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Table 1

Anxiolytics: preclinical predictions and clinical findings.

Compound/mechanism Preclinical prediction Clinical effect

PRX-00023 No laboratory studies performed Significant (Rickels et al., 2008) Agomelatine Inconclusive (Loiseau et al., 2006; Papp et al., 2006) Significant (Stein et al., 2008)Ipsapirone Mixed (Rodgers, 1997) Significant (Borison et al., 1990)SSRIs Mixed (Rodgers, 1997) Significant (Hedges et al., 2007)Buspirone Mixed (Rodgers, 1997) Significant (Rickels et al., 1982)

Alpidem Promising (Zivkovic et al., 1990) Significant (Bassiet al., 1989)

Clobazam Promising (Barzaghi et al., 1973) Significant (Salkind et al., 1979) Fenobam Promising (Goldberg et al., 1983) Significant (Pecknold et al., 1982) Nabilone Promising (Onaivi et al., 1990) Significant (Fabre and McLendon, 1981) Pregabalin Promising (Field et al., 2001) Significant (Lydiard et al., 2010) Deramciclane Promising (Koks and Vasar, 2002) Promising (small sample) (Naukkarinen et al., 2005) Abecarnil Promising (Stephens et al., 1990) Transient anxiolysis(Pollacket al., 1997)Gabapentin Promising (Singh et al., 1996) Equivocal (Pande et al., 2000)Lesopitron Promising (Costall et al., 1992) Equivocal (Fresquet et al., 2000)CRF-1 antagonists Promising (14 tested) (Kehne and Cain, 2010) Not significant (3 tested) (Coric et al., 2010; Kehne and Cain, 2010)CGP 49823 (NK1 antagonists) Promising (File, 1997) Not significant (Czéh et al., 2006)CI-988 (CCK2 antagonists) Promising (Singh et al., 1991) Not significant (Adams et al., 1995)L-365,260 (CCK2 antagonists) Promising (Rataud et al., 1991) Not significant (Kramer et al., 1995)Leviracetam Promising (Goweret al., 2003) Not significant (Steinet al., 2010)LY354740 Promising (Monnet al., 1997) Not significant (Bergink and Westenberg, 2005)Ondansetron Promising ( Jones et al., 1988) Not significant (adjuvant)(Romach et al., 1998)Ondansetron Promising ( Jones et al., 1988) Not significant (monotherapy) (Lader, 1991)Osanetant (NK3 a ntagonists) Promising (Salomé et al., 2006) Not significant (Steckler, 2010)Saredutant (NK2 a ntagonist) Promising (Stratton et al., 1993) Not significant (Steckler, 2010)

Bold and italic, full preclinical–clinical correspondence (∼26% of all cases); italic, partial preclinical–clinical correspondence (∼28%); regular font, mismatch betweenpreclinical and clinical findings (∼42%); gray font, no perceived need forlaboratory testing (∼4%). One can hypothesizethatthe real figures are even worse (see text).

Table 2

Antidepressants: preclinical predictions and clinical findings.

Compound Preclinical prediction Clinical effect

Erythropoietin Promising (Girgenti et al., 2009) Significant (Miskowiak et al., 2010) Ziprasidone Promising (Rajkumar et al., 2009) Significant (Keck et al., 2003) Aripiprazole as adjuvant Promising (Kamei et al., 2008) Significant (Berman et al., 2007)Topiramate as adjuvant Promising (Hargreaves and McGregor, 2007) Significant (Mowla and Kardeh, 2011)Quetiapine monotherapy Promising (Orsetti et al., 2007) Significant (Cookson et al., 2007)Quetiapine as adjuvant Promising (Orsetti et al., 2007) Significant (Bauer et al., 2009)Celecoxib as adjuvant Promising (Myint et al., 2007) Significant (Nery et al., 2008)

