First publ. in: Behavioural Pharmacology ; 13 (2002), 3. - S. 189-201 Apomorphine sensitization: evoking conditions, context dependence, effect persistence and conditioned nature S. Keller, J.D. Delius and M.J. Acerbo Allgemeine Psycho logie, Universitat Konstanz, 78457 Konstanz, Germany Correspondence to J.D. Delius, Allgemeine Psychologie, Universitat Konstanz, 78457 Konstanz, Germany. E-mail: juan.delius@uni-konstanz.de When repeatedly administered a dose of apomorphine (Apo), pigeons, much like rodents, show behavioural sensitization. In birds this sensitization expresses itself as an increasing pecking response to the drug and is found to be partially dependent on the environmental context in which Apo takes efl'ect. In the first experiment we examined what efl'ect difl'erent inter-Apo administration intervals have on the development of Apo sensitization and found that, with some sma ller variations, intervals between 3 hours and 5 days all yielded comparable courses of sensitization. In the second experiment we examined how long pigeons had to be exposed to the same distinct cage to reveal a maximal context-dependent sensitization. Pigeons were therefore repeatedly injected with Apo and consistently placed in an experimental cage for difl'erent lengths of time (5 to 60 min; the overall drug efl'ect lasted for about 1 h) before being returned to their standard home cages. Subsequent tests in the experimental cage and a standard cage showed that 20-min Ilost-injection exposures were sufficient to yield a maximal response in the experimental cage. After training with 20- and 60-min exposures, the pigeons pecked about three times more in the experimental cage than in the standard cage. This confirmed the marked context dependency of the sensitization effect. In the third experiment, groups of pigeons were injected repeatedly with Apo and directly afterwards placed either consistently into the same experimental cage or into different experimental cages. The same-cage group evidenced a significantly much stronger sensitization than the difl'erent-cage group. A cage-habituation group served as a control for the possibility that the weaker sensitization of the different-cage group might be due to a cage novelty efl'ect. This cage-habituation group was run under the same conditions as the difl'erent-cage group but with additional exposures to the crucial cage while injected with saline. This extra treatment did not augment the pecking response to Apo in that cage. In the fourth experiment we examined how long the sensitization to Apo lasts and found that, even after 2 years of drug abstinence, it only waned to 50% of the original asymptotic response. The overall results sUPllort the hypothesis that a very major part of the sensitization to Apo in pigeons is due to a conditioning to the environmental context and to the drug state itself. Keywords: pigeon, apomorphine, dopamine, pecking, sensitization, conditioning, memory INTRODUCTION Psychostimulant substances, several of which are ab used by humans, are generally known to yield a sensitization effect when they are administered repeatedly to animal subjects. The effect involves an increase of the behavioural response to successive administrations of a given drug dose up to a ceiling response. Because it seems likely that the sensitization phenomenon relates to the development of the drug addiction connected with psychostimulants such as cocaine and amphetamine, it has been the subject of much research . The details of the processes responsible for the sensitization effect are nevertheless still a matter of some controversy. This undoubtedly is due in part to the fact that different drugs, different doses, different procedures, different responses and different species or strains yield sensitization resu lts that often differ in one or more respects. But some of the controversy has also arisen because there are several possible mechanisms that could be involved. Sensitization might, for examp le, be due to a pharmacophysiological up-regu lation of transmitter release or of transmitter reception. This process could be modulated by a non-associative learning process, leading to a familiarization with the environmental context in which the drug takes effect. But sensitization cou ld also be due to an associative classical conditioning of the drug response to external environmental cues or, indeed , to interoceptive cues 189 Konstanzer Online-Publikations-System (KOPS) URN: http://nbn-resolving.de/urn:nbn:de:bsz:352-206713 eli cited by the drugs themselves. T he sensitiza tion might, alternatively, be brought abo ut by a drugrewarded instrum ental cond iti o ning of th e respo nses eli cited by the very same drug (see, for examp le, H in so n and Pou los, 198 1; Kalant, 1989; Wi llner et al., 1992; Stewa rt and Badiani , 1993; A nagnosta ra s and Robinson , 1996; Mattingly ef aI. , 1997; Adams ef al., 2000; C ro m bag ef al., 2000). Coca ine a nd amphetamine, the substa nces with which most of th e a bove- li sted studies were car ried out, are indirect a nd unspecific agon ists of the neurotransmitter dopamine . Some of the complex ities of the sensiti zation data that have given ri se to the varied interpretations mention ed above ma y perhaps be due to this particu la r circumsta nce (Bedingfield et aI. , 1996; Laudrup and Wall ace, 1999). A number of direct and specifi c agonists of dopamine, although not known to be addictive, a lso give rise to behavioural respo nses in rode nts ak in to those elicited by coca ine and amphetamine, including a sensitiza tion upon repeated ad mini strations. The best stud ied of these substances is apomorphine (Apo) , a potent D 1- a nd D 2-type dopamin e recepto r ago ni st. Admin istered in doses of the o rder of 0.5- 5 mgjkg to mice and rats, it eli cits a bout of stereotyped oral responses (sniffing, licking, gnawing) and a concom itant period of increased locomotor activity, that under certain circumstances a lso exp resses itself as climbing or turning behaviour (Mo ll er et aI. , 1987a; Mattingly and Gotsick , 1989; Mattingly et al., 1997 ; T irelli a nd Heidbreder, 1999a; Battisti et aI. , 2000). Most, but not a ll , studies on sensitization to Apo in rod ents have focused on the locomoto r responses because they a re si mple to measure with actometers o r rotameters. However, these responses are not particu la rl y specific to Apo , or ind eed to psychostimulants genera ll y, there bein g many other treatments that ca n eli cit an a na logo us motor hyperactivity . We have, therefore, chose n to investigate the sensitiza tion phenomenon in p igeons which , much as chi ckens and other avians , respond to Apo injections with a pro longed bout of repetitive pecking and littl e o r no a ugmented locomoto r activity. T hi s response of bird s, first described by Ams ler in 1923, is in fact one of the most impressive examples of a drug elicitin g an overt behavioura l respo nse. Even though it has been in vestigated repeated ly since it was discovered (e.g. Dhawan et aI. , 1961 ; Brunelli