Putative AD Wit Fast Onset

7/27/2019 Putative AD Wit Fast Onset

1/9

&p.1:Abstract BIMT 17, the only compound reported to be afull 5-HT1A agonist and a 5-HT2A antagonist at the fron-tal cortex, was assessed in three animal paradigms sensi-

tive to antidepressants in rats: olfactory bulbectomy(OB), differential-reinforcement-of-low rate 72-s (DRL72-s) and learned helplessness (LH). In the OB rats,BIMT 17, given once daily for 14 consecutive days at anIP dose of 10 mg/kg, but not of 20 mg/kg, reduced theincrease in ambulation of OB rats, 24 h after the last ad-ministration. In the DRL 72-s test, BIMT 17 had a differ-ent profile than imipramine. A single IP injection of 5,10, 15 or 20 mg/kg BIMT 17, in contrast to the samedoses of imipramine, did not affect response and rein-forcement rate in DRL 72-s 1 h after the administration.On the other hand, BIMT 17 slightly shifted the peak ofthe interresponse time (IRT) distribution towards shorterIRT duration, while imipramine shifted the peak of theIRT distribution towards longer IRT duration. In the LHtest, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17,given 30 min before testing, reduced the number of es-cape failures in LH without altering the intertrial cross-ings. This effect was also induced by a repeated, but notsingle, administration with 8 or 16 mg/kg imipramine.The plasma levels following IP 10 or oral 48 mg/kgBIMT 17 were in the same range. These results indicatethat BIMT 17 does not behave like imipramine in all thetests, and suggest that BIMT 17 acts through differentmechanisms of action than imipramine. Only clinical tri-als will tell whether these mechanisms will be relevant,but if so, BIMT 17 might induce a faster onset of thera-peutic activity.

&kwd:Key words BIMT 17 Animal models of depression Serotonin&bdy:

Introduction

BIMT 17 (2H-benzimidazol-2-one, 1,3-dihydro-1-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]) (Fig. 1)has recently been described as the first compound capableof inhibiting forskolin-stimulated cAMP (Borsini et al.1995b) and electrical activity (Borsini et al. 1995a) in therat frontal cortex, by activating postsynaptic serotonin (5-HT) 5-HT1A receptors and antagonizing 5-HT2A receptors(Borsini et al. 1995a,b). This mechanism of action in thefrontal cortex has also been reported for antidepressantsfollowing chronic treatment (Borsini 1994). Thus, BIMT17 may represent a prototype of a novel class of antide-

pressants with a potential faster onset of action. Interest-ingly, in the chronic mild stress model in mice, an animalmodel sensitive to antidepressants, a single administrationof BIMT 17 had an effect similar to that following repeat-ed treatment with fluoxetine (Willner 1995). An antide-pressant-like effect of BIMT 17 has also been reported inthe forced swimming test in mice (Cesana et al. 1995).

The purpose of the present study was two-fold: a) toevaluate further the antidepressant potential of BIMT 17in the rat and b) to confirm the faster onset of activity ofBIMT 17. The effect of repeated treatment with BIMT 17was evaluated in the olfactory bulbectomy (OB) modeland the effect of a single administration of BIMT 17 in the

F. Borsini (u) R. CesanaBoehringer Ingelheim Italia, Via Lorenzini 8, I-20139 Milano, Italy

J. Kelly B.E. Leonard M. McNamaraPharmacology Department, University College Galway, Ireland

J. Richards L. SeidenDepartment of Pharmacological and Physiological Sciences,University of Chicago, 947 East 58th Street,Chicago, IL 60637, USA&/fn-block:

Psychopharmacology (1997) 134:378386 Springer-Verlag 1997

O R I G I N A L I N V E S T I G AT I O N

&roles:F. Borsini R. Cesana J. Kelly B. E. LeonardM. McNamara J. Richards L. Seiden

BIMT 17: a putative antidepressant with a fast onset of action?

&misc:Received: 10 March 1997 / Final version: 9 July 1997

Fig. 1 Chemical structure of BIMT 17&/fig.c:


2/9

379

differential-reinforcement-of-low rate 72-s (DRL 72-s)paradigm. In addition, to evaluate further the possibility ofa faster onset of action of BIMT 17, the learned helpless-ness (LH) model was used, and the effect of a single ad-ministration of BIMT 17 was evaluated in comparison tosingle and repeated treatments with imipramine.

Material and methodsProcedures involving animals and their care were conducted inconformity with the institutional guidelines, in compliance with na-tional and international laws and policies (EEC Council Directive86/609, = J L 358,1, Dec. 12, 1987; NIH Guide for the Care andUse of Laboratory Animals. NIH publication no. 8523, 1985).

Bulbectomized rats

This experiment was carried out by M. M., J. K. and B. E. L.