Lamotrigine Promising (Consoni et al., 2006) Significant (Calabrese et al., 1999)Omega-3 fatty acid as adjuvant Promising (Carlezon et al., 2005) Significant (Nemets et al., 2002) Melatonin as adjuvant Promising (Mantovani et al., 2003) Significant (Serfaty et al., 2010) Agomelatine Promising (Papp et al., 2003) Significant (Kennedy and Emsley, 2006) Escitalopram Promising (Montgomery et al., 2001) Significant (Wade et al., 2002) Zinc as adjuvant Promising (Kroczka et al., 2000) Significant (Siwek et al., 2009) Risperidone as adjuvant Promising (Nowakowska et al., 1999) Significant (Mahmoud et al., 2007) Ketamine Promising (Chaturvedi et al., 1999) Significant (Berman et al., 2000) Pramipexole as adjuvant Promising (Maj et al., 1997) Significant (Goldberg et al., 2004) Pindolol as adjuvant Promising (Redrobe et al., 1996) Significant (Maes et al., 1996) Milnacipran Promising (Briley et al., 1996) Significant (Guelfi et al., 1998) Duloxetine Promising (Katoh et al., 1995) Significant (Nierenberg et al., 2007) Mirtazapine Promising (Haddjeri et al., 1995) Significant (Montgomery et al., 1998) S-adenosyl-l-methionine Promising (Czyrak et al., 1992) Significant (Salmaggiet al., 1993)Venlafaxine Promising (Yardley et al., 1990) Significant (Schweizer et al., 1991)l-Triiodothyronine Promising (Heal and Smith,1988) Significant (Posternak et al., 2008)

Scopolamine Promising (Mancinelliet al., 1988) Significant (Furey and Drevets, 2006) Fluoxetine Promising (Schmidt et al., 1988) Significant (Bremner, 1984) St. John’s wort Promising (Okpanyi and Weischer, 1987) Significant (Schmidt and Sommer, 1993)Trimipramine Promising (Parale and Kulkarni,1986) Significant (Assalian et al., 1985)Carbamazepine Promising (Maj et al., 1985) Significant (Post et al., 1986)

Sertraline Promising (Koe et al., 1983) Significant (Reimherr et al., 1990)Citalopram Promising (Hyttel, 1982) Significant (de Wilde et al., 1985)

Amitriptyline Promising (Katz and Hersh, 1981) Significant (Lauritsen and Madsen,1974) Bupropion Promising (Sorokoet al., 1977) Significant (Halaris et al., 1983)Trazodone Promising (Stefanini et al., 1976) Significant (Kellams et al., 1979)

Desipramine Promising (Anon., 1965) Significant (Dahl et al., 1982)LY2216684 No data available Significant (Dubé et al., 2010)Methylphenidate as adjuvant No data available Significant (Lavretsky et al., 2006)Donepezil as adjuvant Promising (Maurice et al., 2006) Not significant (Reynolds et al., 2011)Galantamine as augmentation Promising (Sapronov et al., 2006) Not significant (Holtzheimer et al., 2008)

Bold anditalic, full preclinical–clinical correspondence (90% of all cases); regularfont, mismatch betweenpreclinical andclinical findings (5%); gray font, no preclinical datapublished (5%). Note that clinical findings were published earlier the preclinical ones in some instances. Weassume that the clinical study was preceded by unpublishedpreclinical research.

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hyponeophagia (Shephard and Broadhurst, 1982)

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marble burying (Njung'e and Handley, 1991)

hole board (Gardner and Piper, 1982)

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defensive burying (Treit et al., 1981)

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"Other" anxiety tests

Fig. 1. Stacked area plot of the relative share of anxiety tests in laboratory research. Upper panel, the relative share of the most widely used (“popular”) tests (averageshare >1.5%). All these tests can be considered ‘classical’. Lowerpanel: “other tests” reaching at least0.5% share in all anxietystudies. The summed share of thesetests wasbetween10.5% (1990) and 1.7% (1991). Four out of 9 such tests are also ‘classical’ in the meaning defined in the first chapter.

that proposed novel anxiolytics (∼25%). Innovation was negligiblein studies where anxiolytic effects were not detected (∼10%), sug-gesting that novel compounds were not studied further if failedin classical tests performed under classical conditions (Haller andAliczki, 2012).