et aI. , 1975; Laneroll e a nd M illam, 1980; Mach li s, 1980), o ur laboratory appea rs to be the first to have noticed tbat th e pecking response to Apo was subject to sensi tization (Basten-Krefft, 1977; Deli us, 1985). The peckin g response, which can be quantified easi ly and reli ably, and which typicall y consists of seve ra l thousand pecks, is quite specific to Apo . Adm ini stra190 tion of other psychostimulant substances or even , more genera ll y, other dopam ine agonists , eli cits at most on ly a few hundred pecks (Cheng ef aI. , 1975; Goodman , 198 1; Idemudia and McMillan , 1984; unpubli shed experim ents). Comparab ly in tense bouts of peck in g are otherw ise onl y known to occ ur when very hungry pigeons a re given access to a heap of ground gra in mixed with coarse sand , or when hungry pigeons have been specially cond iti oned to peck for occasiona l grain rewa rds (Horster ef al., 2002). It mu st be noted though that Apo- induced peck in g, alth ough motorically very sim ilar to forage peckin g and, in fact , faci li tated by food dep ri vatio n (S iemann a nd Delius, 1992; Wynne and De lius , 1995) , is usua ll y not directed at gra ins, since the drug has a pronounced hunger-s uppressing sid e-effect (Deviche, 1984). Instead , Apo- induced pecking is most ly directed at small contrasting ined ible features of the surround ing environme nt or even of the bird 's own body surface (Keller and Delius, 2001). In previous pub lications we have reported that repeated dai ly injection s of between 0.2 and 2mgjkg Apo doses lead to a progressive in crease of the pecking response up to a dose-dependent asymptote; that this sensitization to Apo is markedly contextdependent; a nd that, in spite of some pecu liarities, it is likely to be due to class ical conditionin g processes (Linden blatt and Delius, 1987; Wynne and Deliu s, 1995; Godoy a nd Deliu s, 1999; Godoy et aI. , 2000; Keller and Delius, 200 I). In the experim en ts reported here, we fi rst exp lored the effect of different tempora l intervals between Apo treatments , ranging between a few hours and several days, on the development of sensitiza tion to the drug. There is evide nce that, in rats, shorter intervals between Apo injections lead to the development of tolerance, and that on ly longer intervals lead to the deve lopment of sensitiza tion (Castro e/ aI. , 1985; Casas et aI. , 1999). Then we exa min ed to what extent the se nsitization a rising in a d istinct env ironment depended o n the durat ion of the Apo-contingent exposure to that particular environment. The background is that an inj ection of the sta nd ard dose of Apo (0.5 mgj kg) begins to have an effect after a few minutes , and yields a maximum rate of pecking some 10 min later. T he respo nse then gradually decreases to a level close to zero with in app roxim ate ly the next hour (Basten-Krefft, 1977; Wynne and Delius, 1995). Next , we assessed the degree of the co ntext dependence of the sensiti zatio n, by compa rin g the effect a rising with treatments in a constan t environment a nd in varyin g env ironments. Using rats and amphetamine, Anagnostaras and Robinson ( 1996) found that although a consta nt environ menta l conditi on yield ed the strongest sensiti zation , a vary ing co ndition still yielded an appreci- ab le sensitization . Fina ll y, we exam in ed the degree to wh ich th e sensitization effect is retained over longer periods of Apo abstinence. In rodents , Apo treatments have been shown to have effects lastin g seve ra l weeks (Matt ingly ef aL., 1989; Battisti et at. , 1999) but there are no data about the durability of the Apo se nsitizatio n in birds. METHODS General Adu lt pigeons (CoLumba Livia), bred from local ho min g stock and weighing between 400 a nd 600 g, were used . New drug-naive pigeons were used in each experim ent except the last one. For these experiments , the birds were moved from a n outside aviary to individu a l sta inless-steel grid cages (40 x 45 x 35cm) located in a well-lit (14 hours da ily) a nd ventilated animal room . In these home cages the pigeons had free access to water and food. The experim enta l cages, which a re described later, were located in a sepa rate, well-lit room equipped with a video camera and reco rd er. Here the pigeons had no access to water or food. T he number of pecks that each pigeon issued during the critical 20-min sessions were later cou nted by a na lysi ng the co rrespond in g videotapes, with the a id of slow-m otio n replay when necessary. T he drug treatments a lways involved 0. 5 mg/ kg injections of racemic Apo (Teclapharm) into the pectoral muscle; the co ntro l treatments always involved injections of an equ iva lent volume of sa lin e. A ll procedures used were in accorda nce with the rules and regul ations of Germ an anima l protection law. Treatment intervals Sixty-nine pigeons were allocated randomly to seve n gro ups of nine or 10 birds each. Each of the pigeons was injected with Apo and placed immedi ately afte rwa rd s into a n expe rimenta l cage. The experimental cages we re standa rd pigeon cages which had their sides and rear wa ll s lined with wh ite cardboard speckled with green dots of 8 mm diameter, at a density of about 10 dots per 100 C111 2 . After 20 min in the expe rimental cages the pigeons were returned to the home cages . Depending on the group that they belonged to, they were treated aga in in the sa me manner after an in terval of either 3, 12, 16, 24, 48, 72 or 120 h. T hi s was repeated for a total of six sessions. T he pigeon s were vid eotaped during each of th ese sessions. Fourteen randomly selected birds out of the short-interva l 3- and 12- hour groups, a nd 14 ra ndoml y se lected bird s out of the long- interval 72- and 120-hour groups , were treated in an analogous manner for three more sess ions after a 3-week break. Exposure durations Thirty-two pigeons were all ocated randomly to four groups of eight bird s each. During a training phase, each of the pigeons was inj ected with Apo and placed immediately afte rwards into a n experim enta l cage, as described above. The pigeons remained there for a period of either 5, 10, 20 or 60 min , depending on the group to which they belonged. Afterwa rd s, but w hil e the behaviour of most pigeons was still und er the influence of Apo (as the effect of the Apo dose mostly lasted for sli ghtly more th an 1 h), they we re returned to their home cages, where they remained until their next daily session . The training procedure was repeated on five co nsecutive days. Each bird was treated at about the same time of the day throughout the experimen t (cf. Arvanitogia nni s et aL. , 2000) . After a break of 2 days, tests took place on two successive days. After being inj ected with Apo , each pigeon was placed for 60 min into the expe rim enta l cage on the first test day and into a standard cage the next day. T hi s latter cage was id enti ca l to the pigeons' home cage except that it lacked the foo d and water troughs a nd was located in the exper im enta l room. The pigeons