Animals. &p.2:Male Sprague-Dawley rats were obtained from HarlanOlac, UK (weight on arrival: 230250 g). The animals werehoused four per cage in plastic bottomed cages and were given a1-week acclimatisation period prior to surgery. They were allowedfree access to food and water throughout the course of the experi-ment. Lighting was controlled on a 12-h light: dark cycle (light pe-riod: 08002000 hours) and temperature was maintaned between20 and 22C. At the time of surgery, rats were individually markedwith an ear notch for identification purposes.

Olfactory bulbectomy (OB). &p.2:Bilateral olfactory bulbectomy wasperformed in rats anaesthetised with 2.5% w/v 2-22 tribromoeth-anol (10 ml/kg IP) essentially as described by Cairncross at al.(1977). The head was shaved and a midline sagittal incision wasmade extending at least 1 cm rostral to the bregma. Sufficientpressure was applied to ensure that the periostium on the underly-ing bone had been penetrated. Two drill holes of 2 mm diameterwere made in the skull 5 mm rostral to the bregma and 2 mm later-al to the midline. For sham animals, the dura was carefully piercedand the wound closed. For OB animals, the olfactory bulbs were

aspirated using a water suction pump. Care was taken not to dam-age the frontal cortex. After the operation, bleeding was controlledby plugging the holes with haemostatic sponge (Haemofibrine,Specialities Septodont, France). Oxytetracycline dusting powderwas sprinkled on the wound prior to closure. The animals were al-lowed to recover for 14 days following surgery; they were handleddaily throughout the recovery period to eliminate any aggressive-ness that would otherwise arise (Leonard and Tuite 1981).

Drug administration. &p.2:After surgery, the rats were allocated to sixgroups (nine animals in each group): sham + vehicle; sham +10 mg/kg BIMT 17; sham + 20 mg/kg BIMT 17; OB + vehicle;OB + 10 mg/kg BIMT 17; OB + 20 mg/kg BIMT 17. The doses ofBIMT 17 refer to its salt form. Body weights of each animal in allthe groups were measured at days 1 and 15. BIMT 17 chloridewas mixed with Tween 80 until a milky, homogenous dispersion

was obtained. Saline was then added, to give a concentration of ei-ther 10 or 20 mg/ml. This was administered IP at 1 ml/kg given asingle daily dose between 0800 and 1000 hours of 10 or 20 mg/kgfor 14 consecutive days. Controls received injections of vehiclealone.

Open field. &p.2:The rats were tested on day 15 of experiment. Thisapparatus is essentially as described by Gray and Lalljee (1974).The open field consisted of a circular base, 90 cm in diameterwhich was divided into 10 cm squares by faint yellow lines. Thewall surrounding the base consisted of a 75 cm high aluminiumsheet. Illumination was provided by a 60-W bulb, positioned90 cm above the floor of the apparatus. All measurements werecarried out in a darkened room on the morning of day 15 between

0600 and 0800 hours. Each animal was placed in the centre of theopen field apparatus and the following parameters were measuredover a 3-min period: ambulation (number of squares crossed),rearing (number of times the rat simultaneously raised both fore-paws off the floor of the apparatus), grooming (number of timesthe rat stopped and groomed itself) and defaecation (the numberof faecal boli deposited).

Data analysis. &p.2:Two-way analysis of variance was performed toevaluate body weights. If any statistically significant change was

found, the data was further analysed using the Student NewmanKeuls test. These results are expressed as group mean and standarderror of the mean. Kruskal-Wallis test was performed on the datarelative to the open field test. If any statistically significantchanges were found, these data were then tested using a Mann-Whitney U-test. These results are expressed as group median andinter-quartile range.

DRL 72-s

This experiment was carried out by J. R. and L. S.

Animals. &p.2:Fifteen male Sprague-Dawley rats (Hotzman, Madison,Wisc., USA) weighing between 350 and 500 g at the time of drugadministration were used. The rats were housed two per cage inhanging stainless steel wire cages. Lights were on in the colonyroom from 0700 to 1900 hours. Food (4% Tek Lab rat chow) wasavailable ad lib. Access to water was restricted to 20 min per day.On training days the rats received 20 min access to water at theend of their training session. On non-training days (weekends),the rats were given 20 min access to water between 1000 and1400 hours.

Apparatus. &p.2:This was according to Richards et al. (1994). The op-erant chambers were 20.5 cm wide, 20.5 cm deep and 23.5 cmlong. The operant chambers had grid floors, aluminium front andback walls and Plexiglas sides. A lever was mounted 3 cm abovethe grid floor 4.5 cm from the nearest side. A downward force ofapproximately 0.15 N was required for a lever press to be detect-ed. A solenoid operated dipper was located 10 cm to the left of thelever. Access to the dipper was through a round 4.5 cm diameterhole in the front panel. Reinforcement consisted of lifting the dip-

per (0.025 ml) from a water trough to within reach of the ratstongue for a period of 4 s. A stimulus light mounted 15 cm abovethe floor on the back wall of the chamber provided the only illumi-nation within the chamber. The stimulus light was turned on whena training session began, and off when the training session ended.The operant chambers were enclosed in 80 quart Coleman icechests to attenuate external stimuli. Fans mounted on the icechests provided ventilation and masking noise. The operant cham-bers were connected to a PDP-11/73 micro computer via a Coul-bourn Lablinc interface. The schedule contingencies were pro-grammed using the SKED-11 software system. The timing resolu-tion of the system was 0.01 s.