Although none of the novel tests appears to be particularlyfrequently used, any of them has the potential of increasing thepredictive value of preclinical research. In the next sections, webriefly review the new tests and models developed since 1985 andinthefinalchapterweevaluatethepossibilityofimprovingthepre-dictive validity of preclinical testing by making use of these novelapproaches.

2. Novel approaches

Novel approaches differ from classical ones in many respects asshown below. One aspect deserves particular attention: it occursthatmodelsof anxiety start to gainterrain. Testsareusuallyconcep-tualized as experimental procedures that imply normal emotionalreactivity(e.g.naturalfear responses)whereasmodels implyabnor-mal emotional reactivity (i.e. the levels of anxiety are increased byexperimental manipulations). In these terms, classical proceduresare all tests; the only exception is conditioned fear that is believedto model symptoms of post-traumatic stress disorder. Even in thiscase, however, the correspondence between behaviors shown inthis test and symptoms of the disorder were recognized after the

classical period (see below). The new procedures that are called

‘etiological’belowaswellastheapproachesthatfocusonthesymp-toms of particular anxiety disorders are true models: their subjectsdevelop a condition that is analogous to anxiety disorders.

2.1. Amendments to classical tests – New variables and

experimental setups

Presently, the elevated plus-maze test is by far the most fre-quently used anxiety test, and perhaps for this reason, it attractedthe largest number of amendments. In a chronological order,Rodgersetal.(1992) werethefirsttoamendthistestbyintroducingthe “ethological measures” (mostly risk assessment activities) in

ordertorevealtheanxiolyticeffectsofserotonergicagentsthatpro-duced mixed effects in classical tests. An interesting new approachrelates to the “one-trial tolerance”phenomenon, i.e. the inabilityof certain anxiolytics to decrease plus-maze anxiety in rodents thathadan earlier experience with the apparatus (File et al., 1993). Thistest,together withthe elevatedT-maze andtheunstableplus-mazewill be discussed in more detail in the chapter “Anxiety disorder-specific tests”. The elevated 0-maze – a circular apparatus withclosed and open sections – was introduced with the aim of elim-inating the central platform that was deemed ambiguous relativeto anxiety (Shepherd et al., 1994). Among the elevated plus-maze-like tests, probably the T-maze brought about the largest changesas it allows the testing of two qualitatively different measures of fear ( Jardim et al., 1999) (also see below). The unstable elevated

plus-maze (King, 1999) aimed at increasing the aversiveness of the

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plus-maze apparatus by oscillating it at high frequency (also seebelow). The elevated Y-maze (Dhara et al., 2002) – which is alsoused to test working-memory – works according to the classicalprinciples of the plus-maze, but the number of closed arms wasreduced to one and shape was changed accordingly. The enclosedt-maze or “t-tube” is one of the possible versions of the Y-maze,where the arms of the maze are in fact tubes, and the firstly visited“arm” is considered the safe one (Gannon et al., 2011).

Amendments were made to other anxiety tests as well, e.g.open-field testing was associated with water deprivation and theplacement of water in the center (Stout and Weiss, 1994). Inthe canopy test, the central zone of the open-field was coveredby a red Perspex circular “canopy” (Grewal et al., 1997), whilein the emergence test, rodents were placed into the open-fieldafter being enclosed into a familiar “start box” and the latencyto leave this box was considered the main measure of anxiety(Paré et al., 2001). In the case of the social interaction test, effortsseem to be directed toward the elimination of tedious behavioralanalysis. In novel tests, subjects are separated by barriers, andthe time spent in close vicinity serves as the measure of anxi-ety (Defensor et al., 2011; Haller and Bakos, 2002; Leveleki et al.,2006; Nadler et al., 2004). New conditioning procedures werealso developed including the conditioned suppression of drink-

ing (McCloskey et al., 1987), conditioned defensive burying (Craftet al., 1988), the recording of conditioned auditory evoked poten-tials (Brandao et al., 2001), and a complex conditioned avoidanceprocedure involving the combination of shuttle box, body tem-perature, ultrasonic vocalization and startle recordings (Sun et al.,2010). The common feature of other novel tests is that they mon-itor anxiety by evaluating a physiological or behavioral responseto an acute stressful event like in the case of, e.g. hyponeophagia.Such procedures include the stress-induced hyperthermia (Zethof et al., 1995), novelty-induced grooming (Kalueff and Tuohimaa,2005), stress-induced elevation of cerebellar cGMP (Fell et al.,2011), and stress-induced foot-tapping (Ballard et al., 2001) tests.The maternal separation-induced ultrasonic vocalization test alsogenerated novel approaches, e.g. the separation-induced distress