were videotaped during a ll the training periods and during both test sess ions. Single and multiple contexts Four different new experimenta l cages were used in thi s ex periment (see F igure 3, top) . Cage A was of cylindrica l shape, 40 cm in diameter, 38 cm deep a nd the floor was 20 cm wide. The walls a nd the floor we re painted white a nd speck led with green dots, 8 mm in diameter, a bo ut 10 per 100 cm 2 . T he front was made of wire nettin g. Cage B was a rectangul ar prismatic plastic conta iner (29 x 5 1 x 25 cm), with rounded co rners a nd edges mad e of transparent, pale-yellow plastic. The floor was a wooden pl atform covered with newspaper. Cage C was a sta nd ard , near-cubic (40 x 45 x 3S cm) cage with the floor , walls and cei lin g lined with turquoise-coloured ca rdboard; the front was made of a stainless-stee l grid. Fi na ll y, cage D was of a triangular prismatic shape, tapering towards the back (55 x 44 x 44 x 36 cm) . T he wire mesh front grid was painted white, the wa ll s, floor and ceiling were lined with chessboard- like cardboard with black and white 7 x 7 cm squares. Th irty-six pigeon s were assigned randomly to three groups of 12 pigeo ns each. Each group was subdivided in four subgroups of three pigeons each. T he pigeons of the same-cage gro up were inj ected with Apo on four successive days and placed consisten tl y into the same experimenta l cage accord in g to the seq uences AAAA , BBBB, CCCC or DDDD, depend ing on the subgroup to which they belonged. T he pigeons of the different-cage gro up a lso received Apo 191 o n four co nsecutive days, but were placed into a different cage each day; the sequences for the four subgroups being ABCD , BCDA, C DAB a nd DABC. Afte r being videotaped in the correspondin g cages for 20 min , the birds were returned to their ho me cages. Each of the birds was exposed to the co rrespo nding cages a t a bo ut the sa me tim e of the day throughout the treatment sequences. T he pigeons from the cagehabituation gro up were treated th e same as the birds of the different-cage g ro up , except that they were additi o na ll y injected with sa line o n each of the first 3 days a nd placed into the cage in which they were to ex perience Apo o n their final day. T hi s extra-cage ha bituation p rocedure was run acco rdin g to the schedules ODD, AAA, BBB o r CCC, depen ding on the subgro up to which they be lo nged. One-ha lf o f the pigeons received the ha bitu atio n trea tment a bo ut 4 h before a nd the other ha lf a bout 4 h after their Aporela ted treatment. When ex posed to their last cage unde r the intl uence of A po, that particular cage was as familiar to them as the respective cages were to the sa me-cage gro up . A fter their four sensiti zation session s, the pi geo ns of sam e-cage gro up were placed into th eir co rrespo ndin g cages for three daily 20-min sessio ns afte r hav ing bee n inj ected with sa lin e a nd vid eotaped in the usua l way. The reco rding of an a nalogo us treatment given to the pigeons of the different-cage group was m a rred by a vid eo- recorder failure. The cage- habituation group pigeons were not sa line-tested. Sensitization persistence F ifty- four prev iously Apo-sensitized p igeo ns were used in this experimen t. Of these, 47 pi geo ns had participated in the treatment-interval experiment described ea rli er. The seven additional pigeons had been trained exactly as t hose of the 24- ho ur interval g roup of th at experiment while se rvin g in an experiment reported elsewhere (Acerbo , 200 I) . A ll the pigeo ns had thus bee n previou sly sensitized to asymptotic responding with five o r six injections of Apo a nd 20-mi n expos ures to the gree n dots/ white background ex pe rimenta l cages. The pigeons had then been return ed to a n outsid e av ia ry. Fo ur o r S days before the retention test, th ey were again ho used in indi vidu al ho me cages. They were di vided into gro ups, ba lanced, as far as feasib le, for the va ri o us treatment co nditi o ns that they had bee n exposed to during the se nsiti zation trainin g. The g roups were tested fo r th e a mount of peck ing induced by the renewed administration of O.S mg/ kg afte r experimental breaks lasti ng an average of 2.2 mo nth s (between 2 a nd 3 months, 33 pi geon s), prec ise ly 6 1110 nths (nine pigeons) , precisely 12 month s (five pigeo ns) a nd a n average of 23.3 months (between j 7 192 a nd 32 month s, seven pi geo ns). T he pigeons were placed for 20 min into the experimental cage a nd vid eotaped . The 23 .3-111o nth gro up bird s we re in fact first tested after hav ing bee n inj ected with sa line for o ne sessio n a nd were o nl y then subj ected to a co mplete Apo-resensitization treatment over seven d a il y sessio ns. RESULTS Treatment intervals F ive pigeon s be lo nging to vario us grou ps exhibited ex tremely weak peck ing reaction s throughout. As subsequentl y di scovered , they were all descended from a breeding lineage that consistently produced offspring nea rl y unresponsive to A po (Keller, 2001 ; cf. Overstreet a nd Pucilowski, 2000 for d ata on rats). These pigeo ns were excluded from the eva lu ation, so that the g roups fina lly included betwee n 8 a nd 10 pigeons each. T he mean pecking respo nses ± standard errors (SE) per group per session were comp uted. A ll g ro ups showed the characteri stic sensi tiza ti o n curve. The curves of three represe ntative treatment g roups a re shown in F ig ure I , uppe r panel. The differences between the groups were assessed using the mean pecking shown by each pigeon during the fift h and sixth session s; that is, when the pigeons were ex hibiting a near-asymptotic respon se. Ave rages ± SE of these mean scores were calculated for each treatment group a nd are shown in F ig ure I , lowe r panel. It can be seen tha t the shortes t inter-session intervals of 3 and 12 h yielded asymptot ic pecking scores that were a bout 1000 pecks hi gher th a n those co rres pondin g to th e longer inter-session intervals, ranging from 16 to 120 h, w hereas t he results of the 72- ho ur-in terva l g ro up suggest a min or intermed iate peak . Mann- W hitney tests showed that, except for the 72-hour g roup results , the diffe rences between the short- a nd long-interval g roups we re a ll sig nificant at the P < O.OS level. The stro nger respo nse of the bird s treated with sho rter interva ls ( 14 pigeons: 3- a nd 12- ho ur groups pooled) , compared with those treated with lo nge r inte rval s ( 14 pi geo ns: 72- a nd 120- ho ur gro ups pooled) , present at the e nd of th e o rigin a l sensitization (3993± 144 a nd 3474± 167 pecks; M a nn- Whitney, P < O.OS) was no lo nger present after a 3-week break (3781 ± 26 1 a nd 398 1 ± 120 pecks; NS). Howeve r, after a resensitization treatment over three session s, the o ri gin a l diffe rence re-emerged pa rtia ll y, but witho ut quite reachin g sig nificance. Exposure durations Inspection of the vid eo tapes recorded durin g the trainin g periods , whil e the pi geons were in the 4500 •/ c E <J) -" u Q) 0... ~ 3000 0 C\J 1500 o 1---I .iI1- 12h '-7 , ~'24h • • • •• .' ••••• • I .'