Training. &p.2:Upon arrival in the colony the rats were adapted to the20 min per day access to water regimen for 1 week. The rats werethen trained to bar press in over-night training sessions using an

alternative FR1, FT 1-min schedule. Rats which did not acquire thelever press response after five overnight training sessions were man-ually trained to press it. The rats were then shifted to a DRL-72-straining regimen. DRL 72-s overnight training consisted of six 1-hsessions with a 30-min time-out (house light off) between eachsession. The rats were trained overnight on the DRL 72-s schedulefor 10 nights. After completion of overnight DRL 72-s training therats were trained during daily (5 days a week) 1-h sessions on theDRL 72-s schedule. The rats had received daily 1-h DRL 72-sschedule sessions for 10 weeks before drug testing was initiated.

Drug administration. &p.2:Both BIMT 17 chloride and imipraminechloride (Ciba) were injected IP 1 h before the session in doses of0, 5, 10, 15 and 20 mg/kg, calculated as a salt. The compounds


3/9

380

were dissolved in vehicle (V) to form a solution of 1 ml/kg for in-jection. BIMT 17 was combined with Tween 80 in a ratio of 1 mgBIMT 17 to 4 mg Tween 80. A glass vial and a small magneticstir rod were used to obtain a homogeneous dispersion. Water wasthen incrementally added to obtain the appropriate drug dose.This procedure resulted in a clear fluid with no visible particles.Tween 80, 80 mg/ml water, was used for the BIMT 17 vehicle in-jection. The vehicle for imipramine was saline. Drug doses wereprepared immediately before administration. The doses of BIMT17 and imipramine were given in ascending order. Drugs were ad-

ministered on Tuesday and Friday of each week. Control perfor-mance was the average of the Thursdays which occurred duringeach drugs dose-response determination. BIMT 17 and imipra-mine were tested using a cross-over procedure. Eight of the ratsreceived the BIMT 17 dose determination first, followed by theimipramine dose determination. The remaining seven rats re-ceived the imipramine dose determination first, followed by theBIMT 17 dose determination.

Data analysis. &p.2:Response rate, reinforcement rate, peak area (PkA),and peak location (PkL) measures were determined for each rat.The PkA and PkL metrics quantitatively characterize the profile ofthe interresponse time (IRT) distributions generated by respondingon the DRL 72-s schedule (Richards and Seiden 1991; Richards etal. 1993a). Rats well trained on the DRL 72-s schedule generateIRT distributions which have well defined peaks. PkA indicates

the area of the IRT distribution peak and PkL indicates the loca-tion of the IRT distribution peak.In Fig. 4, the BIMT 17 vehicle histogram (top left histogram)

illustrates how the profile of the IRT distributions was quantita-tively characterized by PkA and PkL. The single shaded histogrambar on the left indicates the burst component of the IRT distribu-tion (IRT < 6 s). The bars to the right of the burst component indi-cate the pause component of the IRT distribution (IRTs 6s). Theconnected dots indicate the expected appearance of the pausecomponent of the IRT distribution if the rat emitted the same num-ber of responses, but randomly in time with respect to the preced-ing response. This expected curve is called the corresponding neg-ative exponential. PkA is indicated by the shaded region of the ob-tained IRT histogram above the corresponding negative exponen-tial. The peak location (PkL) is the median IRT duration which bi-sects the shaded region above the corresponding negative expo-nential. Decreases in the value of PkA indicate that the rats are re-sponding in a less coherent fashion and that the distribution ofwaiting times (IRTs) is more dispersed. Increases in the value ofPkA indicate that the rats are responding in a more coherent fash-ion and that the IRT distribution is less dispersed. PkL indicatesthe central location of the peak. A decrease in the value of PkL in-dicates the rats are not waiting as long between responses. An in-crease in PkL indicates the rats are waiting longer.