vocalization model developed for chicken (Prigol et al., 2011),and the acoustic startle-induced and shock-induced ultrasonicvocalization tests (Kaltwasser, 1991 and Baudrie et al., 1993,respectively).

2.2. Etiological models

Anxiety disorders are often precipitated by stressors that affectanxiety in conjunction with particular genetic backgrounds. There-fore, studying anxiety in animals that underwent various stressfulprocedures and/or are prone to heightened anxiety due to theirgenetic background offers the chance of creating etiological mod-els of anxiety, i.e. procedures that render animals akin to humanssuffering from anxiety disorders. Similar methods are common in

the preclinical testing of antidepressants, but relatively novel inanxiety research.

2.2.1. Combining anxiolytic drug testing with stress exposure

The notion that anxiolytic effects may depend on stress expo-sure came from human studies showing that the beta-adrenergicblocker oxprenolol ameliorates anxiety symptoms resulting fromenvironmental stress (McMillin, 1973, 1975). The idea rapidlypenetrated laboratory research; e.g. it was suggested that the anx-iolytic effects of the benzodiazepine result from the inhibition of the stress-induced activation of noradrenergic neurotransmission(Fuxe et al., 1975). Later research suggested that the ameliora-tion of stress-induced increases in classical anxiety measures ispredictive of anxiolytic efficacy even in the absence of, or minor

effects under, basal conditions (CCK agonism: Koks et al., 2000;

NPY gene disruption: Thorsell et al., 2000; neurosteroids: Guidottiet al., 2001; V 1b antagonism: Griebel et al., 2002; CRF 1 antago-nism: Heinrichs et al., 2002; mGlu2/ 3 agonism: Schoepp et al., 2003;CCK2 antagonism: Wang et al., 2011). About 8% of the studiespublished in 2010 and the first half of 2011 combined classicalanxiolytic testing with prior stress exposure suggesting that thisapproach starts to gain terrain (Haller and Aliczki, 2012). Recently,a chronic stress-based zebrafish model was also developed (Piatoet al., 2011). Models involving the exposure of subjects to preda-tor odors or alarm substances can be considered specific variantsof stress models. Rats exposed to trimethylthiazoline (fox fecesodor), and zebrafish exposed to alarm substances (e.g. hypoxan-thine 3-N-oxide) show fear reactions and it was suggested thatthis behavioral response may be used to test anxiolytics (Parraet al., 2009; Rosen et al., 2008; Speedie and Gerlai, 2008). All thesestudies, however, suffer from the lack of proper pharmacologicalvalidation and/or stressful procedures were not yet standard-ized. As such, the wider applicability of these approaches remainsunclear.

There were only a few attempts to validate stress-induced anx-iety as a paradigm for anxiolytic drug testing. Korte et al. (1999)suggested that inescapable electric shocks administered beforeplus-maze exposure may improve the preclinical testing of anxio-

lytic agents. A similar suggestion came from a study investigatingthe long-term social deficits induced by electric shocks (Hallerand Bakos, 2002; Leveleki et al., 2006). It was also suggested thatsocial instability administered prior to classical testing for anxi-ety unravels the anxiolytic effects of buspirone that often providesinconsistent effects under conventional conditions (Haller et al.,2004). It was proposed that pre-exposure to restraint before foot-shocks enhances conditional fear responding, a putative modelof post-traumatic stress-disorder (Rau et al., 2005). Finally, alarmpheromone-induced changes in the acoustic startle reflex werepharmacologically validated as a model of anxiety in rats (Inagakiet al., 2010).