•..•••• .-- l 1 ......--- I I l::::::::::===:t _ ! 120 h t;:/r • • I ••••••• ••• • ••••••••• ••••• • 4 3 Sessions 5 6 • • expo std. 1'1/ 2 -I 3500 exp.cage .~ o 2500 C\J -- <J) -" u ,f 1500 4500 c 'E o C\J 500 3500 5 <J) TI ,f 40 20 60 min Exposures 2500 o 24 48 72 96 120 h FIGURE 2. Mean pecking scores ± SE during the test sessions in the experimental and the standard cages, as a function of the exposure durations under the influence of Apo in the experimental cage during training. The two cages employed are shown schematically. Intervals FIGURE 1. Three examples of the mean sensitization cou rses ± SE produced by groups subjected to different Apo treatment intervals (12-,24- and 120-hour groups; upper panel) and average ± SE near-asymptotic responding as a function of all the treatment intervals used (lower panel). The experimental cage is shown schematically. experimenta l cages, showed that the pigeons responded to the Apo administrations with pecking responses evincing much the same time course as described before. It was a lso obvious that they showed increases in responding with the repeated Apo administrations; that is, that they developed a progressive sensitization to the drug. D irect observations confirmed that the pigeons also continued to peck in their home cages for about just over 1 hour after each Apo injection . T he cross-welds of the steelgrid home cages served as pecking targets (cf. Wynne and Delius, 1995). One pigeon belonging to the 60min exposure group showed an extremely weak pecking reaction throughout. It also descended from the previously mentioned Apo-unresponsive lineage. This pigeon 's data were excluded from the evalu ation we now describe. The numbers of pecks that each pigeon em itted during the first 20 min of each of the test sessions were counted by analysin g the videotapes. F igure 2 shows the mean pecking scores ± SE calcu lated from these data, and corresponding to the four gro ups during the test sessions in the experimenta l and the standard cages. The mean pecking scores obtained in either cage ranged from about 1000 to 3000 pecks per 20 min , indicating the incidence of sensitizations that ranged from weak to strong when compared with those illustrated in Figure I. The group with as-min training exposure to the experimental cage showed nearly identical, though relatively weak, responses in both cages. With the lO-min and 20-min training exposures to the experimental cage, increasing divergences between the mean pecking response shown in the two cages become apparent. Both the increase in experimental cage test pecking and the decrease in standard cage test pecking from the 5- to the 20-min training conditions were significant (Mann- Whitney tests, P < 0.05). The further increased experimental cage exposure of 60 min during training did not yield any further differentiation of test responding in the experimental and the standard cage. The differences between experimental and standard cage pecking followin g the 20- and 60-min training were, howeve r, significant in each case (Wilcoxon tests, P < 0.05). Notice that the total mean pecking scores in the experimental and standard cage 193 added u p to a n almost co nsta nt 4000-odd pecks per 40-m i n overa II tes ti ng time, regard less of th e d iffe ren t tra inin g expos ure co nditi o ns. Co ntrary to wha t cou ld perhaps be expected (cf. O hyama et al., 200 1), mean peck co unts, extend ing to the second a nd third 20-m in periods of the 60-min test session s belo ngin g to the 5- min gro up a nd the 60min g roup pigeons, yie ld ed no significant evidence that the temporally patterned regimes of train ing had led to temporally modulated patterns of se nsiti zed responding. •• 0 o ° 194 0°. .... ". to ., '0' ••• '0' 0'0 • : ' • ••••• •• ' '0' °0 ." •• e . . . . . . . . 0, I:;: ........... '\ I~ '.. : ,° 0 ....... eo: ."- / Single and multiple contexts The data of o ne pigeon of the sa me-cage gro up had to be excl uded because it was Apo- unrespons ive, fo r the reaso ns descri bed ea rli er. A pigeon from the cagehab itu ation group also had to be excl ud ed because it became ill during the experiment. F ig ure 3 summ a rizes the res ults of the ex periment. T he sa me-cage g roup showed a very marked se nsitizat io n . T he different-cage and th e cage- hab ituation groups evinced co nsiderab ly weaker sensitizations . Co mpari sons of the pecking scores shown during the first and the fourth sess ion showed the large increme nt of the same-cage gro up to be hi ghl y signifi ca nt at the P< 0.005 level (Wilcoxon tests) , while the sma ll increments of the other two g roups were significa nt at the lower P < 0.05 leve l (Wi lcoxo n tests). A betwee n-group comparison of these increme nts showed th a t there was no significa nt difference between the different-cage gro up a nd the cagehab ituation gro up (mea n increment sco res 65 1±278 and 703 ± 2 11 pecks, respectively), but that there were hi g hly signifi ca nt d ifferences between both o f these groups and the same-cage g roup (mean in crement score 2065 ± 236 pecks; Mann- Wh itney tests, P < 0.005). Note that the tra inin g involving on ly four sessions, rather than the more usua l five o r six sess ions, did not a ll ow for fully asymptotic sensitization levels. T he re lative ly large SEs associated with these sco res are no do ubt due to the fact that the different cages modulated the amount of pecking that Apo e li cited in them . It is well established that the amount of pecking induced by Apo in pi geo ns, and also chi ckens, is influenced by different visual cha racteristics of the surro un d in g env iro nments (Brunelli et at. , 1975; Lanerol le and M ill am, 1980; Kell er and De li us, 200 1). Neverth eless, even in the plainer cages, Band C, the pigeons showed a high incid e nce of peckin g. The fact that the pecking scores of the first sessions of a ll groups were even som ew hat hi ghe r than usua l (see F ig ure I) indicates that the cages emp loyed were su itably respo nse suppo rti ve. T he responses of the variou s subgro ups dea ling with different cages , or cage seq uences, did ' 0 ~=:.-; ___ .. _ ......::?:-,:-=::,=:,"::..":..\ __ -.r _ ... __ [. -----_ ....- ----_.... _--~\ I I ------. .---I 3000 1/-1 c 'E • 0 C\J 2000 ~0 Q) O I 7~1 a.. different I~ 1 11 ------- fl 1- 6 I --I1 I,abituation II I .... 