A two-factor ANOVA, with treatment order as a between-groups factor and drug dose as a within-groups factor, was donefor both BIMT 17 and imipramine to determine if treatment orderaffected the results. The results of this analysis showed no signifi-cant between group differences. This result indicated that therewas no effect of treatment order. After determining that there wasno effect of treatment order, the data were combined and analyzedusing within group t-tests. Control values (average of the Thurs-days which occurred during each drugs dose response determina-

tion) for each measure were compared to each drug dose (includ-ing vehicle) using within group t-tests. A Bonferroni correctionwas used to guard against a type 1 error due to multiple compari-sons. The overall level of significance was set at P


4/9

381

Fig. 2 Effect of BIMT 17 in the open-field in sham and OBrats. Results are expressed as median, and interquartile range (inbrackets), of nine animals. Rats were placed in the open fieldafter 2 weeks of treatment with BIMT 17 (IP, once daily). The testwas carried out on day 15, i.e. 24 h after the last injection.# P


5/9

382

Fig. 3 Effects of BIMT 17 andimipramine on response rate,reinforcement rate, peak area,and peak location. Peak areaand location are metrics de-signed to measure the IRT dis-tribution profile (see text andFig. 4). BIMT 17, imipramineand vehicle were given IP 1 hbefore the session. * P < 0.05

versus respective V-group&/fig.c:

Group Treatment Dose No. of intertrial crossingsmg/kg median (interquartile range)

Acute bimt 17

IS Vehicle 0 0.5 (01)IS+ Vehicle 0 2.0 (03)IS+ BIMT 17 24 0.5 (01)IS+ BIMT 17 36 2.0 (14.5)IS+ BIMT 17 48 2.0 (14.5)IS+ BIMT 17 60 2.0 (0.54)

Acute imipramine

IS- Vehicle 0 0 (00.5)IS+ Vehicle 0 0.5 (01.5)IS+ Imipramine 4 1.5 (0.52)IS+ Imipramine 8 0 (01)IS+ Imipramine 16 0 (00)

Repeated imipramine

IS Vehicle 0 0 (00)IS+ Vehicle 0 0.5 (01)IS+ Imipramine 4 0.5 (02.5)IS+ Imipramine 8 0 (00.5)IS+ Imipramine 16 0.5 (01)

Table 1 Effect of acute BIMT17 and imipramine, and repeat-ed imipramine on the intertrialcrossings in the LH test in rats&/tbl.c:&tbl.b:

BIMT 17 was given orally30 min before testing. Imipra-mine was given as a single or arepeated administration. Imi-pramine was given as a singledose 30 min before testing. Re-peated administered imipra-mine was given i.p. 2 h after in-escapable shock on day 1,twice daily on days 2 and 3,30 min before testing on day 4.Group sizes were constitutedby 16 rats for BIMT 17 experi-ment and by 8 rats for the imi-pramine experiments. Kruskal-

Wallis test: P >0.05&/tbl.b:

ministration of 4, 8 and 16 mg/kg imipramine (Fig. 5)was completely devoid of effects (Kruskal-Wallis testP = 0.88). The repeated administration of 4, 8 and16 mg/kg imipramine decreased the number of escapefailures of helpless rats during the shuttle-box test ses-sion (Kruskal-Wallis test P = 0.001), without affectingthe number of intertrial crossings (Table 1), 8 and16 mg/kg being the active doses.

Plasma levels

The plasma levels (g/ml) of BIMT 17 60 min after itsIP administration with 10 or 20 mg/kg were(mean SEM) 1.24 0.05 and 1.59 0.18, respectively;whereas 30 min after its oral administration with48 mg/kg they were (mean SEM) 1.27 0.36.


6/9

383

Discussion

Given orally, BIMT 17 is less potent than when given IP(Cesana et al. 1995), and this finding has been confirmedin the present study where IP 10 mg/kg and oral48 mg/kg gave similar plasma levels. Both the OB andLH models only permit the observation of very strong ef-fects, due to either the small window for drugs to restorea normal behaviour or to the variability of data. In fact,in both tests, the data were expressed as median and in-terquartiles because the distribution of values was notGaussian. This might explain why the effect of BIMT 17in the OB model apparently appears similar at both dos-es, 10 and 20 mg/kg, but only the lowest dose induced astatistically significant effect. Similar considerationholds with the LH model, where the highest dose exertedan effect which was smaller than that observed at a lowerdose. Alternatively, it may be that doses greater than10 mg/kg IP (or 48 mg/kg PO, which produces similarplasma levels of 10 mg/kg IP) interfere with rat perfor-mance, as also evidenced by DRL 72-s.

Fig. 4 Interresponse time (IRT)histograms visualizing howBIMT 17 and imipramine effect-ed the DRL 72-s IRT distribu-tion profiles. The IRT distribu-tions are bimodal with one modeat short IRT durations (IRT< 6 s ; shaded histogram baronthe left) indicating bursting and asecond mode at longer IRT dura-

tions (IRT 6 s; open histogrambars) indicating pausing. Thissecond mode shows that the ratshave learned to wait between re-sponses (although not quite longenough). The BIMT 17 vehiclehistogram (top left histogram) il-lustrates how the IRT distribu-tion profile is quantitativelycharacterized by the peak area(PkA) and peak location (PkL)metrics (see text for explana-tion). The triangle in the burstcategory indicates the relativefrequency of burst responsespredicted by extrapolation of thecorresponding negative expo-

nential into the burst component.The single dot at the far right ofthe histogram indicates the rela-tive frequency of IRTs > 144 spredicted to occur in the tail ofthe corresponding negative ex-ponential. Similarly, the singlehistogram bar at the far rightin-dicates the relative frequency ofIRTs > 144 s in the tail of theobtained IRT distribution. Thedashed vertical line indicates the72-s IRT duration requirementfor reinforcement. The histo-grams represent the averagedrelative frequencies of 15 rats&/fig.c:

