CSRTT.Animals examined months following limbic seizures in-
duced by lithium and pilocarpine [(3S,4R)-3-ethyl-4-[(3-methylimidazol-4-yl)methyl]oxolan-2-one] appear to share atleast a trend toward increased impulsivity. Two monthsfollowing lithium-pilocarpine–induced seizures these rats,unlike controls, failed to acquire DRL 6- or 12-second behaviorwith responding biased toward short IRTs ,3 seconds(Harrigan et al., 1990). These lithium-pilocarpine–treatedrats exhibited “extreme necrosis in the amygdal, pyriform-entorhinal cortices and the dorsomedial and lateral thalamicnucleiar groups,” as previously described by Persinger et al.(1988). More recently, the behavior of rats with limbic seizuresfollowing lithium-pilocarpine treatment was examined usingthe 5-CSRTT several months following motor seizures. Theserats showed trends toward an increased percentage of pre-mature responses that were correlated negatively with neu-ronal density in hippocampal field CA3 and the IL (Faureet al., 2014). Thus, while rats performing aDRL schedule weremore severely impaired than those engaged on a 5-CSRTT, theshared valence of effects with this manipulation is in keepingwith anatomic results described subsequently.
Shared neurocircuitry underlying impulsivity on DRL sched-ules and the 5-CSRTT is also supported by results of gestationalmethylazoxymethanol acetate (MAM), (Z)-hydroxymethylimino-methyl-oxidoazanium, treatment. Treatment of pregnant femalerats with MAM on gestational day 17 results in adult offspringwith a range of thalamocortical histopathological alternations,prefrontal cortical and striatal neuron electrophysiologicalchanges, and increased sensitivity to amphetamine withstriking congruence to features observed in patients withschizophrenia (Moore et al., 2006; Lodge and Grace, 2009). Asimilar course of gestational MAM treatment in rats has alsobeen to increase impulsivity in adult offspring trained on DRL20-second behavior: exemplified decreased reinforcement rate,modestly increased response rate, decreased efficiency, andapproximately a 5-second shift toward short IRTs as calculatedby themean IRT (Featherstone et al., 2007). In the latter study,surprisingly, the only effect of gestational MAM treatment inadult rat offspring was a trend toward increased prematureresponses on the 5-CSRTT. A rodent magnetic resonanceimaging study has reported significant parallel findings injuvenile and adult offspring of MAM-treated dams to thestructural findings in adults with schizophrenia, such asincreased ventricle size and reduced hippocampal, cerebellum,and whole brain volumes, along with evidence of decreasedconnectivity frommajor fiber tracts in the forebrain (Chin et al.,2011). However, it is unknown what regions altered by thisdevelopmental insult are responsible for the apparent increasein motoric impulsivity since a range of cortical regions (mPF,orbital PFC, parietal, andhippocampal) and subcortical regions(dorsal striatum) from offspring of MAM-treated dams showstissue weight reductions. The significance of these results forthe DRL 72-second schedule as a screen for antidepressantdrugs is that suicide victims dying with MDD also exhibitdecreases in lateral ventricular size in addition to decreases inthe prefrontal cortical thickness and hippocampal volume(Koolschijn et al., 2009; McKinnon et al., 2009).The 5-CSRTT has been characterized from a neuroanatom-
ical perspective with significantly greater granularity thanmost behavioral tasks, including DRL behavior. Both tasksappear to require the PFC in keeping with a close relationshipbetween a range of executive functions and different anatomicand functional regions of the PFC. Several excitotoxic lesionstudies demonstrated the increased impulsive (premature)responding in the 5-CSRTT following ventromedial PFC (e.g.,IL) or anterior cingulate cortex lesions (Muir et al., 1996;Chudasama et al., 2003a,b). In contrast, lesions restrictedto the dorsal anterior cingulate cortex impaired discriminativeaccuracy, while lesions largely restricted to the dorsal mPFC(e.g., PL) also were impaired in choice accuracy in contrast toincreases in perseverative responding with orbitofrontallesions (Muir et al., 1996; Chudasama