1000 ~ I I 3 2 4 Sessions FIGURE 3. The four experimental cages (schematic) used and the mean pecking scores ± SE of the same-cage, the differentcage and th e cage- habituation pigeon groups. not differ from each other sufficient ly to wa rrant sepa rate a na lyses. When tested after havin g been injected with saline, the pigeons of the same-cage g roup responded with a mean rate of 54 ± 10 pecks per session. This is an obv ious ly much weake r response than tbat shown in the sa me context by the same pigeons after Apo admini stration, but it conforms with the after-sa line response obtained in other Apo-sensiti za tion ex periments (47±9 pecks). It is significantly hi gher than the after-sa lin e respo nse shown by unsensitized, sa lin eo nl y trained co ntro l pigeons ( 10 ± 7 pecks; MannWhitney test, P < 0.05) participating in the same ex peri me n ts. 100 % c 80 o E<ll • \ ill a: 60 40 o 6 12 Pause 18 24 months FIGURE 4. Mean percent retention ± SE ofthe sensitized pecking response to Apo after experimental breaks of increasing length. Four different groups of pigeons were Apo-treated to asymptote (100%) and were tested for retention after various experimental breaks. Sensitization persistence T he pecking scores of each pi geo n during the only (or first) retention test session unde r the influence of Apo were expressed as a percentage of the average number of pecks produced by the sam e pigeon during the las t two sessio ns of tra ining. T his no rmalization se rved to neutra lize the variations in asympto te due to the varyi ng tra ining cond ition s to which the pigeons had been subj ected (see F ig ure 1). F ig ure 4 shows the means of these percentages ± SE, plotted as a functio n of the retention in terva l. It is noteworthy that the mea n test sco res drop gradu a lly with t he lengthenin g of the retention interva l, but th at even after a lm ost 2 years, the p igeons still yielded a pecking respon se th at am ounted to 53 ± 7% of the original asymptotic sens itization. By the fifth day of being resensitized , these latter birds regained their origin a l average asy mpto tic response scores. T heir mean pecking response under the influence of sa line (29 ± 2 1 pecks per 20 min) was a lso about midway between that obtain ed immed iately after a n Apo sensiti zation (47 ±9 pecks) and that pertain ing to a co ntro l sa line-o nl y tra ined gro up ( 10 ±7; these latter being the same two scores mentioned a bove) . A separate ana lys is did not reveal a n y signifi cant differences in response retention that co uld be att ributed confidently to the various treatment intervals used during the o ri ginal sensiti zation training (see above, T reatment intervals). DISCUSS ION In a series of previous studi es we have esta bli shed t ha t the sensitization to Apo, with respect to the peck in g respon se in pigeons, is importantly co ntextdependent. O n the basis of this a nd additiona l evid ence, we have a rg ued that th e sensitization m ost li ke ly a ri ses thro ugh a cl assica l, Pav lo vi a n cond iti o ning process (Linden bl att a nd De lius, 1987; Burg ef al., 1989; Wynne and Delius, 1995; God oy a nd Deli us, 1999; Keller a nd De liu s, 200 I). T his cond itio ning acco unt ass umes that the Apo adm inistration in p igeo ns yield s a protracted unconditi oned stim ulus (US) state that elicits a pro lo nged uncond it ioned repetitive pecking response (UR). The environmenta l co ntext in which s uccess ive ad mini strations of Apo have their effect funct io ns as a co nd itio ned stimulu s (CS) that com es to e li cit a n increas in g co ndi t io ned peck in g response (CR) , which a dd s progressively to t he UR triggered by the drug. T his brings a bo ut a n in creased respo nse to the same Apo dose a nd a lso brings a bo ut the co ntext dependency of the response increment, which a re characte ri stic of the pigeons' sensiti zatio n to A po. F urth erm o re, the account ass um es that stimulus gene ra li zation is li kely to be at least partly responsible for the se nsiti zation compon ents th at prima facie appea r to be context ind epe nd ent. T hese are t he portio ns of the sensitization increments that become m a nifest in env iro nments that are apparently d ifferent fro m , but which on c lose r examinati o n nevertheless sh are simila riti es with , that in wh ich the pigeons were exp licitly sensitized. T he concept of stimulu s genera lization refe rs to the circum stance that it is a comm o n finding in co nditioning experiments th at, o n su itable testing, pa rt of the CR transfers to stimuli that a re p hysicall y o r pe rceptuall y p artly simi la r to the original training CS (Domj a n, 1993). T hi s acco un t a lso ass um es th a t injected Apo, besides having an und isp uted US effec t, a lso has a n inte roceptive CS effect, a nd that the overall context CS to wh ich the pecking CR deve lops incorporates th is Apo-eli cited CS compone nt as an inevita ble part element. T his means that the exterocepti ve co n text stimuli are on ly fu lly effective as a CS triggering a pecking CR when they a re com bined with the in teroceptive state induced by the a dmini stratio n by Apo. Expos ures to the exteroceptive environm ent after contro l salin e admini st ration e licit a weaker, partia l pecking CR (Wynne and Delius, 1995; Godoy and Deliu s, 1999; Keller a nd Delius, 200 1). In the same vein , the circumstance that a CS-no-US condition necessarily lacks the Apo-med iated in te rocept ive CS component a lso exp lains why no late n t inhibitio n or response extin ction effects can be demonstrated in connection with Apo sensitizations in pi geons (Wynne and D elius, 1995; Godoy and De lius , 1999). In more us ua l conditioning expe rime nts, s uch repeated CSno-US pa irings a lways lead to a prospective or 195 retrospective weakening of the CR (Domjan , 1993). In what follows we d iscuss the result of the present experiments in the li ght of the above cond iti on in g acco unt of Apo sensitization. Treatment intervals Successive repeated administrations of the same Apo dose, with inter-treatment intervals ranging from 3 hours to 5 days , all yield ed pronounced sensitizations. Contrary to what has been found in rats (Castro et al., 1985; Casas et aI. , 1999; see also Mattingly et al. , 1989), we obtained no evidence that shorter inter-injection intervals lead to tolerance instead of sensitization. Such an effect would have needed some ad-hoc accounting within our conditioning hypothesis. However, an as yet unpublished experiment in which pigeons received Apo with intra-peritoneal osmotic pumps at a rate of approximately 0.5 mg/kg Apo per day for 7 days revealed a markedly weaker sensitization when the birds were subsequently tested with intramuscul a r inj ections of 0.5 mg/ kg Apo. This might indicate the development of some tolerance (cf. Nelson and Ellison, 1978; Post, 1980 : rodents, amphetam ine). Note, however, that when definite tolerance occurs in the context of other drugs, it has also been found to be modulated by context conditioning (Kim et al., 1999). The shorter treatment intervals of 3 and 12 h actua ll y produced a somewhat higher sensiti zation asymptote than the longer treatment intervals of 16, 24, 72 and 120 h in our experiments. Notice that because the three latter intervals are a ll multiples of 24 h, the co rrespond ing pigeons were a lways injected at about the same time of day. The shorter intervals imply that injections took place at different times of day. It has been shown that the effect of Apo adm inistration in rats is modulated by a diurnal rhythm (Nagayama et aI. , 1978; Nakano et al., 1980; see a lso Gaytan et aI. , 1999: amphetam in