2.2.2. Genetic background and anxiolytic drug testing

Genetic bases forhuman anxiety were forlongsuspected(Slater,1964), and strains selected for anxiety-related traits occurredrather early (Maudsley “reactive” and “nonreactive” rats: Sudakand Maas, 1964; Broadhurst, 1975; “high” and “low” mice: DeFrieset al., 1974). These rat and mouse lines selectively bred for open-field behavior were later followed by rat and mouse lines selectedfor plus-maze anxiety (Liebsch et al., 1998; Kromer et al., 2005).Strains selected for other traits also showed large differences inanxiety levels and as such were added to the list of genetic anxi-ety models. Such models include spontaneously hypertensive rats(Gentsch et al., 1987), the Roman and Syracuse strains selectivelybred for learning abilities (Chaouloff et al., 1994; Brush, 2003),rats selected for alcohol sensitivity (Hine, 1995) alcohol preference(Colombo et al., 1995), and responsiveness to amygdala kindling

(MohapelandMcIntyre,1998). Inadditiontothisgrowinglist,thereare uncountable transgenic mouse lines that show altered levelsof anxiety (see Finn et al., 2003; Hovatta and Barlow, 2008, forreviews). Some transgenic lines were actually proposed as geneticmodels of human anxiety (Campbell et al., 1999; Ramboz et al.,1998; Stenzel-Poore et al., 1994). It was also suggested that cer-tain strains – not selected for anxiety-like behaviors – are bettersuited to anxiety studies than others because of their high levelsof innate anxiety (Belzung and Griebel, 2001; Rex et al., 1999) orbecause they are better fit for particular tests than others (HascoëtandBourin,1998;BelzungandBerton,1987). Thislistdemonstratesthat anxiety research has many valuable resources to study thegenetic underpinnings of anxiety. Potentially, the genetic modelscan also be used for the preclinical testing of novel anxiolytic com-

pounds. However, such proposals are relatively recent, despite the

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long history of genetic anxiety models, e.g. Keck et al. (2001) pro-posed that rats selectively bred for high- and low-anxiety-relatedbehaviors are especially well suited for the evaluation of CRH1receptor antagonists. In the same year, Belzung (2001) proposed ingeneral thatstrain differences in anxiety-like behaviormaybeusedas a tool in assaying anxiolytic activity of new drugs, although shepointed out that differences in anxiety levels are not necessarily inlinewith sensitivity to anxiolytic effects. Thelatter assumptionwasprovenexperimentallyin thesame year (Bertetal.,2001). One yearlater, Ramos et al. (2002) proposed that Lewis and spontaneouslyhypertensive rats may be genetic models for anxiolytic drug test-ing. Similar proposals were made for: db/db diabetic mice (modelfor type-2 diabetes-related neurobehavioral complications includ-inganxiety)(Sharmaet al., 2010), the HighAnxietyBehaviormouseline (general model) (Sartori et al., 2011), and the F344 rat straindeemed appropriate for startle paradigms (Steiner et al., 2011). Itwas also suggested tat the High Anxiety Behavior rat line may besuitable for finding novel targets for anxiolytics (Landgraf et al.,2007) and that the BALB/C mouse may be especially suitable fortesting CRFergic agents and benzodiazepines (Conti et al., 1994;Griebel et al., 2000).

2.2.3. Models of chemically induced anxiety

Anxiety models based on drug treatment were proposed ratherearly(-carboline-induced anxiety, Skolnick et al., 1984). Althoughcertain compounds do induce anxiety in humans, chemical modelswere not developed to study these specific conditions. The basicidea was that chemically induced anxieties allow the detectionand/or testing of novel anxiolytics by producing pathological lev-els of anxiety, because the drug-induced neuronal dysfunctions aresupposed to be similar to neuronal dysfunctions that underlie anx-iety disorders. In this respect, these models may be classified intothe category of etiological models.