et al., 2003b). Converg-ing evidence for the role played by the IL in suppressingpremature responses with the 5-CSRTT are direct regionalinfusion studies with 5-HT2A and 5-HT1A receptor agonistsand the competitive NMDA receptor antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (Muir et al.,1996; Winstanley et al., 2004; Carli et al., 2006). In contrast tothe increase in premature responses with intra-IL corticallocal administration, infusion of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid into the PL directly dorsal to theIL impaired accuracy and increased omissions (Murphy et al.,2005). Thus, the IL appears to be an especially important
region regulating motor impulsivity as measured with the5-CSRTT.The only published DRL neurocircuitry study where the
majority of the ILs and PLs were destroyed with an excitotoxiclesion found that compared with sham-treated mice, the micewith lesions exhibited a flattened, wider IRT distribution (Choand Jeantet, 2010). Mixed results were observed in lesionstudies examining acquisition of DRL behavior. Severalstudies reported either a decreased reinforcement rate cou-pled with increased response rate while another demon-strated an increase in very short IRTs (Numan et al., 1975;Nalwa andRao, 1985). However, several other studies failed todemonstrate an effect of medial frontal cortex lesions, al-though in one study the lesion may have spared the IL (Kolbet al., 1974; Finger et al., 1987). Several other studies withmPFC lesions that clearly appeared to spare the IL did nothave an effect on DRL responding (Neill et al., 1974; Neill,1976). Similar to experiments with the rodent 5-CSRTT,orbital frontal lesions may produce perseverative respondingin rats on a DRL 20-second schedule (Kolb et al., 1974). Thus,further fine-grained anatomic work in light of modern neuro-anatomical knowledge is clearly required, especially sincedissociations in the mediation of different executive functionshave been observed across distinct regions of the PFC inrodents on the 5-CSRTT, as described previously.The hippocampal formation appears to be involved in
suppressing premature impulsive responding. A more exten-sive body of evidence exists for the DRL schedule (comparedwith the 5-CSRTT), where studies testing DRL neurocircuitryreviewed elsewhere generally have found large increasesin responding, especially following aspiration or electrolyticlesions (Gray andMcNaughton, 1983). Cytotoxic hippocampallesions in both rats and mice—particularly when involvingboth the ventral and dorsal hippocampus or complete CA1/CA3/dentate gyrus involvement—also increased DRL re-sponse rates, decreased reinforcement rates, decreased effi-ciency, and resulted in a leftward IRT distribution shift(Sinden et al., 1986; Reisel et al., 2005; Cho and Jeantet, 2010).With regard to the 5-CSRTT, only excitotoxic lesions of the ratventral hippocampus (VH) increased premature (impulsive)responses, while no effect was observed with dorsal hippocam-pus lesions (Abela et al., 2013). Not surprisingly, the SSRIescitalopram reduced the number of premature responsesobserved after the VH lesion, whereas the DAT inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazinedihydrochloride was without effect (Abela et al., 2013). In anadditional refutation to a unitary impulsivity hypothesis, theseVH lesions did not affect reversal learning, where the rats arerequired to inhibit previously reinforced responses. The influenceof the VH was replicated and extended to suggest that obligatefunctional interactions of the IL and VH exist by makingdisconnection lesions of the IL and VH on opposing hemi-spheric sides (e.g., left IL and right VH lesions) in contrast toipsilateral lesions of both structures (Chudasama et al., 2012).The primary observation was that while both ipsilateralcombined lesions of the IL and VH, and while the disconnec-tion lesions increased premature responses 2 weeks followingsurgery, increased responses were only observed for thedisconnection lesions (left IL and right VH lesions) 2 monthsfollowing surgery. Thus, both the IL and VH appear to worktogether in modulating waiting behavior before making anappropriately timed response to obtain a reward.