e), but it is unlikely that the differences between the shorter and longer interval are due to this factor , because the 16hour group, which yielded a lower asymptote, was also injected at differing times. Another possibility is that the stress arising with more frequent injections might have potentiated the Apo effects. Stress, alth ough arguab ly stronger and more lastin g than mere i.m. injections, has been shown to en han ce Apoinduced responses in rats (Csernansky et aI. , 1984; Cabib et al. , 1988). However, the resu lts of a separate experiment, in which this stress hypothesis was specifically examined in pigeons by treating them with supernum erary saline injections, did not yield any significant support (Keller, 200 I). In rats , it has been found that the peak Apo plasma concentration occurring some 5 min after an Apo i.p. 196 I11J ection is reduced to half within about 20 min , and that Apo bound to striatal neural tissue has a sim il ar half-life (Martres et aI. , 1977; Smith et al., 1979). Assumin g that comparable Apo clearances app ly in i.m . Apo-injected pigeons, then the stronger sensitization seen with the shorter treatment intervals can hard ly be due to a bodily accumul ation of Apo. Nevertheless, on being re-treated after a 3-week break, the pigeons treated with the shorter 3- and 12-hour intervals no longer revea led a higher mean rate of responding, compared with the pigeons treated with the longer 72- and 120-hour intervals. Thus , the difference between shorter- and longer-interval treatments seemed to arise because at first an Apo injection somehow leaves a rapidly decaying trace , that nevertheless lasts for somewhat lon ger than 12 h, which then turns into a weaker, more slowly decaying trace lasting at least 120 h. The results show that distributed trials (long intervals) are as conducive to learn ing as the same number of massed trials (short intervals). While in humans the former training regime tends to generally lead to more co nditioning than the latter, in an im als thi s phenomenon is far less clear-cut (Domjan, 1993) . The little evidence that is available concern ing pigeons suggests that the two conditioning regimes make little or no difference to their learning performance (Xia et al. , 1995). Exposure duration As the pigeons' exposure to the experimenta l cage under the influence of Apo increased from 5 min to 20 min , the pecking ex hibited during the subsequent tests in this cage increased from about 2000 pecks to about 3000 pecks per 20 min. Comparisons with the sensitizations shown in Fig ure I indicate that the present sensitization levels ranged from medium to high. The results establish that experimental cage exposures of 20 min suffice for producing a maximal sensitization , since longer, 60-min training exposures did not yield stronger test responses. Training sessions lasting 20 min , but not less, are thus sufficient to assess the full extent of the sensitization to Apo , even though the standard 0.5 mg/kg Apo dose induces a pecking response that actua lly goes on for about 60 min or sli ghtl y longer. At the same time, as the pigeons ' exposure to their home cages under Apo during the training phase increased inversely from a few minutes to about an hour, the test pecking in the standard cage rose from about 1000 pecks to about 2000 pecks per 20 min. The generally weaker sensitiza tion revea led in the standard cage was undoubtedly mainly due to the fact that the exposure to the home cages under Apo ma i nl y took place when the effect of the drug dose injected was already waning (eq uivalent to a redu ced UR). However, it is a lso a fact that the pi geo ns expe ri enced the hom e cages during ex tended period s (for about 23 h betwee n sensiti zat ion session s) while they were not und er the influence of Apo. Such a n extensive exposu re to a CS- no-US condition co uld potentially have led to an inhibition and /or extinction effect that cou ld have weakened the pecking C R developing in response to the home cage CS (Domja n, 1993). However, as ex pl a ined at the beginning of thi s Discussion , inhibition and extinction t reatments have previou sly been found to ha ve neg li gible effects o n th e Apo se nsiti za tion of pigeo ns. It is a lso possible that a block in g of co nditioning due to a ce iling effect mi ght have inte rvened (Domjan , 1993' but see Ahmed ef al., 1998), signifyin g t hat within a give n training sess io n the initi a l experime nta l cage would capture most of the co nditioning feasible , leav in g little scope fo r a subseq ue nt co nditioning to the home cage. On the other ha nd , a genera liza tion between the so mew hat similar cages (identica l form , flo o r and fronts) could have led to a pecking C R co mpone nt that was ex pressed in both the experimenta l and sta nd ard cages used during the tests (cf. Godoy a nd Delius, 1999). While, with trainin g expos ures to the experim enta l cage in creas ing up to 20 min , a n a ugmentin g proportion of the sensitized response became tied to that particular cage, this trend did not co ntinue when the releva nt exposures were lengthened to 60 min. The above-mentioned ceiling/ bl ock in g mechani sm could have intervened to truncate the pecking associated with the latte r treatm e nt. 1t see ms possibl e that the co nditi o nin g achievab le within a session was a lready ex ha usted after a 20-min expos ure to the ex peri mental cages. The fact that the mean test responses in both cages ad ded up to a nearly consta nt overa ll response of 4000 pecks per 40 min , irrespective of the training co ndition s, suggests that there was indeed so me overa ll cei ling to the co nditi on in g. This maximum res po nding ca nn ot be ascribed to the hi g hest frequency that pi geo ns ca n physica ll y peck. Such a limi tation ca n on ly be ex pected to playa role with respo nse rates above so me 3600 pecks per 20 min (Ho rste r ef al., 2002). Regard less of these details , the overa ll results co nfirm th e context dependency of the Apo sensiti zation , in asm uch as it was impo rtant ly determined by the exposu res to the two types of cages , even though a ll pigeons received the same regim e of Apo injections . If the sensiti zation induced had been co ntextind epe nd ent, the pecking responses during tes ts shou ld not have bee n affected by variation s in cage ex posure durin g trainin g. Single and multiple contexts The results most directly releva nt to the con diti on in g acco unt a re those of th e sin gle a nd mUltiple contexts expe riment. The single, co nstant-cage CS treatm e nt yie ld ed se nsiti za tion in c rements ro ug hly three times la rger than the different, multiple-cages treatment. The co nsta nt cages can be ass umed to have functioned as consistent CSs, a ll owing the systematic build-up of increasing pecking CRs, while the different cages ca n be expected to have acted as diverse CSs that preve nt the build-up of any sizeab le CRs. The adva ntage of the sa me-cage treatment ca nn ot be exp la ined by th e circ um stance that the pigeo