Bulbectomized rats

The ablation of the olfactory bulbs induces many behav-ioural changes in the rat (Leonard 1984; Jesberger andRichardson 1986). The primary index of potential antide-pressant activity is reversal of increased ambulationscores (Jancsar and Leonard 1983; Van Riezen and Leon-ard 1990). Repeated administration of BIMT 17 at a doseof 10 mg/kg significantly reversed the increased ambula-tion associated with the OB rat in the open field test.Reversal of increase in ambulation in OB rats has alsobeen reported for antidepressants, both typical and atypi-cal including selective serotonin reuptake inhibitors, butnot for centrally acting drugs which lack antidepressantactivity (Jancsar and Leonard 1983; Leonard 1984; Songand Leonard 1994): repeated treatment with these antide-pressants seems to be necessary to observe an effect (VanRiezen et al. 1977; Leonard 1982, 1984; Song and Leon-ard 1994).

Interestingly, OB rats have an altered 5-HT metabo-lism in the frontal cortex (Lumia et al. 1992), and in oth-


7/9

384

er brain regions. In addition, OB mice showed an in-crease in 5-HT2 receptors only in the frontal cortex (Gu-revich et al. 1993) and, in these animals, repeated admin-istration with amitriptyline and trazodone had the com-mon effect of reducing the number of 5-HT1A receptorsin the frontal cortex but not in other areas (Gurevich etal. 1993). The OB rodent model has been suggested as amodel for agitated hyposerotonergic depression (Lumiaet al. 1992). Thus, BIMT 17, an agonist at 5-HT1A recep-tors and an antagonist upon 5-HT2A receptors in the fron-tal cortex (Borsini et al. 1995a,b), showed an antidepres-sant-like effect in the OB model following chronic ad-ministration.

DRL 72-s

The profiles of the acute effects of BIMT 17 and the an-tidepressant imipramine on DRL 72-s performance arevery different. BIMT 17 had no effect on response andreinforcement rate while imipramine decreased responserate and increased reinforcement rate. BIMT 17, but notimipramine, induced decreases in PkA. BIMT 17 shiftedthe PkL toward shorter IRT durations while imipramineshifted PkL toward longer IRT durations. Previous re-

search (Seiden et al. 1985; Marek and Seiden 1988a;Richard et al. 1993b) has shown that a variety of antide-pressant compounds shift the peak of the IRT distribu-tion toward longer IRT durations without decreasingPkA. This shift in the IRT distribution toward longerwaiting times results in an increased reinforcement rate.By these criteria, BIMT 17 does not resemble the acuteeffects of antidepressants on the DRL 72-s screen. Al-

though BIMT 17 did not affect response and reinforce-ment rate at the doses tested, it did significantly affectthe IRT distribution profile. The shift in the peak towardshorter waiting times and the increased dispersion of thewaiting times indicates that BIMT 17 disrupted perfor-mance at doses greater than 10 mg/kg.

It has been suggested that antidepressants may act inDRL 72-s by blocking 5-HT2 receptors and activating 5-HT1A receptors (Marek and Seiden 1988b; Marek et al.1989a,b). Even if not all 5-HT1A agonists exert an anti-depressant-like effect in this test (Richards et al. 1994), itis surprising that BIMT 17, a 5-HT2A antagonist and 5-HT1A agonist in the cortex, did not affect DRL 72-s be-

haviour. The fact that BIMT 17 is the first full postsyn-aptic agonist (Borsini et al. 1995a,b) differentiates itfrom the other agonists. In fact, it should be pointed outthat 8-OH-DPAT and buspirone do not behave as ago-nists in the frontal cortex (Borsini et al. 1995b). Singledoses of 8-OH-DPAT and buspirone (Borsini et al.1995a), imipramine (Ceci et al. 1992) or fluoxetine (Ceciet al. 1993) increase the firing rate of frontocortical neu-rons, whereas BIMT 17 decreases the firing rate by acti-vating 5-HT1A receptors (Borsini et al. 1995a). In addi-tion, BIMT 17 has a direct action on postsynaptic 5-HTreceptors (Borsini et al. 1995a; Cesana et al. 1995),whereas all the other compounds referred to seem to ac-

tivate presynaptic 5-HT mechanisms. It may be that thisdifference in the mechanism of action can explain thedifferent effect of BIMT 17 in comparison with antide-pressants in this animal model.