It wasproposedthatanxiolyticdrugtestingmay be improvedbythepre-treatmentof subjects withhaloperidol(Russelletal.,1987),cocaine (Ettenberg and Geist, 1991), pentylenetetrazol (Palit et al.,1998), mCPP (Bilkei-Gorzó et al., 1998), CO2 inhalation (Bailey and

Nutt, 2008), yohimbine (Crespi, 2009), and clomipramine (neona-tal) (Andersen et al., 2010). It was suggested that some of thesecompounds may be useful in the case of certain drug classes only(e.g. -carbolines and mCPP would be useful in testing GABAer-gic and serotonergic anxiolytics, respectively), while others wouldmodel specific anxiety disorders (e.g. CO2 inhalation would modelpanic, while neonatalclomipramineand trimethylthiazolinewouldmodel obsessive–compulsive disorderandspecificphobias,respec-tively). No such limitations were assumed with other compoundsthat were proposed as general models for the testing of novel anxi-olytics. Although chemically induced anxiety models may provideuseful information, one should also note that unpredictable inter-actions may occur between the agent used to induce anxiety andthe agent being tested for anti-anxiety activity.

2.3. New ways to study anxiety

In addition to amendments made to classical anxiety tests, alarge number of tests were introduced where anxiety is measuredin novel ways. This is achieved either by studying behaviors thatare not covered by the classical anxiety tests or by developing teststhat putatively model specific types of anxiety.

2.3.1. New anxiety-like behaviors and study subjects

Tests falling in this category are assumed to reveal anxietyresponses that are qualitatively different from those evaluated bythe classical tests. Such tests include the mirror chamber, whereanxiety is indicated by the avoidance of a chamber that contains a

mirror (Toubas et al., 1990), the marble burying test that putatively

models neophobia-related anxiety (Njung’e and Handley, 1991),the skin conductance reaction/habituation test (Quermonne et al.,1993), the mousedefense test battery, which models anti-predatordefense, i.e. a naturalistic form of anxiety (Griebel et al., 1995), andthe elevated platform test, where the measure of anxiety is freez-ing shown on a small elevated platform (Miyata et al., 2007). Amore sophisticated model of anxiety is the electrophysiological-voltammetric evaluation of yohimbine effects on noradrenergicfiring (Crespi, 2009). In the open space test of anxiety, mice aresubmitted to a 3D spatial navigation task in a modified radial mazewith flexible arms that can be raised above or lowered below thehorizontal plane of a central platform (Ennaceur et al., 2006). Thetest exposes subjects toa situationwhere they would be tempted toexplorebutcannotescapeoravoidtheanxiogenicfactorasopposedto classical exploratory tests endowed with shelters (e.g. the darkcompartment in the light/dark box or the closed arms in the plus-maze). The open-space test may be perceivedas variant of this test;in this case, the apparatusconsists of twoslopedarms(Michalikovaet al., 2010).

Finally, the introduction of zebrafish into anxiety researchresulted in a large number of anxiety tests that are based on vari-ous behaviors and behavioral responses seen in this species, suchas exploratory behavior in a circular tank (Peitsaro et al., 2003);

novelty-elicited diving response (Levin et al., 2007), antipreda-tory response (Bass and Gerlai, 2008), cocaine withdrawal-inducedhyperactivity (López-Patiño et al., 2008), behavioral responses toalarm substances (Speedie and Gerlai, 2008), behavioral responsesto animated predator image (Gerlai et al., 2009); hypoxanthine3-N-oxide-induced alarm responses (Parra et al., 2009), lightconfinement-induced freezing (Blaser et al., 2010), light/darkchoice (Champagne et al., 2010), novelty-induced anxiety asassessed by locomotion patterns (Cachat et al., 2010), escape andavoidance in larvae (Colwill and Creton, 2011), social preference(Braida et al., 2012), thigmotaxis in larval zebrafish (Schnörr et al.,2012), and animated bird silhouette-induced alarm response (Lucaand Gerlai, 2012).

2.3.2. Models specific to particular anxiety disordersEach anxiety disorder involves an anxiety dimension, but

their symptoms show large differences, e.g. the persistent anx-iety seen in generalized anxiety disorder is quite differentfrom the short-lasting but intense anxiety seen during panicattacks, obsessive–compulsive disorder is characterized by repet-itive actions, while post-traumatic stress disorder detaches fromall other anxieties by virtue of the complexity of its symptoms(American Psychiatric Association, 1994). The selective pharma-cological sensitivity of anxiety disorders (Bandelow et al., 2012)reinforces the view that these are relatively distinct mental dis-orders. In this section we briefly review attempts to model thesymptoms of particular anxiety disorders; such models have thepotential of leading to disorder-specific and more efficient treat-

ments.