ns of this group had beco me more ha bituated to the particu la r cage to which they had been ex posed. A contro l group of pigeo ns also exposed to different cages und er Apo, but sepa rately habitua ted unde r sa line to the critical final cage, did not exhibit any marked se nsitization. Note that using rats and amphetam ine, Anagnostaras a nd Robinson ( 1996) found that although a constant enviro nm enta l condition yie ld ed tbe stronges t se nsiti zation , a Illultiple e nvironmental condition still yie lded a sizeab le se nsitization. However, the ir multipl e environment tra inin g involved a , perhaps criti ca l, double exposure to the sa me rotamete r co ntext. Our present results co rro bo rate ea rlier findings that Apo-sensitized pecking was only fully evident in the same cage in which the sensiti za tion had ea rli e r taken place, but not in a n a lternative, quite diffe rent cage. The res ults a lso co nfirm that me re cage context familiarity plays at most a minor role in the se nsiti zation to Apo in pigeons (Godoy a nd D elius, 1999). T he results are a lso in line with the findin g that, given a choi ce, pigeo ns wi ll a lm ost exclusive ly peck a t stimuli belon gi ng to the contex t in which they were se nsi tized , a nd do not peck at stim uli belo nging to an a lternative co ntro l co ntext in which they had been treated with sa lin e (Keller a nd Delius, 200 1). Co ntra ry to what Burg ef al. ( 1989) had su rmi sed on the basis of a less elaborate expe rim ent the differentcage-t reated pi geons did not deve lop to lera nce (see a lso under Treatment inte rva ls). The lesse r, but still sig nifica nt, res pon se increm ents obtained in the different-cage a nd th e cage-habituation g ro ups show that there is nevertheless a sma lle r compone nt of sensitiza tion that is apparentl y context-independent. We cannot exclude the possibility that this weaker sens iti zat ion component might be due to a physiopharmacological up-regu lation of the efficacy of the drug. H owever, it must be kept in mind that, a lth ough the cages used with the two g roups were different from Apo sess ion to Apo sessio n, the co mple te co ntext lin ked with the successive Apo trea tments was not wh o ll y different. The handlin g 197 a nd the injection proced ures, and the furni shin gs of the experim enta l roo m (video ca mera, li ghts, windows, ta bles , etc. ), rema in ed the same across th e different-cage treat ments. A lso, not to be forgo tten, the behavio ura l state indu ced by the dru g was li ke ly to be the same. T hese co mmon a lti es wou ld co nstitute a co nstant contex t CS element di sconnected from the d ifferent-cage context CSs. T hi s constant context co uld be respon si bl e fo r a t least some peck in g C R , and th us for at least so me of the sensi ti za tion increment shown by the different-cage and the cageha bitu ation groups. T hat the admini stra ti on of Apo does actually lead to a detecta bl e interoceptive sta te has been demonstra ted recentl y in a n as yet unpubli shed dru g di scrimina ti o n experiment of o urs. In this ex periment the same hungry pi geo ns lea rned to peck one key fo r food reward after having been inj ected with saline, a nd to peck a nother, a lternative key after hav ing been injected with Apo (cf. Jarbe, 1984; Ta ng and Code, 1989). It is known that d opamine recepto rs a re present in the retina of bird s (cf. Rohrer and Stell , 1995; see also Drumh ell er el al. , 1995: mamm a ls). When these receptors a re activated by a systemic Apo adm ini strati on they ca n be expected to lead to th e genera tion of a stimulus state tha t is likely to mod ify the perception of ex teroceptive visual stimu li (Djam goz and Wagner, 1992). Apo adm ini stration can thus be expected to create a n ow n CS to which a n own C R ca n be attached (we refe rred to this process a bove) but, furth ermore, to tinge the perception of environ menta l co ntext CSs, so th at th ey a re no lo nger effectively equiva lent with the same ex teroceptive co ntex t CSs perceived in the a bsence of the dru g. T hi s latter process ex pl a in s, as a lready expound ed in the Introd uction , why sensiti zed pigeo ns, when treated with saline to test fo r the presence of a pecking CR Apo , ex hi bit a respo nse that is on ly a sma ll fraction of the sensitizatio n increme nt, as in fact rep li cated in thi s a nd t he persistence expe riment. T he then effective environm enta l context CSSa lillc is necessa ril y onl y very pa rti a ll y eq uiva lent to the total environment- dru g CS Apo that acted during the sensiti zation tra inin g, and ca n thus onl y comma nd a CRSa lillc fraction o ut of the tota l CRApo that is refl ected by th e se nsitizatio n increme nt (Godoy a nd Delius , 1999). Sensitization persistence Although not particu la rl y suppo rtin g the conditi o nin g account, the lo nger-term persistence of the sensitizatio n to Apo found in this experiment is, at the same time, not at a ll contrary to it. The slow decay of sens itization , to about ha lf in 2 years , can be compa red with a simil a rl y slow rate of fo rge ttin g, fou nd when pi geons were co ndition ed to visual J98 stimu li (Vaughan a nd Greene, 1984; Fe rse n and De li us, 1989). T his is a dura bility that goes we ll beyo nd the persistence of t he few weeks so far d ocumented in rod ents (Mattin gly et aI. , 1989; Batti sti et al., 1999). Beyond th is, we no te that, as a lready remarked above, the pecking respo nse of sensiti zed pigeo ns exposed to the env iro nm enta l co ntext afte r saline ad mini stration was again considera bl y weaker th an, but nevertheless propo rtional to , the response shown when exp osed to the same co ntext after Apo admini stration . Pa rti a lly simil a r co nditi oning accoun ts as those co nsidered here have been considered by seve ra l a uthors in co nnection with the sensit iza ti on to d ifferent psychostill1u la nt dru gs (includin g Apo) with respect to vario us responses in different species a nd stra ins of rod ents. T hese acco un ts have been suitab ly reviewed, usefull y uni fied and co ntrasted with a lterna tive accounts by Anagnostaras and Robinson ( 1996; see below for so me mo re recent studies). However, it is a lso true tha t they co ul d not accommod ate some of the results they reviewed with th e classical co ndition ing acco unt they distilled. But then, th at acco unt did not emph asize the role of two factors that we consid er to be crucia l: the stimulus ge nera liza tion that ca n occ ur between contexts a nd the in teroceptive stimu lu s effects that drugs ca n produce. Co ncernin g the latter effects, Stephens et al. (2000) have recently shown in connectio n with amphetamine sensitization in rats th at a n interoceptively acting dru g (chl ordiazepox ide), which initi a lly d oes not yield an overt behavioural respon se, can come to act as a potent co ntext CS contro lli ng a sizea ble C R (see a lso Pert ef aI., 1990; K im et al., 1999). Simil a rly , essentia l US-derived contributi ons to fin a lly