Learned helplessness

Among the animal models of depression, the LH pos-sesses an interesting degree of face validity and pre-dictive validity (Willner 1991). In fact, reversal of LH isobtained after repeated, but not after acute, administra-tion of tricyclic antidepressants, monoamine oxidase in-hibitors, selective 5-HT reuptake inhibitors and electro-convulsive shock. Reversal of LH is also obtained afteracute administration of psychostimulant compounds (e.g.amphetamine) but in contrast to antidepressants, theyalso affect locomotor activity, increasing the number ofintertrial crossings (Christensen 1993). The reversal ofLH observed after the single administration of BIMT 17did not seem to depend on modification of the number ofintertrial crossings. Thus, BIMT 17 induced an antide-pressant-like behavioural effect in the LH paradigm aftera single administration whilst antidepressants must begiven repeatedly.

Fig. 5 Effect of BIMT 17 and imipramine on the escape failuresin the LH test. Results are expressed as median, and interquartilerange (in brackets). BIMT 17 (top panel) was given orally 30 minbefore testing. Imipramine was given as a single (middle panel) ora repeated (bottom panel) administration. Imipramine was given asa single dose 30 min before testing. Repeated administered imi-pramine was given IP 2 h after inescapable shock on day 1, twicedaily on days 2 and 3, 30 min before testing on day 4. Group sizeswere constituted by 16 rats for BIMT 17 experiment and by eightrats for the imipramine experiments. # P < 0.01 versus IS+ (Wil-coxon two-sample test); * P < 0.01 versus vehicle-treated group(Dunn test)&/fig.c:


8/9

385

It is worth noting that a supersensitivity of 5-HT2 re-ceptors possibly related to LH behaviour has been sug-gested and that the repeated administration of antidepres-sants induces a down-regulation of these receptors whichparallels the reversal of LH behaviour (Barone et al.1990; Nakai et al. 1995). In addition, it has been reportedthat fluoxetine, after repeated treatment, prevents the es-cape deficit in this animal model also by activating 5-

HT1A receptors, although a different experimental proto-col of the test was used (Gambarana et al. 1995). Inter-estingly, the helpless behavior is reversed in the LHmodel by repeated treatment with putative 5-HT1A ago-nists (Giral et al. 1988) and it has been shown that theireffect is due to the activation of postsynaptic 5-HT1A re-ceptors (Martin et al. 1990, 1991). Moreover, it has beenreported that LH induction modifies in vivo cortical 5-HT release (Petty and Sherman 1983; Petty et al. 1994)and that tricyclic antidepressants normalize this change(Sherman and Petty 1982); such effects correlate withantidepressant concentrations in the anterior neocortex(Petty et al. 1982). The prefrontal cortex was the only

brain region in which microinjection of 5-HT reversedlearned helplessness 1 h after injection (Petty and Sher-man 1980).

Due to the serotonergic activity of BIMT 17, it is notsurprising that BIMT 17 can reverse the behavioural def-icit of rats in the LH after a single administration.

General discussion

The purpose of this study was two-fold. Firstly, to con-firm the potential antidepressant activity of BIMT 17 aspreviously shown in two animal paradigms sensitive to

antidepressants, i.e. the forced swimming test (Cesana etal. 1995) and the chronic mild stress procedure (Willner1995). Thus, BIMT 17 was tested in OB rats, in the LHprocedure and in the DRL 72-s model and induced anti-depressant-like effects in the former two paradigms butnot in the latter one.

Secondly, to confirm the faster onset of action ofBIMT 17, as has already been seen in the chronic mildstress procedure (Willner 1995), by using the LH para-digm where it was found that BIMT 17 induced antide-pressant-like effect after a single administration.

It is worth noting that BIMT 17 and not imipramineinduced an effect in the LH, whereas imipramine and notBIMT 17 induced an effect on DRL 72-s. These differ-ences are not surprising, as these two compounds mayexert different effects on the 5-HT-containing neurons. 5-HT uptake inhibitors, after a single administration, aremore effective on the dendro-somatic region than on thepostsynaptic 5-HT receptors (Adell and Artigas 1991;Artigas 1993; Bel and Artigas 1993). Thus, the differenteffect of BIMT 17 and the 5-HT uptake inhibitors maydepend on this different location of action. This may bealso substantiated by the fact that the 5-HT1A agonist, 8-OH-DPAT, produces an effect when microinjected atpostsynaptic receptors in the LH paradigm whereas the

action of a low dose of fluoxetine in the DRL 72-s para-digm is reduced after destruction of 5-HT-containingneurons by a selective 5-HT neurotoxin (Marek et al.1989a). Similar results with fuoxetine and the 5-HT neu-rotoxin were also obtained in the LH test (Martin et al.1990). Thus, the different activities of acute BIMT 17and imipramine may depend on their postsynaptic(BIMT 17) and presynaptic (imipramine) component. In-

terestingly, when the postsynaptic component of imipra-mine is unmasked after repeated treatment, an effectcommon to antidepressants (see Borsini 1994), imipra-mine was also active in the LH. A study to investigatethe exact mechanism of action of BIMT 17 in the LH iscurrently under investigation.