2.3.2.1. Post-traumatic stress disorder (PTSD). In chronologicalorder, the first disorder-specific tests aimed at modeling PTSD. Thebasic approach was and remains the conditioned fear test that ini-tially was developed as a test of acquired anxiety (Price, 1972),but relatively soon was recognized as modeling symptoms of PTSD(Ottenweller et al., 1989). The test was amended over years inseveral ways. The effects of electric shocks were augmented byexposure to situational reminders before testing (Pynoos et al.,1996), by the use of congenital learned helplessness-rats that aremore prone to develop behavioral abnormalities in response toshocks (King et al., 2001), and by the application of immobiliza-tion stress or protracted social isolation before shock exposure

(Rau et al., 2005; Pibiri et al., 2008, respectively). New measures of

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PTSD-likesymptoms werealso introduced, e.g.the non-habituationof the acoustic startle response subsequent to shock exposure(Garrick et al., 2001). Particular PTSDsymptomswere alsomodeledby using this paradigm, e.g., avoidance responses in a shuttle box(Kobaetal.,2001) andunfamiliarobjectburying(Mikicsetal.,2008)were proposed to model PTSD-related hyper-vigilance.

As an alternative to shocks, Adamec and Shallow (1993)introduced cat exposure as a naturalistic way of traumatizing rats.Similar albeit milder effects were obtained with predator odor(Adamec et al., 2006). Recently predator stress was combined withchronic social instability (Zoladz et al., 2008). Other PTSD modelsinvolve the successive application of restraint, forced swimming,and anesthesia (time-dependent sensitization/single prolongedstress, Liberzon et al., 1997), completed later with a subsequentfoot shock (Wang et al., 2008). The experience of suffocation wasalso used to model PTSD (underwater trauma/water immersiontest, Richter-Levin, 1998). Other PTSD symptoms involve contin-uous administration of corticosterone (Levy et al., 2001) or socialdefeat (Pulliam et al., 2010).

2.3.2.2. Panic disorder. The first models of panic were likelyinspired by drug challenge studies performed in humans (e.g.Charney et al., 1984), as the first laboratory model combined

imipramine treatment with conditioned drinking suppression(Fontana and Commissaris, 1988). Non-pharmacological modelssoon followed. It was proposed that ultrasonic vocalization asso-ciated with aversive stimulation (Molewijk et al., 1995) as wellas behavioral responses of mice to their natural predator therat (Griebel et al., 1996) are panic-like, and may serve to screenanti-panic compounds. Recent variants of these models involvedefensive escape behaviors induced by ultrasound application inLister-hooded rats (Klein et al., 2010), and the exposure of mice toRainbow Boa (Uribe-Marino et al., 2012).

Modificationsoftheclassicaltestsalsoresultedinputativemod-els of panic. Graeff et al. (1998) suggested that one-way escapein the elevated T-maze may be associated with panic disorder,whiletheunstableelevatedplus-mazemay modelextremesinanx-

iety including panic-like responses (King, 1999). Finally, transgenicmice over-expressing the neurotrophin-3 receptor were proposedas a model of panic disorder (Dierssen et al., 2006).

2.3.2.3. Obsessive–compulsivedisorder. Obsessive–compulsive dis-order is usually modeledby stereotyped behaviorsthat arebelievedto be associated with anxiety. All the available models involvepre-test manipulations that trigger stereotyped behavior exceptfor the marble burying test, where spontaneous marble bury-ing per se is believed to be a compulsive/stereotyped behavior(Gyertyán, 1995). Noteworthy, this test was introduced as a gen-eral anxiety model and is also used to model depression (Njung’eand Handley, 1991). There are several models, where stereotypedbehaviors are triggered by food deprivation or reward omission.