effective CS have been reported to occ ur in more conve nti ona l va rieties of classica l cond iti o ning in rats (Bouton, 1993). Within a nother fra mewo rk, but a lso in ra ts, Dwo rkin and Dworkin ( 1995) have d ocumented that intern a l physiological events of one a nd the same qua li ty can act both as a CS (sma ll rise in blood press ure) and as a US (l arge rise in blood pressure). When repeated ly occurring in sequence, they yield a kind of a utoconditi o ning, in the sense that compensatory fa ll s in bl ood press ure, a t first o nl y occurrin g as URs in response to large rises in bl ood pressure, co me to be triggered as a CR by sma ll rises in blood pressure. We must co nsid er briefly the exten t to whi ch our expand ed cond itioning sq uares up with the sensitization resu lts obta ined with Apo in rodents. Ca rey ( 1986) fo und that t he cont raversive and ipsiversive rotation in duced by Apo and amp hetam in e in unilatera ll y 6-h ydroxyd opa min e substa ntia nigra lesioned rats co ul d be d ir-re renti ally co nditi oned to two different environm ents, in the sense that the rats showed congruent co ndit ioned rotational responses when pl aced untrea ted in the two different co ndi ti oned stimulu s co ntex ts. T hi s res ul t fits in easil y with the co nditi onin g hypo thesis. Mo ller et al. ( 1987a, b) describe tha t after se nsiti zat ion (conditi oning) with Apo in a sa lient co ntex t, rats ex hibi ted more co nditioned sniffin g, licking a nd gnawin g (high-dosetreated anima ls) or resting a nd napping (Iow-dosetreated anim als) when tested in that context a fter sa line administration and after Apo administration than after a contro l (pseudo-cond itioning) treatment. As the authors themselves no te, these results a re co nsonant with a conditi oning acco unt. T irelli a nd He idbreder (I 999a, b) fo und that sensitiza ti on to Apo with reference to a climbin g respo nse in mice was ma inl y context dependent. T he a uthors themselves ascribe the co ntext-dependent sensitizati on to a Pav lovian co nditio ning p rocess a nd co nclud e that it is definitely not d ue to a fami li a rization with the tra ining co ntext. Battisti et al. (J 999, 2000) described that, a fter a single high dose of Apo (or amphetamine), mice became se nsitized with resp ect to a stereotypical repetitive hea d a nd fore limb response to a later lower-dose cha ll enge in the same, but not in a different, environmental co ntext. But they also found t hat afte r three da ily repeated hi gh doses of Apo (or amph etamine) given in the same environmenta l co ntex t, sensitiza tion was la ter shown in response to the lower dose of Apo (or amphetamine) in both the sa me a nd a different co ntex t. The context-dependent form of sensitization was found to be susceptibl e to exti nction , but the co ntex t-ind ependent extinction was found to be resistant to ex tinction. C learly, context-depend ent sensitization agrees with a conditioning acco un t. T he deve lopment of an apparently context-i ndependent se nsiti zation with repeated drug admini strations co uld be due to the interoceptive co ntext induced by th e Apo itself having acquired most of the co ntro l over the response. Mattingly and Gots ick (1989) found a partial context dependence for sensitization with reference to loco motor activity trigge red by Apo in rats, but could not observe a loco motor CR when the rats were exposed to the relevant environment after being inj ected with saline. T hi s mi ght a lso indicate a strong condi tion a l contribution of the interoceptive drug co ntext. In co ntrast , Mattingly ef al. ( 1997) found that rals sensitized to Apo with respect to a loco motor respo nse in an activity drum or o n a running whee l a nd la ter tested in a wheel and a drum d id not revea l a ny co ntext dependency. This argues against a cond itioning account unless some extreme stimu lus ge neralizatio n was at p lay . However, only rats Apose nsitized in a mo bil e whee l, bUl not ra ts Apo- sensitized in a locked wh ee l, ex hibited a strong locomo tor resp o nse when tested in a mobile w heel. A ltho ugh the auth o rs explain both of these results with a non-con tex t-depend ent respon se enhancement due to a n instrumenta l co nditi o nin g process (cf. Wi ll ner et aI. , 1992), the la tter result can also be in terp reted as indicating a context dependency, in asmuch as a moving a nd a locked whee l und o ubted ly co nstitute two quite different kin ds of senso ry co ntexts. A more curso ry readin g of the many recent studies on the sensi tization to ampheta mine and coca ine , both in direct and unspecific ago nists of dopamine, in dicates that many, but by no means all , report the occurrence of environmental context d epend ent se nsitization attribu ted to classical co nditi oning (e.g. Ca rey and Gu i, 1997; Liena u a nd K uschinsky , 1997; Bad ia ni et at., 1998; Browman et al. , 1998; Nakam ura et aI. , 1999; Adams et al., 2000; Arvanitogia nni s et al., 2000; C rombag et aI. , 2000, 200 1). Instances of environmental co ntext independent sensitizations, o f environmental context novelty depend ent sensitizatio ns, of relativel y weak salin e-elicited C R s a nd even o f sensitiza ti o n di ssociated from corresponding CRs are a lso reported . Some, but poss ibly not a ll , of these findings might be expl ained by appealin g to the effect of va rying in teroceptive contexts elicited by the drugs, and by a co nsequent enhancement o r suppress io n of generali zation processes. The difficulty is that the st udies that have yielded results that a re not easil y acco unted fo r by co nditioning have often employed paradigms th at a re not particu la rl y suitab le for assessment of that circ um stance. A cautio us, but perhaps realisti c, co nclu sion might be to ass um e that the se nsiti zati ons to diverse drugs under diverse regimes in diverse anima ls and ga uged by diverse behaviours are being brought a bo ut by severa l d ifferent mechani sms, with classica l co nditi onin g being one of them. However th a t may be, the present resu lts co ntinue to support the hypothesis that in pigeons and with respect to the peck ing reaction , sensitizatio n to Apo is due principa ll y to a combined Pavlovia n co ndi tioning to the externa l context provided by the surrounding enviro nment and to an inner co ntex t suppli ed by the drug i tsel f. Acknowledge me nts T hi s researc h was supp orted by research grants from the Deutsc he Fo rscllllngsgemeinschaft, Bonn. We tha nk Ines Krug a nd Anke McLintock, Ko nsta nz, for va ri ed assistance, D r Adr ia na Godoy, M idaga, for muc h adv ice, Jennifer Lee, KOl1 stanz, for improvements to la ng uage a nd Dr Ju lia Delius, Berlin , for bibli og rap hi c a nd ed ito ri al he lp. 199 REFERENCES Ace rbo MJ (200 I). T he dopam ine a nd glu tamate ro le in associa ti ve lea rnin g by the p igeo n ( Columba /ivia ) . D isser ta ti on, Ko nsta nz Un iversity. Adams .I U, Ca reri J M, Efferen TR, Rotrose n J (2000). 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