In conclusion, taken as a whole, these results indicatethat BIMT 17 does not behave like imipramine in all thetests and suggest that BIMT 17 acts through differentmechanisms of action than imipramine. Only clinical tri-als will tell whether these mechanisms will be relevant,but if so, BIMT 17 might induce a faster onset of thera-peutic activity.

&p.2:Acknowledgements This study was mostly supported by IMIcontract no. 55312/46.

References

Adell A, Artigas F (1991) Differential effects of clomipraminegiven locally or systemically on extracellular 5-hydroxytrypta-mine in raphe nuclei and frontal cortex. Naunyn-Schmiede-bergs Arch Pharmacol 343: 237244

Artigas F (1993) 5-HT and antidepressants: new views from mi-crodialysis studies. Trends Pharmacol Sci 14: 262

Bel N, Artigas F (1993) Chronic treatment with fluvoxamine in-creases extracellular serotonin in frontal cortex but not inraphe nuclei. Synapse 15: 243245

Barone P, Atger F, Martin P, Puech A, Fillion G (1990) Increasednumber of 5HT2 receptors in the learned helplessness rat.Eur J Pharmacol 183: 19001901

Borsini F (1994) Balance between cortical 5-HT1A and 5-HT2 re-ceptor function: hypothesis for a faster antidepressant action.Pharmacol Res 30: 111

Borsini F, Ceci A, Bietti G, Donetti A (1995a) BIMT 17 a 5-HT 1Aagonist/5-HT2A antagonist, directly activates postsynaptic 5-HT inhibitory responses in the cortex. Naunyn-SchmiedebergsArch Pharmacol 352: 283290

Borsini F, Giraldo E, Monferini E, Antonini G, Parenti M, BiettiG, Donetti A (1995b) BIMT 17, a 5-HT2A antagonist and 5-HT1A receptor full agonist, in rat cerebral cortex. Naunyn-Schmiedebergs Arch Pharmacol 352: 276282

Cairncross KD, Wren AF, Cox B, Schnieden H (1977) Effects ofolfactory bulbectomy and domicile on stress induced cortico-

sterone release in the rat. Physiol Behav 19: 485487Ceci A, Baschirotto A, Borsini F (1992) Effect of 5HT monoamine

uptake blockers and 5HT1A agonists on spontaneous firing rateof prefrontal cortical neurons. Soc Neurosci Abstr 18: 317.1

Ceci A, Baschirotto A, Borsini F (1993) Effect of fluoxetine onthe spontaneous electrical activity of fronto-cortical neurons.Eur J Pharmacol 250: 461464

Cesana R, Ciprandi C, Borsini F (1995) The effect of BIMT 17, anew potential antidepressant, in the forced swimming test inmice. Behav Pharmacol 6: 688694

Christensen AV (1993) Learned helplessness: an animal model ofdepression? Neuropsychopharmacology 9: 167S

Gambarana C, Ghieri O, Taddei A, Tagliamonte, de Montis MG(1995) Imipramine and fluoxetine prevent the stress-induced


9/9

386

escape deficits in rats through a distinct mechanism of action.Behav Pharmacol 6: 6673

Geoffroy M, Scheel-Kruger J, Christensen AV (1990) Effect ofimipramine in the learned helplessness model of depression inrats is not mimicked by combination of specific reuptake in-hibitors and scopolamine. Psychopharmacology 101: 371375

Giral P, Martin P, Soubrie P, Simon P (1988) Reversal of helplessbehavior in rats by putative 5-HT1A agonists. Biol Psychiatry23: 237242

Gray JA, Lalljee B (1974) Sex differences in emotional behaviour

in the rat: correlation between the open field defecation andactive avoidance. Anim Behav 22: 856861Gurevich EV, Aleksandrova IA, Otmakhova NA, Katkov YA,

Nesterova IV, Bobkova NV (1993) Effects of bulbectomy andsubsequent antidepressant treatment on brain 5-HT2 and 5-HT1A receptors in mice. Pharmacol Biochem Behav 45: 6570

Jancsar S, Leonard BE (1983) The olfactory bulbectomized rat asa model of depression. In: Usdin E, Goldstein M, FriedhoffAJ, Georgotas A (eds) Frontiers in neuropsychiatric research.MacMillan, New York, pp 357372

Jesberger JA, Richardson JS (1986) Effects of antidepressantdrugs on the behavior of olfactory bulbectomized and sham-operated rats. Behav Neurosci 100: 256274

Leonard BE (1982) On the mode of action of mianserin. Adv Bio-chem Psychopharmacol 31: 301320

Leonard BE (1984) The olfactory bulbectomized rat as a model of

depression. Pol J Pharmacol Pharm 36: 561569Leonard BE, Tuite M (1981) Anatomical, physiological and be-havioural aspect of olfactory bulbectomy in the rat. Int RevNeurobiol 22: 251286

Lumia AR, Teicher MH, Salchli F, Ayers E, Possidente B (1992)Olfactory bulbectomy as a model for agitated hyposerotoner-gic depression. Brain Res 587: 181185