The thalamusmay provide an appropriate neuroanatomicalsubstrate for indirect interactions between the IL andVH. Thereunions nucleus is one of the midline and intralaminarthalamic nuclei (e.g., nonspecific thalamic afferents) havingneurons that either project to the mPFC (including the IL)and/or the hippocamapal formation (including the CA1 field,entorhinal cortex, and subiculum) in a bidirectional manner(Cassel et al., 2013). With respect to the rat 5-CSRTT, localneurotoxic lesions in the reunions nucleus increased pre-mature responses, while also decreasing perseverative re-sponses through 2 months following surgery (Prasad et al.,2013). Lesions of the medial dorsal thalamic nucleus thatspare the reunions nucleus have also been found to increasepremature respondingwith the rat 5-CSRTT (Chudasama andMuir, 2001). While no studies have been performed withselective midline or intralaminar thalamic nuclei in rats andthe DRL, human subjects with Korsakoff’s syndrome havebeen found to exhibit disruptions of DRL performance;namely, Korsakoff patients increase response rates with a left-shifted IRT distribution as a function of increasing the sched-ule time requirement from the DRL 3-second behavior up tothe highest schedule tested, the DRL 18-second behavior(Oscar-Berman et al., 1982). The subjects with Korsakoff’ssyndrome appeared more impulsive when compared withalcoholic subjectswithKorsakoff’s syndromeorhealthy subjects.Selective alterations in appropriate midline and intralaminarthalamic nuclei or appropriate segments of the medial dorsalthalamic nucleus in rodent or nonhuman primate DRL studiesare required to understand whether the damage in the medialthalamus (including midline thalamic nuclei), mammillarybodies, or corpus callosum is responsible for motoric impul-sivity present in subjects with Korsakoff’s syndrome (Pitelet al., 2012; Nardone et al., 2013).Initial similarities have emerged for lesion studies with
the 5-CSRTT and more limited work on DRL scheduleswith respect to the ventral striatum or nucleus accumbens.While nucleus accumbens core or shell lesions did notincrease 5-CSRTT premature responses, a differential effectof these lesions was seen on the impulsivity-inducing effectof d-amphetamine (Murphy et al., 2008); namely, the corelesions further increased premature responses inducedby d-amphetamine, while the shell lesions attenuated theamphetamine-induced increase in premature responses.Acute deactivation experiments with the GABAA receptoragonist muscimol [5-(aminomethyl)-1,2-oxazol-3-one] also re-veal distinct profiles with either nucleus accumbens shell orcore inactivation (Feja et al., 2014). Acute inactivation of theshell increases premature responses, while acute inactivationof the nucleus accumbens core results in a large increase inomissions.Other pharmacological manipulations also suggest dif-
ferential effects of the nucleus accumbens shell and coreregions on premature responses with the 5-CSRTT. Forexample, the dopamine D2 receptor antagonist eticlopride[5-chloro-3-ethyl-N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-2-hydroxy-6-methoxybenzamide] decreases amphetamine-induced impulsivity when the antagonist is infused into thecore, but increases amphetamine-induced impulsivity whenthe antagonist is infused into the shell (Pattij et al., 2007).In an analogous manner, the dopamine D2/3 receptor agonistquinpirole (4aR,8aR)-5-propyl-1,4,4a,6,7,8,8a,9-octahydropyr-azolo[3,4-g]quinoline) increased premature responding when
infused into the nucleus accumbens core in a subpopulation ofhighly impulsive Lister hooded rats, while no effect wasobserved for infusions into the shell region (Pattij et al., 2007).A range of 5-CSRTT studies employing excitoxic lesions,