Such models include the assessment of spontaneous alternationin food deprived rats that search the T-maze for reward (Yadinet al., 1991), scheduled polydipsia (excessive water consumptionin restricted schedule-fed rats, Woods et al., 1993); and exces-sive lever pressing following post-training signal attenuation ( Joeland Avisar, 2001). In other models, stereotyped behaviors wereinduced by skin infections (acral lick dermatitis in dogs: Rapoportet al., 1992; barbering ( fur andwhisker trimming ) by laboratorymice:Garneretal.,2004), or bypharmacological treatment. Thelattercat-egoryofmodelsincludesstereotypedorofacialmovementsinducedby striatal serotonin treatment (Yeghiayan and Kelley, 1995) orCRF administration (Salak-Johnson et al., 2004), as well as com-pulsive home site checking after treatment with the dopamineagonist quinpirole (Szechtman et al., 1998), and stereotyped

behaviors induced by neonatal clomipramine (Andersen et al.,

2010). Four relatively recent models make use of transgenic mice.Obsessive–compulsive-likebehaviors in these models include anx-iogenic odor-potentiated repetitive leaping that was induced by acholera toxin transgene in cortical-limbic D1 receptor-expressingneurons (McGrath et al., 1999), plastic-mesh screen chewing seenin 5-HT2C-KO mice (Chou-Green et al., 2003), sequential super-stereotyped grooming induced by a knockdown mutation of thedopamine transporter gene (Berridge et al., 2005), and excessiveself-grooming induced by the loss of the neuron-specific trans-membrane protein SLIT and NTRK-like protein-5 (Shmelkov et al.,2010).

2.3.2.4. Other anxiety disorders. Benzodiazepines readily reduceanxiety-like behavior in the elevated plus-maze, but are ineffec-tive if administered to rodents that have experience with this test.It was hypothesized that this one-trial tolerance’ phenomenon isakin tophobia (File et al., 1993). However, alternative explanationsalso exist (Rodgers and Shepherd, 1993) and subsequent researchdid not support the “phobic theory” of one-trial tolerance (Royet al., 2009). A thorough Medline search identified only two othermodels of phobia: Rosen et al. (2008) suggested that the predatorodor trimethylthiazoline may be used to model phobia in general,

while Barsy et al. (2010) showed that the social behavior of ratspre-exposed to chronic social defeat resembles important aspectsof social phobia. Neither model was validated in pharmacologicalterms.

Finally, there are three models believed to model drugwithdrawal-induced anxiety. The interaction between drug-withdrawal and anxiety is naturally well-studied, and there aremanystudies investigating the effects of anxiolytics in thiscontext.Yet, these studies usually employ classical tests of anxiety ratherthan studying drug withdrawal-specific measures. As exceptions,Knapp et al. (1993) suggested that the number of vocalizationsduring ethanol withdrawal reflects ethanol withdrawal-inducedanxiety. Fukushiro et al. (2011) used the decrease in novelty seek-ing and the increase in environmental habituation to characterize

amphetamine withdrawal-induced anxiety. A zebrafish model of cocaine withdrawal-induced anxiety was also developed (LópezPatiño et al., 2008).

3. Conclusions and suggestions for future research

Any anxiety test hasthe potentialof clarifying yetunrecognizedaspects of fear and anxiety; therefore, from a basic research per-spective,the large numberof tests canbe considered an asset.Fromthe narrower point of view of anxiolytic drug development, how-ever, the brief reviewof classical andnovelapproaches leads to thefollowing, less comforting conclusions:

(i) The comparison of preclinical findings andthe outcome of clin-ical trials demonstrates that the predictive validity of classicaltests is poor, indicating that preclinical approaches need to beimproved.

(ii) A large number of new tests and models were developed overthe last 27 years, by amending the classical tests, combiningthemwith manipulationsthatmimic etiological factors of anx-iety disorders, and by developing entirely new approaches.

(iii) The receptionof newanxiety testswas quitedifferent from thatseen with classical tests, e.g. the elevated plus-maze was usedby 50% of all anxiety studies already in 1990, i.e. just 5 yearsfollowing its introduction, and continues to be used by 50% of such studies ever since. By contrast, even the most “popular”novel approaches are used in a fraction of all studies, manybeing employed only by the laboratory that developed them.

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