Maier SF, Seligman MEP (1976) Learned helplessness: theory andevidence. J Exp Psychol Gen 105: 346

Marek GJ, Seiden LS (1988a) Selective inhibition of MAO-A, notMAO-B, results in antidepressant-like effects on DRL 72-sec-ond behavior. Psychopharmacology 96: 153160

Marek GJ, Seiden LS (1988b) Effects of selective 5-hydroxytryp-tamine-2 and nonselective 5-hydroxytryptamine antagonists onthe differential-reinforcement-of-low-rate 72-second schedule.J Pharmacol Exp Ther 244: 650658

Marek GJ, Li AA, Seiden LS (1989a) Evidence for involvement of5-hydroxytryptamine-1 receptors in antidepressant-like drugeffects on differential-reinforcement-of-low-rate 72-second be-havior. J Pharmacol Exp Ther 250: 6071

Marek GJ, Li AA, Seiden LS (1989b) Selective 5-hydroxytrypta-mine-2 antagonists have antidepressant-like drug effects ondifferential-reinforcement-of-low-rate 72-second schedule. JPharmacol Exp Ther 250: 5259

Martin P, Beninger RJ, Hamon M, Puech AJ (1990) Antidepres-sant-like action of 8-OH-DPAT, a 5-HT1A agonist, in thelearned helplessness paradigm: evidence for a postsynapticmechanism. Behav Brain Res 38: 135144

Martin P, Tissier MH, Adrien J, Puech AJ (1991) Antidepressant-like effects of buspirone mediated by the 5-HT1A post-synapticreceptors in the learned helplessness paradigm. Life Sci 48:25052511

Nakai M, Yamada S, Muneoka K, Tiru M (1995) Increased 5-HT2receptor-mediated behavior 11 days after shock in learnedhelplessness rats. Eur J Pharmacol 281: 123130

Petty F, Sherman AD (1983) Learned helplessness induction de-creases in vivo cortical serotonin release. Pharmacol BiochemBehav 18: 649650

Petty F, Sherman AD (1980) Regional aspects of the prevention oflearned helplessness by desipramine. Life Sci 26: 14471452

Petty F, Sacquitne JL, Sherman AD (1982) Tricyclic antidepres-sant drug action correlates with its tissue levels in anterior

neocortex. Neuropharmacology 21: 475477Petty F, Kramer G, Wilson, Jordan S (1994) In vivo serotonin re-lease and learned helplessness. Psychiatry Res 52: 285293

Richards JB, Seiden LS (1991) A quantitative interresponse-timeanalysis of DRL performance differentiates similar effects ofthe antidepressant desipramine and the novel anxiolytic gepir-one. J Exp Anal Behav 56: 173192

Richards JB, Sabol KE, Seiden LS (1993a) DRL interresponse-time distributions: quantification by peak deviation analysis. JExp Anal Behav 60: 361385

Richards JB, Sabol KE, Seiden LS (1993b) Fluoxetine preventsthe disruptive effects of fenfluramine on differential-reinforce-ment-of-low-rate 72-second schedule performance. J Pharma-col Exp Ther 267: 12561263

Richards JB, Sabol KE, Hand TH, Jolly DC, Marek GJ, Seiden LS(1994) Buspirone, gepirone, ipsapirone, and zalospirone have

distinct effects on the differential-reinforcement-of-low-rat 72-second schedule when compared with 5-HTP and diazepam.Psychopharmacology 114: 3946

Seiden LS, Dahms JL, Shaughnessy RA (1985) Behavioral screenfor antidepressants: the effect of drugs and electroconvulsiveshock on performance under a differential-reinforcement-of-low-rate schedule. Psychopharmacology 86: 5560

Sherman AD, Petty F (1982) Additivity of neurochemical changesin learned helplessness and imipramine. Behav Neural Biol35: 344353

Song C, Leonard BE (1994) Serotonin reuptake inhibitors reversethe impairments in behaviour, neurotransmitter and immunefunctions in the olfactory bulbectomized rat. Hum Psycho-pharmacol 9: 135146

Van Riezen H, Leonard BE (1990) Effects of psychotropic drugson the behaviour and neurochemestry of olfactory bulbectomi-

zed rats. Pharmacol Ther 47: 2143Van Riezen H, Schneiden H, Wren AF (1977) Olfactory bulb abla-tion in the rat: behavioural changes and their reversal by anti-depressive drugs. Br J Pharmacol 60: 521346

Willner P (1991) Animal models of depression. In: Willner P (ed)Behavioural models in psychopharmacology. University Press,Cambridge, pp 91125

Willner P (1995) Animal models of depression: validity and appli-cations. In: Gessa G, Fratta W, Pani L, Serra G (eds) Depres-sion and mania: from neurobiology to treatment. Raven Press,New York, pp 1941

Putative AD Wit Fast Onset

Documents

Transcript of Putative AD Wit Fast Onset