acute inactivation, and local infusion methods also supportsfunctional interactions between the PFC and the nucleusaccumbens with respect to motoric impulsivity. For example,both bilateral nucleus accumbens core and mPFC-nucleusaccumbens core disconnection lesions (unilateral lesions onthe opposite side of the brain) resulted in increased prematureresponses only after a failed trial, but not a correct trial(Christakou et al., 2004). Also analogous to effects of bilateralinactivation in either the ventral mPFC or the nucleusaccumbens shell, a disconnection inactivation of the ventralmPFC and the contralateral nucleus accumbens shell, but notthe core, increased premature responses (Feja and Koch,2015). Finally, infusion of the dopamine D2/3 receptor antag-onist sulpiride [N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-sulfamoylbenzamide] into the nucleus accumbens coresuppressed the increased impulsivity observed for a mPFClesion including the anterior cingulate, prelimbic, and IL(Pezze et al., 2009). Thus, this finding and more recentconverging evidence support important functional relation-ships between the ventral PFC and the nucleus accumbens inmediating impulsivity on the 5-CSRTT (Donnelly et al., 2014).While fewer experiments have examined the nucleus accum-bens in mediating DRL behavior, these few studies areconsistent with findings in the 5-CSRTT literature. Thus,bilateral nucleus accumbens lesions have been demonstratedto increase impulsivity in rats performing under a DRL20-second schedule, while also attenuating the impulsiveprofile of amphetamine on this schedule (Reading andDunnett,1995). Differential effects for nucleus accumbens core and shelllesions are also observed for DRL behavior. Excitotoxic lesionsof the nucleus accumbens core, but not the shell region,increased responding of rats on a DRL 18-second schedule,while only a trend was observed for these same rats perform-ing under a DRL 12-second schedule (Pothuizen et al., 2005).The limited exploration of nucleus accumbens involvement forDRL behavior with respect to impulsivity is generally consis-tent with themore robust literature on the 5-CSRTT.While theneurocircuitry underlying impulsivity with the 5-CSRTT hasbeen explored to a greater degree than the apparent impulsivitywith DRL schedules (increased response rate with leftward-shifted IRTs), there appears to be a striking correspondenceregarding PFC-striato-thalamic-hippocamal and serotonergiccircuitry mediating these two distinct operant paradigms.A single study has examined DRL behavior following
olfactory bulb removal in rodents. This study is intriguinggiven: (1) the generally high selectivity and sensitivity of theolfactory bulbectomy paradigm as a model for testing newchemical entities in a number of commonly used antidepres-sant screens; and (2) the wide constellation of behavioral,endocrine, and immunologic observations in olfactory bulbec-tomized rats resembling patients with MDD (Kelly et al.,1997; Song and Leonard, 2005). Olfactory bulbectomized ratsresponded more frequently and with a lower efficiency on aDRL 20-second schedule than control rats (Thorne et al.,1976). This result is not surprising given relationships be-tween motoric impulsivity and aggression, and given that inearly years of this model, muricide was an important endpointemployed by many investigators.
ConclusionsThe DRL 72-second behavior, while a complex operant
paradigm, provides an opportunity to observe drug-inducedchanges on a dimension of motoric impulsivity related toinhibition of inappropriate responses (e.g., responses prior tothe scheduled defined 72-second waiting requirement) as akey executive function. Both the psychopharmacology andunderlying neurocircuitry that appear to be shared betweenthe 5-CSRTT andDRL schedules emphasize the importance ofimpulsivity for DRL schedules. This raises the hypothesis thatthe demonstrated validity of the DRL 72-second behavior withrespect to accurately predicting antidepressant activity in theclinic may in part reflect the frank improvement in certaincognitive functions that may be disturbed in depressedpatients. This clinical correlation may be most apparentwhen considering agitated and impulsive depressed patients.This improvement in emotional or impulsive response bias ofpatients with mood disorders may be a relatively early eventoccurring on a time frame preceding lifting of the depressedmood and improvement of suicidality. Thus, the DRL 72-secondschedule may be more than just an empirical predictor ofantidepressant drugs. The DRL 72-second schedule may alsobe of heuristic interest with respect to developing new andimproved preclinical antidepressant drug screens/models inthis age of personalized medicine.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Marek, Day,Hudzik.
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Address correspondence to: Gerard J. Marek, Astellas Pharma GlobalDevelopment, 1 Astellas Way, Northbrook, IL 60062. E-mail: [email protected]
